Short Summary: How dietary sugar (fructose) affects the growth rate of cancer.
About the guest: Gary Patti, PhD is a professor at Washington University in St. Louis, holding appointments in chemistry, medicine, and genetics
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Episode Summary: Nick Jikomes talks to Dr. Gary Patti, exploring how cancer cells metabolize sugars like glucose and fructose, focusing on a recent study showing fructose indirectly boosts tumor growth in mice via liver-produced lipids called lysophosphatidylcholines (LPCs). The discussion covers cancer biology basics, the Warburg effect, tumor microenvironments, and the systemic metabolic impacts of cancer, while also touching on dietary implications, fasting, and the complexities of nutrient utilization in cancer progression.
Key Takeaways:
Cancer cells often rely heavily on glucose, excreting it as lactate even when oxygen is available (Warburg effect), but take up more than their mitochondria can handle.
In a study, high fructose diets accelerated tumor growth in mice by 4x, not because cancer cells use fructose directly, but because the liver converts it to LPCs, which tumors use to build membranes.
Tumors are not just cancer cells; they recruit healthy cells in their microenvironment, and their metabolic effects ripple across the entire body, altering distant tissues.
Excessive fructose consumption (e.g., from soda, not fruit) may worsen tumor growth, but cutting it poses little risk and could benefit cancer patients, pending human studies.
Fasting may reduce cancer initiation risk in animals, but its effect on existing tumors is less clear and could worsen wasting (cachexia) in late stages.
The body tightly regulates blood glucose via the liver, so simply cutting dietary glucose won’t starve tumors, highlighting cancer’s metabolic adaptability.
Related episode:
M&M #200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade
*Not medical advice.
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Episode transcript below.
Episode Chapters:
00:00:00 Intro
00:05:35 Cancer Biology Basics
00:11:26 Tumor Initiation and Immune Evasion
00:17:13 Studying Early Cancer with Zebrafish
00:23:19 Metabolic Changes in Tumors
00:29:16 Tumor Microenvironment and Healthy Cells
00:34:28 Glucose vs. Fructose Metabolism
00:40:17 Fructose and Cancer Cell Growth
00:46:04 Fructose Processing in the Body
00:52:49 High Fructose Diets in Mice
00:59:22 Liver’s Role in Tumor Growth
01:06:06 Identifying LPCs as Key Nutrient
01:12:03 LPCs and Dietary Fat Connections
01:17:19 Fructose Intake Implications
01:23:40 Endogenous Fructose and Drugs
01:27:57 Ketogenic Diets and Cancer
01:34:09 Fasting and Cancer Risk
01:39:59 Cancer Phases and Diet Strategies
Full AI-generated transcript below. Beware of typos & mistranslations!
Gary Patti 1:31
yeah. Name is Gary patti. I'm a professor at Washington University in St Louis. Actually wear a few different hats. I'm in a couple different departments, chemistry, medicine and genetics, and I run a relatively large lab. We study cancer and metabolism. I also serve as director of some cores at the university, the clinical research core, as well as some metabolomics and proteomics cores. And then lastly, I'll just mention that I'm also a CSO of a company that does contract research services for for different omics, multi omics technologies.
Nick Jikomes 2:12
Yeah, so, so you've got quite an interdisciplinary lab. You do a lot of stuff that's related to metabolism and metabolomics. You do a lot of stuff related to cancer biology, which will probably be our focus here. Today, we want to get to a paper that I thought was very interesting and very relevant to a lot of people, you know, out in the real world, which has to do with the relationship between sugar metabolism, particular, and and tumor growth. Before we get there, I want to cover off on some basics on cancer biology and and sugar and fructose metabolism. So, you know, I'm somewhat familiar with cancer biology. I'm a biology guy by training, but I was never a cancer biology person. And sort of the cartoon that I've always had in my head, or I had when I was, like a student in college and stuff, is that, you know, cancer is a cell. You know, cancer cells are cells that are have escaped the normal cell cycle regulation, and they're growing uncontrollably, and that that is largely often a genetic thing. So, you know, I learned about oncogenes and tumor suppressor genes, and so the idea was, cancer is typically a series of mutations in specific genes that allow the cell to break free of the cell cycle. Can you just give us a general sense of, are most cancers, or is the average cancer? Whatever that means, is it largely a matter of mutations in genes, or can cancer arise through non mutation mechanisms?
Gary Patti 3:36
Really great question, and a good summary of the historical there's a little bit of history and how the our understanding of cancer has evolved over the last 100 years or so. And I won't impose an age upon you, but I think depending on when you got trained and when you learned about some of the stuff, different items and different aspects of cancer biology were emphasized, actually, the very some of the very some of the earliest discoveries associated with cancer were not based on genetics, but actually were metabolism. The if you go back about 100 years ago or so, there was a German scientist named Otto Warburg who was really the first person to think about cancer from a metabolic perspective, and he noticed that cancer, sugar metabolism, specifically, which we'll get into more here in the next few minutes, was altered in in cancer. And so his definition of cancer, actually, you know, a century ago, was that cancer cells have altered metabolism. And he actually asserted that a certain piece of cancer, the power an organelle inside cells called mitochondria that is sometimes known as the powerhouse of cells. It's where. It's not the only place where metabolism occurs, but at least we teach the undergraduates that that's where a lot of the important metabolism, certainly where most of the energy in a cell is made. He actually argued that what causes. Answer is not oncogenes as you as you described, but actually failed mitochondria, and that it was that alteration in metabolism that was the cause of cancer. Now we know that's usually not the case cancer. Most cancers have completely functional mitochondria, and in fact, they need mitochondria. That's something that our, our perception has evolved over the years about cancer, but, but as genomics evolved there, there is in many fields, cancer fell victim to, sort of being, getting obsessed with molecular biology and genetics, and we
Nick Jikomes 5:35
as a consequence of what the tools were that emerged,
Gary Patti 5:39
exactly, yeah. I mean, I think the Human Genome Project, you know, played a big role in that and the excitement of being able to do sequencing, yeah, and rightly so. I mean, it was an exciting time. In 30 years, we'll look back on today and say, Oh God, they were so, you know, they were obsessed with whatever we're doing today. So I think that that's just how science evolves. But, but, but there was a, you know, we learned that genes, you know, mutations and certain genes, were sufficient to cause cells to behave abnormally, and specifically, not just abnormally in some way, but they lose their ability to to to regulate proliferation, so they proliferate uncontrollably. And that's really the one of the main driving characteristics of cancer cells, is that most normal cells know when to stop growing and stop turning into new cells. But cancers cells don't do that. They they proliferate uncontrollably. And so genes are at the basis of that, and they cause that. But exactly how they cause that, I think, is the really interesting question. So I think what you say is totally correct, but it's only a piece of the equation. You know. How does an oncogene allow a cell to proliferate uncontrollably where a non transformed cell that doesn't have that oncogene doesn't do that? You know
Nick Jikomes 6:58
how? And I guess if you just think about it in sort of common sense terms, it would almost have to be true that in some way, whatever these genes are that might drive certain cancers, they would have to affect metabolism, because, almost by definition, cancer is going to have an altered metabolism because it's it is uncontrolled growth. Yeah,
Gary Patti 7:16
it's actually amazing how, how long that that? I totally agree with you, but there are several decades where metabolism was back burnered As part of cancer. I mean, I think it's fair to say that cancer is a metabolic disease. There are certain hallmarks that classify cancer and altered, deregulated metabolism is one of the hallmarks of cancer. So it's not specific to pancreatic cancer, lung cancer or brain cancer. Altered metabolism is something that most cancers across the board share. Yeah,
Nick Jikomes 7:47
I want to ask a somewhat vague question, but, but it's an important question, and anyone who's not a cancer biologist, like I'm not might wonder this. So obviously, there are different forms of cancer, in the sense that the cancer can arise in different tissues, pancreatic cancer, brain cancer, whatever. But how much, how much diversity is there in terms of the fundamental type of cancer? It is, from a cell biological standpoint, do most cancers? Is it sort of the same basic phenomenon, or is there a lot of variation where two different cancers can behave cell biologically, very different from one another, apart from the fact that both are unregulated cell growth?
Gary Patti 8:29
Yeah, amazing question, and one that I think that we're still trying to figure out, certainly the tissue of origin is what you described. So some cells, some cancer cells, might be derived from pancreatic cells, or, you know what, hepatocytes, or whatever the whatever cell type they originate from, plays a role, because those cells are already programmed to operate in one way. And so certainly you see diversity if you look at tumors and different tissues. But what's really interesting is that there's also quite a bit of diversity in those same tumors. So it's not just diversity between brain cancer and liver cancer, it's actually there are lots of diversity in brain cancer, right? And so I think the certainly, the tissue of origin, plays a big role in how the provides, really a starting point for where how the cell is going to thrive. But the other thing that plays a major role in this is a good segue into some of the other topics we're going to discuss is the environment, because cells to proliferate. So, you know, just to really provide context what we're talking about here, one cell has to turn into two cells. So a cell has to replicate its contents, and to do that, it requires a lot of synthesis. You know, you have to rebuild all of the protein machinery, you have to rebuild all the lipid membranes, you have to rebuild all the genetic material, and that takes a lot of biomass, and you have to build. All that stuff from something, and it takes a lot of energy. And so the question is, what nutrients is a cell going to use to support that anabolic process? And what's remarkable about cancer, I think that's totally fascinating, is the versatility that they have and the plasticity that they have in the nutrients that they can use. It's it's rare that they are limited to one nutrient. You know, we're going to talk about sugar today, and they love sugar. Most cancers are addicted to sugar. And you might think, Well, if we remove sugar, and we've tried this experiment, star of cancer cells of sugar, then does that prevent them from doing that in most case cases, the answer is no. They just move to a different nutrient. So there is a lot of flexibility. They don't always operate. Yes, they start as the tissue of origin. They seem to start in that way. The other thing that happens is that tumors can metastasize. So you can imagine that a tumor starts in, you know, the lung or the breast, and then it metastasizes to the liver. So now you have cells that originated as breast cells, but now they're in the liver in a totally different environment. And so it gets kind of interesting. Do they start behaving more like tumors that would primary tumors that recur in the liver, or do they retain their program that originated in the breast but conduct that in the liver. So you get those kind of interesting questions too, because cancer is mobile.
Nick Jikomes 11:26
So my understanding is cancer, we're basically all getting cancer at some baseline rate, but most cancer cells that emerge get taken care of by the immune system. They're detected. The body notices that they're abnormal and we don't want them, and then we get rid of them. But obviously, in some, some percentage of cases that those checkpoints, those those mechanisms, can't get rid of the cancer, and then, then we get full blown cancer. When we think about cancer generally, is, are there sort of certain phases or or parts of the life cycle that we can talk about where so, so obviously cancer can be initiated. But if a cell becomes cancerous, that doesn't mean we're going to get cancer, because the immune system might might get rid of it, and it often does. What is, what is that transition like? Where you go from a cancer cell start, you know, you get that first cancer cell, and it gets past the normal mechanisms the body has to detect it and become, say, a full blown tumor?
Gary Patti 12:27
Yeah, yeah. So from a metabolic perspective, I think it's a really fascinating question, and it's proven to be somewhat difficult to study, because usually what we're talking about there are small numbers of cells. And if you think about the ways that we generally study cancer, yeah, most of those things are subclinical, like you can't see, yeah, you don't see that. First one, there's no symptoms. Exactly, there's no symptoms, and you can't detect it on a you know, we often use something like a PET scan. I think most people are probably familiar with PET scan. So essentially, what you do is you give patients a radioactive chemical, and then they then you put them in a scanner, and you can detect the uptake of that chemical and and unfortunately, if you have a small number of cells, one cell or a handful of cells, they don't show up on those kinds of on those kinds of tests. So it's proven to be very difficult to study these processes, and the way in which we typically do it is is fairly artificial. So we can study them in things like culture, you know, and cell culture, yeah, we put them in a dish, and you could do things like irradiate them or cause initiation by giving them chemicals and and see but, but how it translates to the body. I think that's an exciting area where we keep pushing Now, the other thing you bring up, which is incredibly important, is the immune system, and that's an area where I think we've seen enormous development and progress over the last 10 years, where it's not just because you're right, the immune system plays a major role in trying to keep things contained and controlled, but it doesn't always work. I mean, a lot of people get cancer, and so, you know, I think one of the really exciting things that's been happening is, is, can you tune the immune system in such a way to make it more aggressive, more active, to go after some of these tumors, and that's when you start getting into the immunotherapies, using the immune system to try to sort of put the immune system on steroids, to go after this stuff. And, you know, it's been pretty, pretty effective, and a lot of difference. It's not, obviously not perfect, but a lot of progress in that space. So
Nick Jikomes 14:29
it sounds like basic the sort of basic problem here is, you can study the origins of cancer. You can look at the birth of that first cancer cell, the early phases of, you know, going from one cell to two cells to a small tumor, it's you can you can study that in a dish, in a artificial setting, which is amenable to experimental interrogation, but obviously that's removed from the natural context of the whole animal that we ultimately want to understand it in actually understanding those early phases of cancer in a whole animal in vivo situation is tough. Be just for the very reason that it's hard to spot it. When it happens, it's small and difficult to detect. And we don't really see these things in animals, for humans, until they're in a much more mature phase. Yeah,
Gary Patti 15:11
yeah. I can give you one sort of, I think what you said is generally true. There are, you know, ways, innovative ways that people are coming up with to try to study this. And I can just give you a little bit of a technical example, if it'd be of interest to and that is a way that we've been trying to tackle this question, using a model organism called zebra fish. And zebra fish are interesting model systems for people that aren't familiar with them. They're about the size of goldfish, and they are aquatic, and they present some advantages there. They're they're translucent, so they're easy to study. And what we what we do, if you put a oncogene in fish, you can put a certain genes, like we use, BRAF, b6, 100 D, which is a mutation that commonly occurs in various forms of skin cancer. And if the fish have that, just like some humans that have genes like you might be familiar with, say, the bracket genes, you have a higher incidence of developing cancer. The fish, too, because they have this gene, will have a higher incidence of developing cancer. And so what we do is we genetically engineer the animals to have this gene, BRAF, e6, 100 E, and then when the gene gets expressed, we use that expression to drive the expression of GFP green fluorescent protein. And what that does, particularly in this unique system of sea bird fish, which, like I said, is translucent, we can put them under a microscope, and when the cell turns cancerous, you see a single cell level it turns green, yeah. So we can do things like ask, start asking questions. You know that we've we've figured out a way to make it more visual so that we could study it more quantitatively at higher detection limits. And we can do things like ask, How does sugar influence initiation, or, How does sugar influence the development those early stages of development before you get a clinical sized tumor? Does diet play a role there? I think those are really interesting questions that, like I said, we're just starting to really develop some tools that are allow us to dig into some of that stuff. So
Nick Jikomes 17:13
again, high level, I would imagine that when a cancer so there's the birth of a cancer cell, most of them aren't going to live long past their birth, because the immune system will take care of them, but when they do get past that, does that involve some there must be some kind of evasion technique that the cancer cells use. Are they able to camouflage themselves or just avoid how do they avoid detection by the immune system to really get going as tumors?
Gary Patti 17:39
Yeah. Well, there's a couple of things that are involved. There's also repair, intracellular repair mechanisms that that can the immune system isn't the only ways. And you know, the things that need to be evaded. There's other DNA repair type systems that can come into play as well. So, you know, fortunately, we have a couple of mechanisms to try to catch these things, but, but the other thing that starts to be really interesting is signaling. So cancer cells at a certain level start to do, start to really when you, when you get enough cancer cells, you start to develop a tumor. And when you have a tumor, at some point, it starts to integrate into the physiological system of the host. So if you think about your body, you have a bunch of different tissues, bunch of different organs. You have liver, kidney, lungs, and when you have a small number of cancer cells, they just operate kind of independently in their own world. But when they get to be a certain size. What starts happening is they start integrating into the physiological system of the host. So they start communicating and signaling with other tissues. So
Nick Jikomes 18:48
they start releasing detecting molecules coming from healthy tissues to literally, sort of integrate physically with with healthy tissue. Yeah, they start
Gary Patti 18:57
engaging and basically biochemical exchange. So they release molecules, they go to other tissues, and that changes, reprograms the tissues that other tissue might, send molecules back, so they have these, this inter cellular communications and exchanges, and that gives them a certain robustness, that that makes them much more difficult to to to try to combat the other thing that tends to happen at certain limits is like we think of vascularization. So you get sprouting, where you actually get more blood vessels that come in and start to feed, because as the as you get more and more cells, you need more and more nutrients. And the blood supply, the nutrients are primarily derived from the blood, and you need blood to do that, so you'll start to actually vascularize the tumor. So they start telling, you know, they start basically manipulating our native responses and using those in pathological ways. And I think, in my opinion, that's one of the most interesting aspects of cancer right now, is that we're, you. We're starting to appreciate that, and some of these things we've known for a while, but it's becoming, I think, even surprising on the context of some of the more historical stuff. And that is, is that they're, they're really able to hijack a lot of the systems that are already in place and use them to their advantage. Yeah?
Nick Jikomes 20:19
So, I mean, I mean, naturally, you think so if, by definition, these cells are growing too fast, so they need to fuel that growth somehow. They're going to need to instigate a remodeling of, say, the vasculature so they can get that extra blood flow they need to support that. They're going to need to sort of suck up extra nutrients compared to what a normal cell would, and that would somehow have to involve, I mean, not only sort of building just the physical capacity to do that, like the blood vessels that will inject all those nutrients, but they, they probably have to signal to other cells to, sort of, I would imagine that, like our cells are normally set up with, with with mechanisms to say, like, you know, the nutrients Have to be apportioned according to the needs of all the cells. And I would imagine there's natural mechanisms that prevent one cell from getting out of control, and some of the cancer cells have to circumvent those things so they can take more than their fair share. Basically, yeah,
Gary Patti 21:12
exactly. I mean, I think that's exactly right. I mean, if you think about just nutrition as a whole, you know, you put new you put food in your body, and that food has to be allocated among all of the trillions of cells in your body. And how does that actually happen? Like, who decides who gets to eat what? And it's actually remarkably complex and symbiotic. You know that one cell the way, it's just totally amazing. I mean, metabolism is just so freaking cool. Because what happens is that some cells say, Okay, well, I'm not going to use these nutrients because we need that nutrient for, say, the brain. The brain is highly specialized, and it's going to, it needs nutrient act, so we're not going to touch that. And then these other tissues over here, we're they're not going to use this nutrient because this so everybody gets sort of a sign certain ways in which they should biochemically behave, so that everything operates correctly in a holistic fashion. Yeah. And what happens with cancer is that they just sort of disobey all those rules. They come in and shake everything up. And not only do they themselves use nutrients in a way that is flies in the face of the whole physiology, but they reprogram other tissues to use nutrients inappropriately, so it just really throws the whole thing out of whack.
Nick Jikomes 22:27
Yeah, yeah. And okay, so you know where we're going to go with this particular fructose paper we're going to end up talking about, but before we get there. But with that in mind when we think about certain types of cancer, tumors. You know, I'll let you decide which ones are the best to talk about. But the tumor microenvironment that gets created to support this unchecked growth that is cancer. What are some of the hallmark metabolic changes? Or is that even a good question, that support that growth? And I guess what I'm really asking there is, is this typically a process that's going to rely on heavily on glucose metabolism? Is it going to be a mitochondria thing? Is it going to involve, you know, using glycolysis more or less? How does a cancer cell oftentimes switch its metabolism relative to a healthy cell in terms of the bioenergetics?
Gary Patti 23:19
Yeah, yeah, there's a ton there. I'll start to tackle some of that, and you can steer me along, as I probably spend the next hour talking trying to answer that one question. So how does a cancer cell so one of the things you said is, how does a cancer cell itself reprogram its metabolism in the face of this anabolic burden that has to replicate? And that alone is an incredibly interesting question, and one that's actually puzzled cancer biologists for over a century. It seems like it should be pretty easy, you know, you say, Okay, well, they the cell needs to replicate, so it should just turn up, dial up all the pathways, you know, everything should be up. It should take up more sugar, it should take up more, more of every nutrient, and just ramp up every minute of all pepper. And that's actually, superficially not what seems to happen. So if you think about I'm going to try to break metabolism down extremely simply here, because I know a lot of people probably aren't into the weeds. Aren't as excited about this topic as I am, but when glucose comes into a cell, it can be really metabolized in two ways. Yep, it can be metabolized without oxygen, which converts it into a molecule called lactate. And when you do that, you only get two ATP, which is the currency of energy in a cell. But alternatively, the glucose can be oxygen can be metabolized oxidatively in mitochondria, totally break it down into CO two. And when you do that, you get something like 30 to 38 ATP. So it would seem that the cancer cell needing a lot of energy, yeah, the second one. Ron, yeah, the second one. But that's actually not what happens. Most of the glucose that enters the cancer cell gets excreted as lactate. So. So you don't get a lot of energy, and most, most of the carbon is wasted because it it's lactate is a byproduct. Okay,
Nick Jikomes 25:06
so, so a glucose molecule can come into a cell, it can go down. You can metabolize it in the cytoplasm without oxygen and get a couple of ATP molecules. Or you can funnel it through a mitochondria, and it's going to do the oxidative phosphorylation, thing, you're going to use oxygen and that you can get a lot more ATP, a lot more bang for your buck that way. You would think naturally, cancer cells got to grow a lot. It's going to probably crank up and use the more efficient way to make ATP. But you're saying that often does not happen.
Gary Patti 25:34
It does not Yeah, that's right. So it's like I said, this has been the paradox. This is something that's almost synonymous with cancer metabolism, called the work. Metabolism, called the Warburg effect, that was observed by this German scientist, Otto Warburg 100 years ago. And we've been trying to figure out why that doesn't happen. As anybody, if we asked 100 people, 100 people would probably say, That's what should happen, why that doesn't happen. And, you know, I think we finally start to understand why. You know, I think we now have a good explanation. For that, but. But the key thing to emphasize here for for the listeners that might be saying, well, you just said that, that tumors outgrow their blood supply, so the reason they metabolize glucose in this way without oxygen is because there's not enough oxygen. So they're doing this because they're hypoxic, is the word, but, and that's a great point, but cancer cells do this in the presence of oxygen. That's really the key thing. Yeah, even though they have oxygen, they still do this.
Nick Jikomes 26:31
So in a sense, they don't need to do it this way, but they choose to. They choose to,
Gary Patti 26:35
and it does seem and so I think we've made a lot of progress. I'm trying to answer this in the last five years or so. And actually what seems to happen is, if I could, if I could, kind of jump to the punch line. What seems to happen is that the cancer cells take up too much glucose. So the reason that most of the glucose gets excreted as lactate is not as was once positive that that it's because the cancer cells don't want to metabolize it oxidatively. But as it turns out, the amount of glucose that they take up is far greater than the amount of maximum glucose they can oxidize. So they do oxidize a lot of glucose in mitochondria, it just turns out that they take up so much more glucose. Okay, mitochondria can support that. It gets excreted. So
Nick Jikomes 27:18
the mitochondria, they're, using the mitochondria. It's just that. It's just that the mitochondria have some there's a rate limiting thing here. They can only process it so quickly, and all the excess stuff will naturally just go to glycolysis. And because they have so much glucose, that's going to be a natural side effect, that seems to bring us to the point of, okay, so they are, they are somehow sucking up a hell of a lot of glucose,
Gary Patti 27:41
exactly, and that's, and that's, you know, really, since the 90s, that's something that we've exploited clinically. So if anybody's wondering, you know, what is metabolism done? Who cares about metabolism? Why does it matter? The best testament as to why metabolism is important is because this is the main way in which we diagnose stage and test tumors how they're responding to therapy. So I alluded to this earlier, but now that we've provided a little more context, I can give a little more detail. So what you'll do is you give patients a radioactive form of glucose, and because tumors take up glucose faster than any other cells, you've probably seen these images, they're PET scans, yeah, and the tumors are really bright because they take up all of the radioactive glucose and most of the other healthy tissues don't. And that's a main way in which we how we diagnose and tumors, you know that they're there, or try to stage how big they are, or how well a person's responding to therapy, as we do this test. Now the other point, if I could go back to your original question, which was really contained a lot of information is that when we think about tumors, an important point is that tumors are not just cancer cells. So cancer cells, I would say, Are these cells that are like you said, have oncogenes. They're malignant. We say they're transformed, but if you look at a tumor, yes, it has these malignant cells, but a large portion of the cells are not malignant. Tumors actually recruit healthy cells to their micro environments, and they abuse them. They're extensively healthy, but they're, they're reprogrammed in a way to support the tumor.
Nick Jikomes 29:16
Wow. It's like someone who's unwittingly recruited into like, like an organized crime scheme, and they're just, they're just the shop operator, but, but they need them to run the operation. Yeah, no,
Gary Patti 29:26
I like that analogy. I mean, the analogy I often use is it's kind of like outsourcing. You know, we said that cancer cells need a lot of materials to build, you know, to build stuff. And just like if you were building a house, you may not want to do everything from scratch. You can go to Home Depot and buy pre made buy pre made toilets or pre made whatever. And that's sort of what cancer cells do. They they can rely on some of these other cells to to outsource some of the production. And so these other cells then can produce things and ship them off to the cancer cells. And then the cancer cells don't have to start from scratch. They can build from these in. Puts a lot of that energy demand and that anabolic burden on other cells. So you had asked maybe for an example, and I could just give you one example that I think is a really easy among the those that are not, maybe one of the easier ones to conceive, and that is breast cancer. So in breast cancer, you have cancer, malignant cells that are juxtaposed next to fat cells, adipocytes. In those adipocytes, an adipocyte is a cell that stores a lot of lipid, and lipid is people probably can appreciate, is a really rich source of energy that you can burn for fuel. And what we know happens actually, not just maybe we can get into this later, not just breast cancer, but but tumors. A lot of tumors have a disposition to want to make themselves adjacent to fat. And what we know happens is that these fat cells channel, funnel the lipids that they have inside to the to the cancer cells, to the malignant cells, so that the malignant cells can use it as a type of fuel or to build things, to build membranes and so forth. So it is literally using the lipid component of these adipocytes to feed malignant cells. Yeah,
Nick Jikomes 31:14
and there's a whole, there's a whole world of stuff here, you know, I've had people on recently, you know, we were talking about things like polyunsaturated fatty acids and the potential role in supporting tumors that originate in colon cancer. And maybe if we have enough time at the end, we'll loop back to metabolic flexibility and lipid stuff, but keeping on the subject of sugar. So hey, I just want to repeat a couple of things for people. So I don't even know if I fully appreciated this, one of the simple, basic things that you said was tumors are not just clumps of cancer cells. It's a whole environment that includes cancer cells and healthy cells that have been sort of recruited into this mass. And so there's normal tissue and cancer tissue in a tumor, the cancer cells themselves, the cells in the tumor, are really good at sucking up a lot of energy, and it sort of alluded at least that they can suck up energy. They'll get energy some way, somehow, no matter what. But they often are using glucose, because that's what's around, and that's what's going to be easiest, in some sense, for them to support this unchecked growth. We've we've mentioned glucose already, before we get into the cancer stuff. More, I just want to give people a bit of a picture on glucose versus fructose metabolism under normal conditions. So glucose and fructose, two forms of simple sugar. What are the key differences there in terms of how cells use these forms of sugar for energy? Yeah,
Gary Patti 32:42
great question. So fructose and glucose are structural isomers. So what that means is that if you look at their components, they're exactly the same. They have the exact same collection of atoms. The only difference is that the atoms are are positioned in slightly different ways, which is why fructose is different than glucose. As you point out, glucose is is we know is key to our physiology. You know, if you think about something like diabetes, hyperglycemia, hypoglycemia, when you go to the doctor, they don't measure fructose. Measure glucose levels. We regulate glucose levels with extreme amount of you know, it's, it's exquisitely controlled. You know, we keep glucose levels in in certain ranges. And if you don't do that, your body is it's bad, you know, you end up with all kinds of different diseases. It's damaging. Glucose comes from the food. Fructose can also come from the food, in fact, increasingly so. And that whole history there is interesting, because one of the questions that I think is really important, and maybe I'll let you decide if you want to go down that path. But why this? Actually, this trend is happening, but we've started to consume more and more fructose, really, over the last 40 years, it's, it's gone up quite a bit, and it's been used in many ways as a replacement of glucose. One of the reasons for that is because fructose, it's actually cheaper. It's, it's cheaper to make, and per molecule of fructose, you get more sweetness out of it, wow. So if you, if you had the exact same amount of fructose and glucose, and I gave both to you, yeah, you would perceive fructose to be sweet. Oh,
Nick Jikomes 34:28
wow. So I, I've, I've known that the fructose glucose ratio, um, has a big effect on palatability and and how sweet we perceive things. So I always assumed that the reason that all of these big companies have converged on these very particular fructose glucose ratios of like 5545 is that they're optimizing for the sweetness that comes from having a little bit higher fructose than you would say, get with sucrose, and that's driving increased palatability and therefore increased consumption, which is going to support their business. Models, what you're saying is actually there's actually, like a dual there's a there's a dual thing here, which is, not only is it modulating palatability by boosting fructose, it actually is more economic for the companies because the fructose is cheaper. Yeah,
Gary Patti 35:13
that's right. And actually you can track some of the stuff back to the the embargo that with with Cuba, back in the Cuban Missile Crisis, when there was a demand to generate, you know, we, we the United States needed to be more self sufficient. And that's when a lot of the production of fructose started occurring. And if you look back historically, that's kind of when there was a flat line, and then all sudden, things started to go up and around that era. Now there have been some flattening of that curve as of recent, because I think people are becoming a little more, thankfully, a little more conscientious about what it is they put in their bodies. I think that's the message for everyone. We should think about what it is we're eating, but, so I think, but, but it's still used massively. I mean, if you walk around and look at the things you're eating, unless you're actively trying to avoid fructose, it's likely that you're consuming quite a bit of it. And so back to your question, though, about how is it metabolized differently? Yeah. So when you look at how glucose gets metabolized in the cell, it actually gets metabolized to fructose. You go through. You go through. If you look at glycolysis, fructose is, is an intermediate of glycolysis, not directly, but it's structuring, okay,
Nick Jikomes 36:37
so it's intermediate of glycolysis. So the thing that gets us to ATPs per glucose molecule in the cytoplasm that's necessarily going to create a fructose molecule in the process of generating that energy? Exactly,
Gary Patti 36:48
yeah, and so, so, and when glucose comes in, it's highly regulated. Utilization of glucose is highly regulated. And the the kind of off on the control switch there, the control valve is really high up. When glucose enters the cell, there's an enzyme, couple enzymes, that controls whether or not how much you want to metabolize it. Now, when fructose enters it's actually possible that it can enter directly. It can bypass that essentially control valve, and enter directly downstream, directly into the fructose intermediate. I see, so essentially, what you're doing is fructose has some capacity to bypass some of the regulatory steps that, historically, that our cells have evolved to basically utilize.
Nick Jikomes 37:36
So I see, so on one hand, this, this. So two things are coming to mind here. For me, it makes sense intuitively that would happen. I mean, if it's an intermediate, you're just you're just skipping the first step because you already have the second step there. But what you're saying is the first part that would normally take you from glucose to fructose is very highly regulated, which would imply that the cell can control and turn things up and down in a very precise manner. If you have excess fructose and you're bypassing that step, you the cells tune ability, its ability to regulate how much of what is happening is going to be less
Gary Patti 38:09
Exactly. Yeah, that's exactly, right. And so, so, you know, the there's a correlation with the consumption of fructose and the obesity epidemic. You know, we've in around the world, but in the United States in particular, there's an increasing amount of obesity. And some have argued that that you know that fructose, the increasing usage of fructose, is associated with that. And it kind of makes sense, just from a very high level perspective, that if you're putting a lot of nutrient in your body, and you can't regulate its utilization, that's going to drive and we know that when you, when you, when you consume more fructose, that you make more fat. That's definitely happening. It promotes de novo lipogenesis. Exactly promotes the Nova lipogenesis. So, so we know that's happening. And so, so, you know, it all kind of makes sense. So the but you're back to your question about fructose. So we know, we've known for 100 years that cancer cells take up glucose, and the question that's emerged in the last couple decades is, well, what happens with fructose? The discovery about glucose was was made 100 years ago, but but fructose wasn't in high utilization back then. So what happens now that that fructose is being utilized to cancer cells. You know, should we be using fructose as an imaging agent? And you can imagine that a fructose could be utilized with greater efficiency and without regulation. These are all the things that seem like they would benefit a cancer cell. We talked about cancer cell wants to proliferate without regulation. That's the definition. So it seems like fructose might be a really great nutrient to support that cause. And there has been some evidence, you know, we're going to get to the paper that you're referring to, where we show that at least in the cancer cells that we studied, that's not the case. But there have been a pro there have been a couple prior studies that it indicates. That in some other cancers, that is the case, that cancer cells can utilize fructose, and that putting fructose into the body gives the gives the cancer cells access to the fructose, and that that escalates, you know, amplifies growth. So
Nick Jikomes 40:17
apart, so fructose is an intermediate in glycolysis. It can be turned glucose. Can be turned into fructose on the way to creating ATP in the cytoplasm. You can also bypass that by just having the fructose directly, sort of plug into that second part there. What about, what about the mitochondria, and what about the the So, so when we, when we think about dietary fructose, so exogenous fructose that we are consuming, is there, I guess the basic question I have is, is, Can fructose be used to create ATP to the same extent as glucose? Are they as efficient at creating energy as one another?
Gary Patti 40:51
Yeah, yeah, yeah. They are. They can both be oxidized in mitochondria. You both. They're both six carbon substrates. They both produce two pyruvates which which go into the mitochondria and get oxidized. So for all practical purpose. Now, there is one caveat, and this could come into play. It's, I think it's potentially interesting. You do make a phosphorylated fructose intermediate, and some have argued, so there's fo what that means is you're adding phosphate to fructose. And some have argued that because you take fructose up with such high avidity and that you can't metabolize it fast enough that you end up putting a lot of phosphate on fructose, and that actually sequesters your phosphate. Now we've been talking a lot about ATP, which is the currency of a cell, right? ATP is got three phosphates on it, right? So
Nick Jikomes 41:42
if you sequester all your phosphates now, you're gonna be energy limited. Yeah. So
Gary Patti 41:45
there is some question as to whether or not fructose might might be playing a role in some kind of ATP limitation in that sense. And there have been, there's this example that people often talk about where they tried to treat diabetics with fructose, because they thought, well, if they can't use glucose, let's try fructose. And that ended badly because of, at least, supposedly, because of the sequestration of the phosphate and some limitations that that had on the regulation of ATP.
Nick Jikomes 42:17
Okay, so now, okay, so glucose, fructose, we've got cancer cells form. They are good at sucking up energy. Are they using? Is there anything notable or weird about cancer cells, generally speaking, in terms of glucose, fructose, do they do they? Are they deviating from normal cells? Use of those things in any notable way.
Gary Patti 42:41
Yeah, it's a, it's a that's a really important question, and one that seems like it should have an easy, obvious answer. And that was really the origin of our study. Is that we, we wanted to take cold cancer cells in the dish, in culture, and give them fructose and and we, we expect it that, and there was literature out there to support it. We expected that the cancer cells would take up fructose and use it like, you know, like crazy, much like glucose. And so we started the this whole paper that you're referring to start it with us taking cancer cells and giving them fructose and making the observation that they actually don't utilize it. And we, we looked at a pretty large number of cancer cells. Obviously, nobody can look at every cancer cell, but we looked at, you know, I don't know, maybe 3040, cancer cell lines. And in no cases did we find now, some were a little better at it than others, but it was not able. Fructose alone was not able to support the growth of the proliferation of cancer cells. In other words, if you took out all the nutrients and you only gave them fructose, they really could not proliferate effectively, but they could with glucose, presumably, but they could all yes and not presumably, we actually tested in every case, they could proliferate with glucose, but they could not proliferate with fructose, yep.
Nick Jikomes 44:02
Which is, which is a little weird, as you said, you would have expected them to be good at using either source. You tested a bunch of different cell types in a petri dish, not in a live animal, but you looked at a bunch of different cancers, and none of them were particularly good at using fructose, even though they could all get by with glucose. Exactly,
Gary Patti 44:16
that's exactly, right. And so we started to try to figure out why that was and the answer proved to be actually quite simple. When you feed fructose into glycolysis, it doesn't just go in directly. You have to modify it a little. You have to add phosphates. And as it turns out, the cancer cells don't have that ability to add the phosphate they lack that they don't have the right enzymatic machinery
Nick Jikomes 44:43
to do it. So part of the changes that make them a cancer cell have have prevented them from having that ability.
Gary Patti 44:50
So that that was, that was kind of where we went next. Because, you know, like I said, we when you think about it, generally speaking, cells have this capacity. Capacity. But then we started asking, Well, is it true that cells in general should have that enzyme? We certainly know that some cells have that enzyme. And in this context, I think it's important to consider how fructose is actually metabolized when you eat it. Because what generally happens is, it turns out, even though we, even though we talk about fructose in its its potential is nutrient, most of the fructose when you could see, even if you're eating, you know, the richest chocolate cake that you can find, you know, stuffed with or whatever, cereal or whatever, that has enormous amounts of fructose, most of that fructose, or even a coke that actually is. It's got high levels of fructose as well. Most of that fructose is drained from the nutrient components by the time that it reaches the blood, it doesn't make it to general circulation. It gets eliminated by the liver and the kidneys and the small intestine. So most of the fructose does not survive into the
Nick Jikomes 46:04
circulation. Why would that be?
Gary Patti 46:07
Yeah, it's, it's an interesting question. So it seems like what happens is that you get a very small, you know, it's about, maybe, I don't know, one, 1/20 of the amount of glucose right after you eat a high meal, a high fructose, rich meal in the blood. But most of the other stuff gets metabolized by the by the liver and the small intestine and and it turns it into other nutrients that that that like fat. You know, we're talking about fat. The liver has a special capacity. You know, we know that the liver, the metabolic capacity of the liver, tends to be much higher than most other tissues. The cool thing about physiology, I think, is that tissues we talked about that earlier, all tissues specialize. They all have unique metabolism. You know, we could talk about glycolysis. Most of glycolysis happens the same across all cells. But as it turns out, if you really dig into it, there's little nuances in every metabolic pathway between cells. And what the liver specializes in is it has enormous metabolic capacity to break down all sorts of stuff, drugs, nutrients, you know, all the kind of extravagant stuff that we put in our body. The liver gets the blonde end up, yeah.
Nick Jikomes 47:17
So is the reason the liver can metabolize fructose more is this. Are the differences, differences between cells here to do with their ability to import the fructose inside of themselves?
Gary Patti 47:30
No, as it turns out, we did look at that the cancer cells have the capacity, and other healthy tissues have the capacity to import it's actually the hexokinase, the Keto hexokinase, enzyme that is deficient in other cells and tissues, and also, there's a specific enzyme called aldolase B that's involved. So those are the two enzymes that are required.
Nick Jikomes 47:52
Okay, so if I'm hearing you correctly here, most cells can import fructose, but only some cells have a kinase, particular enzyme that can, let's say, activate the fructose so that it can be metabolized, which would mean, if I'm hearing you correctly, most cells don't have the enzymatic capacity to metabolize fructose, and so is, you know this. I don't want to get too off track here, but I think some people have argued that fructose can be thought of as a dose dependent toxin. What do you think about that? I
Gary Patti 48:19
don't think that that necessarily changes those concepts. It's just, and I do want to clarify this is to metabolize fructose sufficiently. As it turns out that even the normal glyc If you pour enough fructose and even normal enzymes, they're, they're they're promiscuous, and they can model they can utilize for test systems that are very low efficiency. So this is if you want to use it to support and sustain some biochemical function. Is for proliferation. It's just not, I think most tissues don't have it.
Nick Jikomes 48:53
So is it fair to say that if you consume excess fructose, whatever exactly that means. We'll just leave that kind of open. But if you consume too much fructose, whatever that means, it will be metabolized inefficiently.
Gary Patti 49:08
Well, you will get a little bit of inefficiency in the systemic circulation, but most of it will be no matter how much you put in. The vast majority of it is eliminated before it gets to circulation. So most tissues just don't have access to it. The stuff that gets in your circulation, you say, well, if nobody can metabolize it, where does that stuff go? Yeah, so eventually it can be broken down, like I said. And there are other tissues in the periphery, you know, like, there's a lot of interesting stuff that happens for saying, like sperm that use it as nutrients. So there are other it's not that no other tissue but, but they're pretty limited. And you could just look at the expression of the fructose the fructolytic Enzymes across tissues, which we did, yeah. And you can see in humans that that there just aren't a lot of tissues that have the capacity to express those enzymes, yeah.
Nick Jikomes 49:53
So the body is simply not set up to deal with metabolized fructose to the extent that it is gluten. Goes,
Gary Patti 50:00
That's exactly right. It's not set up as the main nutrient. Like, yeah, yeah. I
Nick Jikomes 50:05
wonder if this, you know, I've read too, because I used to be an evolution guy. So I think in these terms, when you look at the genome of primates, including lineage of primates, that includes us, there's an interesting connection here with uric acid. And I think some people have hypothesized that due to some of the quirks of our evolutionary lineage, we're sort of not meant to have too much fructose, whatever that means, because, because we because of the uric acid connection here, I don't know if it's relevant. No, it's definitely
Gary Patti 50:36
very relevant. I think the other thing that you said there that we should probably point out, because this is a question that people often ask me, people often ask me, is, what is too much fructose? It certainly doesn't mean no fructose. Mean there's fructose and fruit, right? So, you know, we're talking about here the excessive levels of fructose that are in you know, if you're having a big gulp for with lunch and a big goal for dinner, and you're also eating chocolate cake and cereal. We're not talking about eating a pear, right? Or, you know, something like that. I mean, there is fructose, because the sort of extreme version of this is somebody says, Okay, I'm never, especially as we get into the cancer stuff, people, so we're never gonna eat any fructose. And that that's not, I just want to make sure that, that that's not misconstrued, right? It's the excessive amount of fructose that that that causes the issue. We can talk about that in a bit. Why that? Why it has to be large amounts, you know exactly, what is it? It's a dose dependent thing. It's not like, you know, this level is safe, and then if you 7.2 is safe, and some point three is dangerous. And
Nick Jikomes 51:37
maybe to anticipate some of where we go with this, a lot of people get confused on questions like this, because I've heard this an argument put forth many times. It's like, well, sugar is natural sugars, and everything our body's supposed to have glucose and fructose to some extent. And when you look at high fructose corn syrup, the most common type, I think, is the 5545 people will say things like, well, it's only 5545 Sucrose is 5050, that's a trivial difference. But when you think about the big gulp and the dr pepper on top of this, like, like these things accumulating meal by meal over decades, those, those seemingly small differences can really add up over time,
Gary Patti 52:16
absolutely. And I imagine that if you ate enough in whatever form, it would be the same result. Yeah. So, so changing that, you know, the idea of just going to cane sugar and all this goes away, I think, is that doesn't make sense to me. You know, maybe some can make arguments for it, but I don't think that that's very logical.
Nick Jikomes 52:37
Okay, so anyways, back to this paper. You tested a bunch of different cell lines, cancer cell lines, and they were not using the fructose for energy. Yeah,
Gary Patti 52:49
and I want to stage that and contrast that to another finding that we had that was really puzzling. So the before we even did that experiment, what we did is we took mice that had tumors and we put them on high fructose diets. And this would be the extreme version that we're, again, not not eating a pair a day. We're talking about eating, you know, the big goal up in the doctor, just like, what did you literally give them literally? So there's a couple things we did. We either gave them fructose by itself, or we gave them high fructose corn syrup. We either mixed it with their Chow, or we put high fructose corn syrup in the water, which essentially is sort of like turning their water into soda, yeah. And so then they consume it avidly. And so we gave them these, these diets, and quantified how much they took and and we put what you can do is you can transplant a tumor into an animal, yeah, a healthy animal. So it's totally healthy. No cancer at all. No no oncogenes, nothing like that. And you take cells that you grow in a dish, cancer cells that grow in a dish, that are transformed, and you take a few 100,000 of them, and you use a very carefully transplant them in an animal, and then over time that those cells will start to proliferate and grow, and the tumor will get bigger and bigger and bigger and turn into a big mass. And what you can do is you can measure how quickly that happens. And so what we did is we transplant it the same number of cells into healthy animals, and then we put them on various different diets and asked whether or not, if you feed these mice diets that are high in fructose, if that leads to faster tumor growth. So if the metabolic
Nick Jikomes 54:28
context is different, that's going to affect the rate of tumor growth, and you guys can measure that
Gary Patti 54:33
Exactly, yeah. And so what we found was, is that when the animals consume excessive months or fructose, the tumors grow faster. In all cases, we looked at all sorts of tumors, breast tumors, melanoma tumors, one do you go down the line in all cases? Is
Nick Jikomes 54:53
this like a dose dependent thing? 10% more? Is 10% faster growth, or something like that? Or is this like you have to have an incredible amount before you see? Effect? Yeah, we
Gary Patti 55:01
didn't really do the dose dependent. I mean, that's, those are good experiments, and we probably should go and do those. We were just really interested initially, if you, if you, if you had, if you were kind of at the extreme end of fructose consumption, would it have a difference? And we saw, in some cases, I mean, the tumors grew four times as fast. Wow. So just to give you a sense, we're not talking about a 10% 5% difference. I mean, this is, these are really shockingly large differences, yeah, so we did that first, and it said it all kind of made sense. You know, in the backdrop of what we said, fructose looks like, glucose bypasses regularly, you know, kind of made sense. But then, when we took the exact same cells that we transplanted in the animal, and instead of putting them in the animal, we put them in a culture dish and we gave them fructose. They didn't use them either fructose, huh?
Nick Jikomes 55:42
So the cells can't use the fructose themselves in the context of a whole animal. The fructose is somehow making a difference for those cells.
Gary Patti 55:50
Exactly. That's exactly, right? And we were stumped on that for a few years, trying to sort out exactly what was happening and exactly why? Because that seems like a paradox, right? Those two findings don't seem consistent. And so that was really the backdrop, I think, and that's why the paper, I think, what we tried to explain, yeah, and before we
Nick Jikomes 56:11
get to that explanation, I just want to ask one more about the last experiment you described. So you're giving those mice a high fructose diet that was very high in fructose. I know this is mice, humans. It's not a one to one comparison apples and oranges. But caveats aside, is this within the realm of what some humans might be consuming, or is this totally, totally extreme? No,
Gary Patti 56:33
no, no. It's in the I mean, this is, this is, and we, you know, in some sense, we, it was the animals could consume what they wanted because we put we put the we put the and I actually you've had some really interesting podcasts looking at addiction and how food influences our brain and how we want more things. So you know that all comes into play here too, right? But we the animals, could consume the diets as they wished. So we put the high fructose in the water. We didn't infuse them with them. We did do some experiments where we infuse them, but for the vast majority of what we did, yeah, we just gave them access to it. And just like if you, if you gave me access to cake and didn't tell me it was bad, you know, I'd eat a lot actually, yeah, because it was yummy. And so I think the that's basically what happened. So, you know, it's, it's, it's, it's, it's not physiological, super physiological in the sense that we didn't force feed them, you know, amounts more than they wanted to consume. Yeah,
Nick Jikomes 57:33
yeah. So the animals, the animals choosing to eat as much as it wants, which is, you know, at a coarse grain level, this is not unlike the natural situation for a lot of humans there. We're in an environment where we can eat as much fructose as we want, and a lot of people just do,
Gary Patti 57:46
yeah, and I want to make another point here, because this is actually really important. We did our study in female mice. Everything we did was female, and one of the reasons why that proved to be important is because you might say, Well, if you give the animals a lot of fructose, and they're consumed on this fructose, and they get obese. We talked earlier about how fructose can lead to obesity or they develop diabetes, then maybe some of what you're observing with cancer is related secondary to some of these other effects. But what we we did verify in these experiments is that the animals don't gain weight relative to the the control group, and they don't develop insulin resistance, and for whatever reason, reasons that we probably shouldn't get into here, but very interesting that the female mice is recalcitrant to that compared to the male mice, really. So, so they're a little more it turned out, initially we started these experiments looking at cervical cancer, which is a female cancer. So we got a little lucky, fortuitous in that sense, but, but it turned out, yeah, we tested all this in the female mice. And so it is not, it is not because they get fat, I see or obese.
Nick Jikomes 58:54
Yeah. So to clarify, are you saying that you guys chose to use female mice in this study because you wanted to focus on cancer, not have the confounds of insulin resistance and obesity. And you knew separately that male mice are more prone to getting obesity and insulin resistance from a high fructose diet, but female mice are, for some reason, resistant to that. Exactly, really, right? Yeah, let's that's a subject for a different day, perhaps. But yeah, with that in mind, where do we go next in the study?
Gary Patti 59:22
Yeah, so, so, so, yeah. Then the question is, how, how does this happen? You know, what is it that's what's actually driving the growth of the tumors? And we started to develop this idea that, since we, you know when, when you sequence all the different tissues in the animal, and you it's conserved in humans. You could do the same thing in humans, and you look at where the fructose is metabolized, you can see, as I mentioned earlier, and there have been precedents. I mean, there's other literature, some beautiful work out of Princeton, for example, that shown the small intestine and the liver consume a lot of this stuff, but that's where all the gene expression is with respect to these enzymes that are required. So. So become sort of obvious that somehow the utilization of fructose over here is driving tumor growth over there. And how does that happen? And you know, we alluded to this earlier, that that what can happen is that the healthy cells can output a nutrient, and that nutrient can feed cancer cells in a way that drives their proliferation. And so the model that we started to develop was that, although fructose can't be utilized by some tumors directly, I do want to put a little asterisk on that, because if your tumor happens to be in the GI tract, then it can. That's that's the caveat, and we can go back to that later. The tumors we're studying are like in the cervix and in the skin cancer and that sort of thing breast tumors. So the not in the not in the places the tissues of this is actually the question you asked earlier. Tissues that originally have the capacity to metabolize fructose, these are tissues that normally don't metabolize fructose where the tumors are. So the idea is that they're they're recruiting some nutrient that's derived from fructose, and that's actually driving the accelerated
Nick Jikomes 1:01:07
so yeah, so this would explain the mystery that you that you mentioned earlier, of the cells in the dish can't seem to use the fructose, but somehow the cell, the tumor cells in an animal, are benefiting, being able to grow faster from fructose being present. So the idea here is certain cells in the body are metabolizing the fructose, not the tumor cells. That's producing something that then the tumor cell is somehow getting a hold of exactly.
Gary Patti 1:01:29
And if we take, you know, we guess the liver, because that's a big side of natural choice, yeah, yeah, fructose. And so what we did is we took liver cells, hepatocytes, and we cultured them in a dish, and we gave them fructose, and then we let them soak in the fructose for a couple days, and then we take the media that came that, you know, so they're, they're taking up the fructose, using it, and spitting stuff out. And then we took that media and we gave it to cancer cells. And as it turns out, cancer cells will grow on that. So that supports the notion that you just said, you know, that the can't, the cells that have the capacity utilize fructose, take it up, transform it into x, and then x is given to the tumors. And x is a very good fructose is not a good nutrient for the tumors, but x, whatever that X might be, is, wow. And that was really the hunt is, how do we find x? And that's, you know, the other thing I'd like to just point out, because we were talking about this early on, this might be an appropriate time to insert it. You mentioned the word micro environment, and I think that was a really nice summary that you gave that the tumors are not just cancer cells. They're a whole aggregation of a bunch of different cell types. And over the last couple decades, now really largely in part to advances in spatial biology, people have gotten really interested in what's happening in the tumor, micro environment that's really essentially that immediate environment surrounding the tumor. Yeah. And as we discussed, cancer cells manipulate other cells that are part of that so even though they're, you know, by all practical means, definitions are healthy. You know, we don't call them fibroblasts. They're actually called cancer associated fibroblasts, caf,
Nick Jikomes 1:03:11
the cells that are being extorted by cancer, exactly, and that's
Gary Patti 1:03:15
happening in that micro environment. And so as we talk about this, the study, now we go back to the study we just talked about, and we're talking about the liver, let's say, metabolizing fructose and maybe feeding a tumor in the breast. That is not the micro environment. Those are now cells that are removed. You know, they're on opposite sides of the animal. So we've been referring to that as others. Has is the macro environment. So it's not only, I think, what we've moved if we kind of look at the history of cancer metabolism over the last 100 years, we started off by just thinking of the cancer cell and the oncogene and what happens in the cancer cell. Then we sort of came to the appreciation, well, it's also these cells that are immediately surrounding in the micro environment. And now we're saying, Well, it's actually not just that. It's the whole system, the whole animal. Yeah. And just one last point that I want to make, and I think, in my opinion, this is one of the most fascinating observations that, that, that, that we've seen, if you take an animal, a healthy animal, and you transplant a tumor in it, and you compare that to an A healthy animal with no tumor, and you compare the tissue, let's say, you I don't know. Let's add skin cancer. Let's give them a melanoma. We know that the melanoma we talked earlier, that the melanoma lights up because it takes up a lot of glucose, and that's how we diagnose cancer in the clinic and stage it with pet that definitely is the case. And people have really focused on the weird, funky metabolism of the tumor and the adjacent cells, but what we find is that almost every cell that we could find in the animal with the tumor is is screwed up. It's not just, you know, we tend to think of
Nick Jikomes 1:04:59
the. Tumors, the epicenter of the cancer, but there's, but
Gary Patti 1:05:02
it, yeah, it stretches the It spans the entire organism. It's
Nick Jikomes 1:05:06
like an atom bomb goes off, but the radiation effects, you know, can extend for miles, miles.
Gary Patti 1:05:11
It's exactly the right analogy. So it's, it's a huge it's a systemic disease, yeah, yeah, you know, focal point. But it is a whole body issue. It's a whole body disease. And when you look at, I think some of the things that are that, when I look at where the field is going, I think you can see an increase in appreciation for this. And I think as we, as our discussion matures here in the last half of our what we're discussing, I think that'll be interesting to come back to what implications that has? Because I think that's that's going to have big implications of how we think about diet. Yeah, yeah.
Nick Jikomes 1:05:47
Okay, so anyways, fructose can't be used directly by these tumor cells, but other cells are metabolizing it. It's turning into this mystery thing X, and somehow that's assisting tumor growth. So fructose is indirectly facilitating tumor growth. Did you figure out what that mystery intermediate was? Yes,
Gary Patti 1:06:06
we did. It's a at least one of them. There's probably multiple mystery nutrients, but at least a major player is a nutrient called lysophosphatidylcholines. That's a, I know a big, a big, long word that probably a lot of people haven't thought about before, but that's a type of lipid, and it's unique. It's actually the what's happening here is incredibly interesting in the sense that it doesn't, at least for us, it was surprising when we think about what happens with fructose. You mentioned something earlier, de novo lipogenesis. So what happens often when you consume excess amounts of fructose is that your body, specifically, specifically your liver, converts that into lipids, and then those lipids get packaged together in a type of fat called tags, and they get excreted from the liver. Is a lipoprotein particle that floats around in the blood. It's, it's, you know, like VLDL, you go
Nick Jikomes 1:07:05
to all the stuff that we think about when we talk about blood cholesterol and LDLs and stuff, exactly. So,
Gary Patti 1:07:09
you know, we, most people, are familiar with that, because you get it measured, and there's good and bad and all that kind of stuff. So, so a lot of the lipid goes that, that's the destination. But what we found, irrespective of if they have cancer or not. But what we found is that in addition to making those kinds of lipids, fructose causes the liver to excrete this other kind of lipid called these lysophospital coolings. And lysophospital coolings are different than the other lipids that are packaged in the LDL VLDLs, in the sense that they're, they're a little more water soluble. Okay, so when you think about the lipoprotein particles, it's a, it's a very complex, complex biochemical mechanism, because you put all these, because the thing that makes
Nick Jikomes 1:07:53
it's a way for the body to move non water soluble fatty stuff around in the watery environment of our blood,
Gary Patti 1:07:59
exactly. Yeah. So you build this huge particle, and you stick everything inside of
Nick Jikomes 1:08:03
it, and these lipids are more water soluble. They can just kind of go in the blood or whatever, exactly,
Gary Patti 1:08:07
yeah. So they get excreted, and they can circulate without the complexities of that the lipoprotein particles. And that's important, because if you think, Well, how does the cell use the lipids inside of those lipoprotein particles. It's very complex, you know, you have to figure out either how to take the whole particle in, yeah, there's kind of, you know, macro pinocytosis type process into a cytosis process, or you have to chip away at them, you know, open up, okay, I think
Nick Jikomes 1:08:36
I see where we're going here. Yeah, these other cells that are not tumor cells, they're metabolizing the fructose. They're creating these LPCs, these fairly water soluble lipids. Those can now just go through the blood, and the tumor cells will suck them up like they would any other energy source. Yeah.
Gary Patti 1:08:50
I mean, you need a transporter, and we're trying to characterize, figure out exactly how that happens. There's still a lot of work here to do by you know, I think, I think we've uncovered some really good, whatever it is, they've got it, yeah, yeah. And so they're able to utilize these much more directly than than you could with the more complex machinery that's involved in lipoprotein particles. So which is amazing, you know, it's kind of a, kind of a magnificent way for a cell, a cancer cell, to get access to lipids faster, more efficiently, potentially, yeah, yeah.
Nick Jikomes 1:09:26
And what would do, you know yet, what the tumor cells are using these lipids for that supports growth? Is it? Is it for energy, or is it for structural lipid stuff?
Gary Patti 1:09:36
Yeah, yeah. That's a great question. I think those are the two possibilities. Exactly. They can use the lipids for as a source of energy, or they can use them to build other complex molecules. And what we find is that at least in the scenarios that we've studied so far, that it's the latter that they're using them to build other molecules. So if you go back to one of the original statements we made, that when a cell cancer cells, is defined. Designed by an unrestricted capacity for growth. And every time it proliferates, or one cell turns into two, it has to remake all of its membranes. That requires a huge it takes a lot of energy for cell to make palmitate, you know, a lipid, yeah. And if it can take up palmitate directly, that's energy efficient. That's energy much more energetically efficient because it doesn't have to build it, yes, so that that that is primarily what we're seeing. Something like 80% of the of these go that route, yeah, that are used for, for structural membrane lipids. So
Nick Jikomes 1:10:33
these lysophosphatidyl cholines, these LPCs that were, you know, this was the mystery thing, the mystery x we were talking about fructose can turn into that in some cells, and then the tumor cells end up using that after they obtain this from circulation. Do these LPCs have any relationship to dietary fatty acids? Are they made from certain type of fatty acid like that?
Gary Patti 1:10:54
That's a great question, and I think what I'm really excited about now is trying to understand when LPCs go up. So we've, we've learned that if you consume high fructose diets, your LPCs go up. And we can make that same observation in people. So you asked earlier, you know, is this, is this some artifact of doing giving the mice the weird, you know, diet? We see the same thing in people. Yeah. So if you were to start eating high fructose diets, and we measured your blood today, and then in 10 days or a couple weeks after you did it, we'd see increased LPCs in your body as well. So
Nick Jikomes 1:11:31
we know the LPCs go up in humans in response to fructose. So unless the cancer biology is completely different from the mice and the humans here, this is this implies. The implications are pretty obvious,
Gary Patti 1:11:42
yeah, yeah, I think so. But I think where I was going with that is, I think, another really interesting question, and this gets to your point, what other instances do LPCs go up? Right, right? Because it's not something that, at least we've thought about, like, I don't know that we so it is true. If you do high fat diets, you might predict that LPCs go up. Yeah, but what is high fat?
Nick Jikomes 1:12:03
You know, one of my, one of the most annoying things in the literature, to me on the food stuff is, you know, high fat diet is just too big a term, like I said, where my mind was going with this is, if fructose goes to LPC, goes to faster tumor growth, the pool of potential lipids that can be transformed into LPCs might depend, say, on PUFA versus, versus, you know, one type of of dietary fat and so sort of like the potential energy of what the fructose can be turned into to support tumor growth might be limited by something like the dietary fat that comes into play here.
Gary Patti 1:12:34
Yeah, no, I think, I think it's a really great, great question. A lot of the lipid biology for cancer, is, is still pretty nascent. I think it's, you know, we've, we've classified lipids together as a whole is, I totally agree with you. What you just said resonates with me strongly. I wish you would review our, our, you know, our grants and papers with that perspective. Because I think, I think lipids as a whole have been sort of broadly classified. Oh, lipids all do the same thing. But you know when, when you screen, you know certain LPCs, like 18 one appears to be an LPC that's particularly important for these cancer cells. They they seem to like they do better with 18 one than they do some of the other LPCs. Now exactly why that is, we're not exactly sure. You know, I don't know. I think there's a lot of interesting biology associated with specific classes of lipids and decorations and rearrangements, yeah. And I think, I think there's a ton to be learned there, But your point is absolutely well taken. What does this imply for what lip is we should be supplementing our food with, certainly, you know, someone asked me once, what happens if you just consume LPCs? What impact does that have? Does that, you know, does that have? Does that change things? And we didn't do that experiment. We infused LPCs into the to the intravenously, and that that impact. If you just infuse I intravenously, if you infuse LPCs and mice, the tumors will grow faster. Yeah, makes sense, yeah. But, but, you know, remember that when you put something in your body, we've learned from fructose, it doesn't necessarily mean that what you put in your body is what the tumor is going to see. I think if I had to say one really big take home message, it seems so obvious, but I think one really important thing is that when we when we tend to think about at least kind of canonically, when you think about cancer, you say, Okay, I'm going to put x in my body, whether it's glucose or fructose or whatever, because I'm eating a lot of it, and that means that the tumor is going to get that so is it bad for the tumor to have glucose? Yes, I'm not going to eat glucose. And then the sort of this, like simplistic reductionism, that if I don't eat glucose, the tumor won't get glucose, and if I eat a lot of fructose, the tumor is going to see a lot of fructose, but that it's much more complicated,
Nick Jikomes 1:14:51
yeah, yeah, what the tumor sees is not necessarily what you see, because there's all these sort of filtering mechanisms at different levels of regulation.
Gary Patti 1:14:58
Everything gets transformed by. A million different cell types, and so we have to think about, and I think that's, that's what we is we think about the interface of diet and cancer. That's the next frontier. Is trying to figure out, not necessarily, what the nutrients do to the cancer cells themselves. I mean, that obviously is important, if we don't know that LPCs drive growth, that we don't know, to ask what diets increase, LPCs. But I think what we need to ask is, how do diets influence nutrient availability, and then do those nutrient does that change in nutrient availability affect the rate at which tumors can grow?
Nick Jikomes 1:15:33
Yeah, yeah. So, so if you had to sort of compress the takeaways from the study. So we, obviously, we went through lots of lots of detail here, but sort of the overarching questions that an ordinary non biologist might want answers to here, or want to know what the relevance is, is, what do exotic exogenous sugars, things like fructose, things like high fructose corn syrup. Is this basically stating that if you're eating too much high fructose corn syrup, whatever, exactly that means that it has the potential to facilitate tumor growth.
Gary Patti 1:16:10
Absolutely, I think that that is a take home message. Obviously, you know, I can't tell you that we validated this and, you know, have tested it million ways in humans. You know, that's all the next step. We got to take it further. It further. Everything that's in the paper you've mentioned is all in animal models. So, you know, there's, but I think, as you say, there's compelling evidence to compelling reason to believe that this will translate into humans. And I can say that that, you know, I think it's, it's not going to hurt you if you consume less fructose. Let's say it that way, and there is a big possibility that it will benefit you. If you have cancer, you consume fructose, there's a possibility it could hurt you, but I don't see any possibility that it would be bad. Yeah, that's
Nick Jikomes 1:16:55
actually a good way of framing it, because people in the diet nutrition, it's so fascinating but people get so factional and tribal and almost religious with it, I want to repeat what you just said. So there's certainly a lot of downside potential to eating too much fructose, whatever exactly too much means there's probably no downside risk to taking it down and eating less fructose.
Gary Patti 1:17:19
Exactly, okay, absolutely correct. And again, I do want to put the caveat that what we're talking about here is not, you know, avoiding fruit, right? That's not what we mean.
Nick Jikomes 1:17:30
Is it fair to say that, like when you think about it, and we're not saying avoid all fructose or avoid fruit. Part of what that means to me, at least, is natural whole foods are naturally limited in certain ways, right? They have a certain amount of fructose inside of them. They are they contain fiber and other things that will limit the rate of absorption. And you know, our bodies, obviously, by definition, animal bodies, have evolved to extract nutrition from whole foods that are part of the natural environment and have been for 1000s and millions of years. When we start adding things on top of that is where we can start to get into trouble. Yeah,
Gary Patti 1:18:06
absolutely. I think that's perfectly well said, and so you don't The other thing that we didn't mention is that fructose can change the way that other nutrients are metabolized. So it doesn't just, it's not just fructose that gets metabolized. You know, fructose gets metabolized into, we said LPCs. We know that for a fact, but the way the presence of fructose can actually change the way in which glucose is metabolized. So, so, for example, more glucose will make lipids in the presence of fructose than if, if that, if, if you're not consuming fructose. So you activate, you know, the de novo lipo Genesis, and that routes more glucose to lipids than you would if you didn't have fructose present. So if you do everything, that actually equal amount of sugar. But in one case you have fructose, in one case you don't. So maybe you have fructose and glucose and just glucose, but everything is equal, you will make more lipid. Glucose will make more lipids when fructose is present than it does when it's it's just glucose alone. So So it raises yet another complication as we think about diet, it's not just, how does this what is this nutrient get transformed into, and how could that feed cancer? But how does the presence of nutrient a affect the transformation of nutrient B, because it could be that the presence of nutrient a makes nutrient B get transformed into something else, and that's what's feeding the so it's an extraordinarily complex situation, and I think that's why we just need more research in this space. Yeah, you know, I think it's one of the more, important areas. And maybe, you know, who knows? Maybe, with the current interest in the in the administration, maybe this is an area we'll see more resources invested.
Nick Jikomes 1:19:50
I mean, just to sort of reiterate or riff on something you said a moment ago, let me ask this question, what would happen if someone was consuming zero fructose? Anything break? Would anything go wrong that we know about? No.
Gary Patti 1:20:03
In fact, you can make fructose endogenously, so if you, and this is a little bit in the weeds, but it might help think about your question. So we, actually, we developed, as part of this study, we developed a drug that blocks the metabolism or fructose in the liver. So, and it's actually already exists the drug we didn't, we didn't invent it. We didn't design it or synthesize it. It was developed because it was developed in the context of fatty liver or steetosis, you know, fatty liver disease. And basically the idea is, could, if we block the utilization of fructose, might that minimize fatty liver disease. Now that went through clinical trials and and it's not currently moving forward, but the drug was out there that exists that prevents the metabolism of fructose in the liver. And so we wanted to actually give that drug to animals and put them on high fructose diets and ask if we gave that drug, you know, in theory that should prevent the liver from making these LPC molecules, yeah, and if they don't make if they don't convert fructose into LPCs, then the tumors shouldn't grow faster. And that's actually what happened. The tumors didn't grow faster. But kind of an unexpected, surprising result that we found is that when we administer the drug in some scenarios, the drug actually reduces tumor growth more than if the animals weren't eating fructose at all. In other words, imagine that you get a certain tumor growth without fructose, yep. And then you give this drug, which blocks fructose metabolism, but you don't give the animals fructose, so you expect
Nick Jikomes 1:21:47
all of the fructose is endogenously produced, yes.
Gary Patti 1:21:51
So, so what? So you kind of stole the punch line, but sorry, so, but that's okay. But why is it that you, you the drug has an impact even when there's no fructose present. And we think that at least part of that reason is that the the fructose is being produced endogenously, yeah, through, through a pathway called the poly all pathway that that's present in cells, and that that so, so the reason I go through that big, you know, it was a big, long tangent, but the reason I mentioned that is because you ask, how important is fructose? And if you don't consume it, and for whatever reason, your body needs it as a political intermediate or capacity, you can make it Yeah. So you
Nick Jikomes 1:22:30
not only want to have Yeah, not only that, but when I think about endogenous synthesis of things, right? I'm not, this is not, I don't want to make a blanket statement, but when your body has the ability to synthesize something from scratch, it generally, as long as you're otherwise healthy, will make just as much as it needs. So for example, most animals, not humans, but many animals, have endogenous vitamin C synthesis capabilities. So they don't need to worry about how much vitamin C they consume. Their body will make exactly what they need. As long as they're getting all the nourishment, other nourishment they do need, I would naturally think it's probably similar with a human being. If we can produce fructose endogenously, then we probably don't need to think too much about trying to get some
Gary Patti 1:23:12
Yeah. No, I think that's a good, good rationalization, and certainly with fructose, particularly because when you produce it endogenously, it's regulated, yeah. As what you're basically saying is that your body regulates it, so you tend to not have to worry about excessive production, because your evolution tends to allow us to produce what we need when you when you're eating, you know, entire chocolate cakes, that's a situation where you lose the regulation component. Yeah, yeah.
Nick Jikomes 1:23:40
And, you know, this is beyond the scope of our discussion, but obviously the time with cancer stuff is what you just, what we just learned from you. But excess fructose consumption also, as we touched on, you know, it can promote fatty liver disease, insulin resistance, potentially in a sex dependent manner, and lots of other stuff besides cancer.
Gary Patti 1:23:58
Yeah, exactly, yeah. And I think, you know, we're just scratching the surface for, you know, we talked about sugars today, but there's a lot of other sugars. You know, we're interested in some, some other artificial sweeteners. Yeah, we're interested in, it's not just fructose and glucose. There's, if you go look at your, your your favorite, you know, foods that they're going to have other sugars in there as well, and and so this question is interesting. The discussion we had today is quite interesting for fructose. Certainly, that's the most important just if you look at consumption rates. But there are other sugars that that I think are that we're learning are going to play an important role in the same context as well, some other sweeteners that I think are going to be equally important and have similar types of effects. So and some of these, I think the scary thing with some of the other sugars that we're looking at is that some of these things are considered, you know, imagine if you're on an Atkins diet or non ketogenic diet, where you're trying to avoid sugars and use artificial sweet. Errors. But if the cancer cells can use those sweeteners or they can make these LPCs, that's not necessarily the way to go.
Nick Jikomes 1:25:07
And so what would be your so given this study and everything you know about fructose, cancer, all this stuff, what would be your take on questions that people are asking in society around high fructose corn syrup versus cane sugar, how much is too much? And all that stuff to sort of preempt you there. My sort of general take on all those things is, you know, okay, high fructose corn syrup is 55% fructose, 45% glucose. Cane sugars, 5050, if I would say a 5% difference is a 5% difference, if it's in the context of eating 200 grams of added sugar a day, that's probably not meaningful, but a 5% difference is a 5% difference. It's gonna nudge things a little bit one way,
Gary Patti 1:25:46
yeah, yeah. I mean, I guess my take is, you know, yeah, quantitatively. I believe what you're saying is that that makes sense to me. I think the idea that we can, if we get rid of high fructose corn syrup and move to cane sugar, that everything goes away, that all the issues that we've associated with fructose are going to be obviated. I think that is nonsensical, Yeah, but you're right. It's not exactly the same. So you might see some biochemical differences, because quantitatively, there's subtle differences in the fractions. But I think the idea that just moving away from high fructose corn syrup and going to can sugar is going to eliminate the phenomena like what we saw in this paper, and like, you know, associate with liver disease and obesity, I think that's very unlikely. So
Nick Jikomes 1:26:33
maybe another way of saying that would be, you know, if you're drinking a liter of American Coke a day and you switch to Mexican Coke, probably not going to move the needle, especially if nothing else in your life is changing. But if you were to switch to Mexican coke and cut down the volume you're consuming, that could make a difference Absolutely.
Gary Patti 1:26:52
And I would say cutting down the volume is much more important than the cane sugar or fructose.
Nick Jikomes 1:27:01
One of the difficulties preparing for this was, you've done so much that it was difficult to difficult to pick exactly what to talk about. But I definitely wanted to talk about this fructose paper. What else you know, just in the realm of cancer biology in general, can you tell us about, say, dietary sugar versus dietary fat? And I want to keep it you know, we've got just a few minutes. A few minutes left. I want to keep it pretty broad. Earlier. You mentioned, for example, this notion of, okay, well, cancer cells are growing. It's unchecked growth. So they're very metabolically expensive. They have to suck up and use a lot of energy, if they like, to use things like glucose for energy. And they suck up a lot of glucose, it makes sense to deprive them of glucose, intuitively as a way to try and treat or slow down the tumor. That would actually bring us to questions of like, okay, if someone has a tumor and we put them on, say, a ketogenic diet, is that known to have any kind of effect on tumor growth? Yes,
Gary Patti 1:27:57
it's a great question, and I think that very empowering the people who have cancer, because it's something you can control. The idea that you could change your diet and that might have an impact on your the course of your disease, I think is is very enticing idea, and I'm very optimistic that that is a possibility. Certainly, the example that we outlined with fructose is maybe a good starting point, right. If you consume more or less fructose, it's likely to impact the course of your disease. Again, with the caveat that we need to do more studies in humans to say that definitively. But the idea that you could do a ketogenic diet and quote, unquote, starve the cells of glucose has not worked, and that's something that people have thought about for a long time. You know you can imagine decades ago. It's not a it's not such a big leap conceptually to say, if we know cancer cells are addicted to glucose, what happens if I stop eating glucose? And it really does get at this idea that we chatted about a couple minutes ago that that it's, you have to think about this in the physiological context. You know, if we had cells in a dish, and we had media, and we just put the cells and we said, we're going to take glucose out of the media. Yeah, that might, that might work. But we mentioned earlier that glucose is is regulated in our blood with exquisite regulation. So you know, if you don't eat glucose, your blood glucose doesn't drop, you know, I mean, it drops a little, but you it has to be maintained in a certain range, because your your brain needs glucose, and so you can't just because you stop eating glucose doesn't mean that you glucose disappears from your blood and that the tumor doesn't have access to it, and what's really interesting. So maybe I could just mention briefly another study that we did, the tiling related to this. So what does happen if you, if you stop eating glucose? Like, let's say, because it's a really interesting question to think about, right? If you're not a metabolism person, like, let's say you don't eat for two days. Yeah, and I just said, but your glucose levels are maintained. Like, how does that actually happen? And the way it actually happens, it goes back to the liver, which in many ways, is the kind of control center of metabolism in the body. Your liver makes glucose. And kind of what you're saying earlier, like, if you need something, you make it. And so your liver will take other things in your body and make glucose out of them. And so that's how you maintain your your levels of glucose in your blood. This is the
Nick Jikomes 1:30:26
process of gluconeogenesis. Gluconeogenesis, you can take a chunk of muscle and turn the protein into sugar, if you need
Gary Patti 1:30:31
to exactly so anything that's glucogenic, you can turn back in the glucose. You can't turn everything in the glucose, but a lot of stuff, you can. And so what ends up happening is that when you have tumors, what we found is that when you have a tumor, tumors take up tons of glucose. That whether so normally in your body, and hopefully every you know, all of our listeners body that gluconeogenesis only happens when you're when you're deprived of new you're having to consume glucose. But what happens when you have a tumor is that gluconeogenesis is happening constitutively. It's always happening even really, because the tumor is consuming so much glucose, yeah, yeah, that it starts to lower the level of glucose in the blood. So
Nick Jikomes 1:31:15
it's on your body. In a sense. It's like your body's starving, even though it's not starving, yeah, exactly,
Gary Patti 1:31:19
yeah, yeah. So the glucose starts to drop, you know, because the tumor is consuming the glucose, and your body says, Well, I gotta keep the glucose levels high, you know, within this range. So it starts making it in the liver. So that kind of illustrates, again, and that's not a tumor in the liver, per se. That's a tumor anywhere in the body, yeah, but it's, again, this physiological response that that's happening. So I think that's, you know, really pretty fascinating. Maybe just one other thing I'll, I'll comment on in connection to that, when we think about the whole body, you know, I've been really emphasizing that cancer is a whole body disease, and from a metabolic perspective, there's another thing that happens when patients have cancer that represents that probably most emblematically. And there's a phenomenon called cachexia, cancer associated cachexia, and it reminded me because you said you can take a piece of muscle and turn it into glucose, and what happens in cachexia is that patients will start to lose body weight, so they'll start to lose fat, and they'll start to lose muscle mass. And in many cases, the reason that a patient dies from cancer is associated with cancer cachexia, not because of the tumor, per se, but often it's because of cachexic response, and that's just waste away. Basically, you waste away, yeah, and that's basically what's happening. So it doesn't matter where you're doesn't matter where your tumors, I mean, you could have a pancreatic tumor, but your muscle and your arms and your legs and your fat tissue around your body gets dissipated. So that that's, you know, when you said, you said that, I think metaphorically, kind of whimsically, is maybe a joke, but, but that actually is not so far away from what actually can happen, yeah,
Nick Jikomes 1:33:02
yeah, wow. Yeah, your body so the tumor is just using so much sugar that your body thinks it's sugar deprived, even though you're maybe eating an otherwise normal diet, and you will quite literally start breaking down your muscle and turning it into sugar. Yeah, exactly to feed the term tumor,
Gary Patti 1:33:17
yeah, yeah. 100%
Nick Jikomes 1:33:20
Wow. Is there any connection between constant nutrient, constant nutrient and caloric surplus and the probability of getting cancer? So another way of saying this, if cancer is unchecked, cell growth and cancer cells are always popping into and out of existence, but we normally detect them and then get rid of them. But sometimes they can take a hold and the tumor will grow and all that stuff will happen is, is there any reason to think that are cancers more likely to stick and turn into full blown tumors in a state where you're always you always have calories around. You, always have surplus nutrition. You're never fasting. You're never cycling in between, say, ketosis and non ketosis. Is that just, is that a risk factor itself, just always having surplus energy? Yes,
Gary Patti 1:34:09
absolutely, I believe. So I think I the evidence is out there to extrapolate from. I and there's a couple reasons. It's a little bit of a convoluted question, but I will tell you personally that I do fast. And for seven years I fasted where I only ate two hours a day.
Nick Jikomes 1:34:32
So you're a daily intermittent faster, yes,
Gary Patti 1:34:36
but, but the the to get to your question, perhaps more precisely, that one of the complicated, one of the reasons it's complicated to answer your question is if you're constantly in a state of excess calories, you become obese. And we know for a fact that obesity is associated with increased risk of certain cancers. Now exactly why that is, is a. Complicated question, and something that we're trying to sort out. As I mentioned earlier, we do know that cancer cells prefer to localize next to in pockets of fat. Exactly why that is? Is it because they're getting extra nutrients, you know, the fat can? You know, there's signaling going on? You mentioned earlier about different kinds of signaling lipids, that may be a role there. So we don't know exactly why that happens, but it's absolutely the case that that obesity does increase your incidence for for contracting certain kinds of cancers.
Nick Jikomes 1:35:36
Interesting, yeah, and, I mean, yeah, it makes sense. I mean, it just makes perfect sense. So, so, so, so you do daily intermittent fasting? Yes, interesting. And so is there? Is there any reason to, I mean, this might be too much detail, but is there any reason to think about, do you think daily intermittent fasting has benefits above and beyond intermittent fasting, like if you're just fasting, you know, every couple of months, or something like that, for a day or two. Does the pattern and tempo the fasting make a difference? Is there any literature on that with respect
Gary Patti 1:36:08
to cancer? Yes, I don't. One of the challenges that we have, we've done quite a bit of experiments in this space. One of the challenges you have is that animals, you know, we use a lot of mice, and we use a lot of zebra fish as model systems. And one of the challenges that you have is, let's say that you fast, you know, a fish for 10 days. What does that mean? Like, how does that compare to how we fast? So I could tell you exactly the fasting intervals and how they impact the fish, but how to translate that into humans? You know, it's much harder to do that, and I think that's why, you know, my clinical colleagues that that you know, are moving more and more towards doing clinical trials with nutrition is going to be so key. And hopefully the animal work that we've done, we and many, many others can provide some some, hopefully some, some ideas that hopefully we'll be able to test in the clinic. But the answer is yes, you can change the intervals of these fasting periods, and they do have an impact. And what you'd like to do is to try to make it the most palatable as possible, right? So, yeah, what's the minimum amount of how? What's the least amount of times that you can fast for the least amount of hours? And that's what everybody will do, right? If you only have to fast once every six months, that's what we should do, but, or at least, maybe that's what, what one would choose to do. But we don't have that worked out yet. And who in humans, like I said, maybe we have some data that would be supportive in animals, but trying to correlate that is challenging, yeah,
Nick Jikomes 1:37:33
but I guess the punchline here is, it sounds like what you're saying is that in animal models, and some animal models, fasting does affect doing some amount of fasting will decrease the odds of cancer, and the exact way that you do the fasting does have some effect, yeah.
Gary Patti 1:37:48
And I also want to be clear here that what that what we're talking about here, is not if you have cancer. So if you have cancer and you try to fast, that is different. You know, you got to this point earlier than, than, than actually initiating cancer. So there's a difference there. So and fasting is not equal across both of those paradigms. So when you if you have already a tumor that's been clinically detected, fasting there, the evidence is relatively weak that it's that it has much of an impact. Now it probably, it might have an impact when combined with certain therapies. You know, I think that. But there's so many combinations, it's hard to you know that there's a lot of possibilities to test there, or perhaps fasting. You know, there's others. There's some really nice work out of Duke, for example, that shows that maybe you don't have to fast everything. You know, the beauty of the ketogenic diet is, you can eat as much as you want, you just can't eat glucose. And it might be well, you could eat as much as you want. You just can't eat this essential amino acid. And there's some work coming out, like on methionine and things like that. But there's a difference when you already have the tumor. And I think the dietary strategies that will emerge if you already are unfortunate and you have cancer, this is what you should do, versus you don't yet have cancer. What dietary practices should you use to limit your chances of getting cancer? And kind of circling back to contextualizing this with all fructose, for example, our study showed, and this is something that people often ask, that I think is not, is not our intent, and if we communicate it that way, it was a mishap on our part, but that what our study shows is that if you already have a tumor and you eat excessive fructose, it will make your tumor grow faster. It does not say that if you do not have cancer and you eat fructose, that you're more likely to get cancer. Yes, those are very separate things, because, as you pointed out earlier on, and it was a perfect way to start our conversation. The the process of initiation is different biology than the process of the tumor development and progression. And so those are different phenomena. So what we're talking about here in the fasting is the the former, that initiation process versus the the progression and development. Yeah,
Nick Jikomes 1:39:59
yeah, I would have. Actually. I mean, my, my naive prediction would be that if you already have a tumor or any sort fasting well, because the tumor is good at sucking away energy that your your body would otherwise need, you might just promote wasting of your healthy tissue,
Gary Patti 1:40:11
exactly. And cancer associated cachexia, as I mentioned, is a big part of the demise, yeah. And one of the things that that people have worked on is how to limit that, and one way to potential strategy to limit that is to infuse nutrients, to put people on excess nutrients to prevent that from happening. So I think you're right. That is, certainly there's some complexities there, but I think that maybe the take home message is that cancer biology is complex. There's different phases of it. And depending on which phase you're in, you really have to contextualize the therapy to that particular phase. So that's the key point, I think, yeah,
Nick Jikomes 1:40:49
well, I think that's a great place to end it, Gary. Thank you very much for your time. This was fascinating. This is one of the best ones I think I've done in a while. And yeah, I would, I would recommend everyone who's interested in metabolism cancer. Generally, check out Gary's work because you you've got a voluminous set of things that you've investigated here, way more than we can get into. But the new paper on dietary fructose, I thought was, was particularly interesting and very well done. So thank you for your time. And do you have any final thoughts you want to leave people with? Yeah,
Gary Patti 1:41:17
no, I really appreciate it. It's a lot of fun. And I just shout out to the first author of the person who did the study, Ronnie Fowler Greider, who's led all the work and deserves all the credit for everything that we discussed today. All
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