Make no Mistake. A standard Raw diet and a Ketogenic Diet formulated for cancer are two ENTIRELY different diets. Standard raw diets are still giving cancer much of what it needs to thrive. Whereas a Ketogenic diet is depriving cancer of some of the tools it needs to thrive.

This is a great presentation by Angela Poff PhD. If you’re like me, it helps to read and then re-read technical information like this. Simply watching this video, the average person may miss a whole lot of information because it will go right over your head. So, I painstakingly made my own “show notes” from her you tube video on the ketogenic diet, how it can be beneficial for cancer. What is trying to be targeted, WHY tumors behave the way they do, and HOW we think ketosis can influence these phenotype’s. The notes are transcribed verbatim for the vast majority of the presentation, some of it I had to condense down.

I added hyperlinks on the “scientific” words that not everyone may understand what they mean. so click on those links to learn more about those !

the video is right below, and my “notes” are right underneath.

 

What, Why & How ketogenic diet for Cancer

1. What are the aspects of cancer behavior and cancer metabolism that we are trying to target?
2. Why do tumors behave like this in the first place?
3. How do we think that ketosis can influence those phenotypes (behaviors) of the cancer ?

all credit/rights reserved to Angela Poff PhD

Research associate south Florida USF
original YouTube interview can be found here

What are we trying to target with cancer is this metabolic phenotype. Cancer exhibits a different type of metabolism, we call this the Warburg effect, this is one type of metabolism that cancer exhibits. And the Warburg effect really refers to this abnormal situation where tumors will preferentially, even in the presence of oxygen, utilize these glycolytic and fermentation metabolic pathways.
So when we consume energy metabolites like glucose they get taken up into the cells, they go through a variety of metabolic pathways to get turned into energy. It is ABNORMAL for most of our healthy cells to choose to ferment that pathway-unless they have to. So usually oxygen is the limiting step in that process. If oxygen is not available, then our cells will choose to undergo fermentation.  But normally most healthy cells don’t do this as a means to make most of their energy. But this is actually what the Warburg effect is. Tumors quite often take in lots of glucose and shipping them through the fermentation pathways instead of shipping them all the way into the mitochondria to make energy that way. That is what the Warburg effect is.

Why do tumors do this? It seems odd that tumors would prefer to use the fermentative pathway to make energy. Fermentation to make energy is a really inefficient way to make energy. You only make a couple of ATP per glucose molecule that get consumed. Where if you were to instead fully utilize those mitochondrial metabolism pathways you would make a lot more energy. But energy is only half the story. If you think about a growing tumor, that tumor has to not only have energy to provide the fuel to run these new pathways , but it also needs new building blocks for the tumor. Meaning the tumor has to grow new lipids, DNA, and proteins in order to actually grow new tumor cells and tissue. So that’s kind of both sides of the coin that really need to be fulfilled to allow this unbridled growth that is characteristic of tumors. And the Warburg metabolism , the Warburg effect, really bestows many effects onto the tumor to help satisfy those conditions. So while you’re not making as much energy through the energy pathways of the Warburg metabolism, in fact you’re actually being able to instead of completely oxidizing those glucose molecules all the way through the mitochondria where we would wind up breathing off all those carbons of glucose of co2, instead of doing that we can make a little bit of energy in those primitive pathways of fermentation and then take those glucose carbons and ship them towards new biomass synthesis. So what that means is we’re taking those glucose carbons and now we’re making new protein, new lipids to form the new cell membranes, new DNA so that the tumor can grow. So many research scientists think that a primary reason this is a really common feature of tumors, is in fact this is an adaptive phenotype of tumors. The tumor realizes that there is actually a lot of benefits to adapting this metabolic scenario. It is true that in many proliferating tissues we actually see this similar metabolic phenotype, such that if a tissue is proliferating rapidly you see more of a glycolytic phenotype than an oxidative phenotype. So when we look at the Warburg effect we see that there is actually benefits that it bestows onto the tumor , which really makes it a good therapeutic target. Because if this type of metabolism is being used preferentially by the tumor in order to support this rapid unbridled growth , then we can understand if we can block that metabolic phenotype some other way, that maybe we can reduce some of the those benefits that the tumor was experiencing. There’s also suggestions that this Warburg effect is also possibly in some cancers, downstream of metabolic dysfunction. Such that, rather then the tumor choosing to perform Warburg metabolism because it is beneficial to the tumor, maybe to some degree it is having to do this BECAUSE the mitochondria are damaged. And this is what some individuals call the metabolic theory of cancer , and there certainly is a lot of evidence to support that mitochondrial , morphology structure , is often very abnormal in tumors and possibly this is one reason that the Warburg effect also happens. So regardless of WHY we think the Warburg effect is occurring in tumors, everyone pretty much agrees that is seems to be present to some degree in most tumors. Which again, makes it a really good therapeutic target so this is something that we can try to target and possibly could be beneficial as a therapeutic target  for many different cancer types.  And that’s one big reason we’re interested in trying to target this phenotype.

8:45
So we talked about why tumors have this abnormal metabolism but why do we think ketosis could impact it ?

What are some of the metabolic changes that occur on a ketogenic diet?
Glucose lowers.

and that is exactly what researchers suggested early on could be a good reason to study the ketogenic diet for. And in fact we do see that there is clinical data and pre-clinical data that under the context of the ketogenic diet, tumors take up less glucose.  

now remember, the metabolism of tumors, that Warburg effect, accentuates these glycolytic and fermentative pathways. And glucose is that substrate that feeds into those pathways. So right off the bat this is an obvious reason to start suggesting that maybe we should at least study that the ketogenic diet might impact tumors simply by reducing the availability of the primary substrate (sugar) for this metabolic phenotype.

My notes: we have to remember that this is being discussed for humans, not dogs. So when she mentions that glucose levels don’t decrease that much, this is different in dogs.
in the dogs we can very easily reduce glucose levels by more than 50%! A typical glucose reading on a dog eating kibble is easily over 100mg/dl, whereas with my own personal experience feeding keto to my dog, her glucose levels got as low as 30 mg/dl. That’s a 70% reduction !

11:22 INSULIN .
Insulin is a growth factor and it’s a very potent growth factor that is very important for many cancers , so a lot of tumors will have up-regulate receptors on their cell membranes, same for insulin like growth factor (IGF receptors) and we see over-activation of the insulin Pi3 kinase AKT signaling inside the cancer cells. And that pathway will help promote the cells proliferation which means they promote the cells ability to divide, to make new cancer cells and also stop responding to signals to induce apoptosis or cell death. So, insulin, again is another aspect of why a ketogenic diet could be useful for a treatment of cancer, because many tumors thrive on excess insulin signaling. We know on a ketogenic diet that insulin is ALSO reduced, and we’re eliminating the macro-nutrient that most spikes our insulin (carbohydrates) .

Lactate production is another aspect of ketogenic therapy that may explain, in pre-clinical models at least, why we do see some therapeutic benefit from a ketogenic diet. Remember that I said glycolytic fermentative metabolism is often very important for tumors and what the end product of that is, is lactate. Lactate is an acid and it gets shipped out of the cancer cell into the tumor micro-environment, and it acts there to decrease the PH of the tumor micro-environment and actually promote the aggressive phenotype of the tumor. So lactate is known to really contribute to the aggressive capacity of the tumor, specifically its ability to invade the local tissue around the tumor and potentially access vasculature in order to metastasize and form a tumor somewhere else in the body. So again, a ketogenic diet is reducing the flux through this glycolytic fermentative pathway such that maybe less lactate is being produced and then maybe less lactate is getting out into the tumor micro-environment.

13:59 Decrease in inflammation
We’ve known for a long time that the metabolic state of ketosis is associated with a reduction of inflammation. And within the past few years we’ve actually began to uncover a lot more mechanistic explanations as to why that may be happening. Part of it is most certainly a reduction of glucose. But actually the KETONES themselves could be playing an important role in this story too. The major ketone beta-hydroxybutyrate  (BHB) was described just a few years ago as an HDAC inhibitor (Histone deacetylase inhibitors) this actually is an aspect of tumor metabolism signaling where you can actually influence the gene expression of the tumor. So that is going to be impacting gene expression, and theres a large variety of genes that influence inflammation and oxidative stress which is also very tightly related to inflammation in the tumor. So we know that ketones, and the primary ketone beta-hydroxybutyrate can actually impact those effects on the tumor on the signaling level. So the primary way tho, that beta-hydroxybutyrate (BHB) seems to impact inflammation on a signaling level that we currently know of , is its impact on something called the inflammasome so the nlrp3 inflammasome is a component of the innate immune system that actually gets activated in chronic diseases associated with inflammation but also within the tumor micro-environment and it incites inflammation. So it was described a few years ago that beta- hydroxybutyrate can actually inhibit the assembly of the inflammasome and therefore may explain why we see a reduction in inflammation associated with a metabolic state of ketosis.

16:11 Ketones and ketosis could influence gene expression

I mentioned that beta-hydroxybutyrate can function as an endogenous Histone deacetylase inhibitor, so HDAC inhibitors are actually a class of anti-cancer drugs , so there are synthetic ones on the market and currently being utilized in various cancers and its because of their ability to basically reopen up expression of certain tumor suppressor genes within the tumor in a way that would basically put some brakes on the tumors growth and survival. Here we see the primary metabolite that gets elevated in response to a ketogenic lifestyle, beta-hydroxybutyrate (BHB) will actually be able to influence gene expression. Now, theres not really been much research specifically in tumors themselves looking at the ability of  BHB to influence gene expression through this mechanism, but there is some work showing that under the context of the ketogenic diet, the gene expression profile of the tumor changes. Dr. Adrienne Sheck based out in phoenix , she has done some incredible work showing that when you look at the gene expression of a tumor from an animal that was fed a ketogenic diet, it actually looks a little more like healthy tissue  than tumorous tissue , so suggesting that the diet is somehow affecting the genes expression. So that was something that she had shown a few years ago and now we know that ketones themselves can influence gene expression, so again this where we’re seeing some of these pockets of data come out that have not necessarily been proven to be directly causative or explain what we’re seeing, but suggestive and supportive that this idea that ketosis may be a potential therapy for a variety of reasons. And one of the things that one of the studies looking at the effects of BHB as an HDAC inhibitor actually showed that of the targeted genes that were influenced by BHB actually were related to antioxidant capacity , so the study showed that endogenous antioxidants genes like catalase , Super Dioxide Dismutase (SOD) were actually upregulated in response to  BHB signaling  but when we take that information and think about what that could mean, it could mean that we have some kind of impact on the oxidative stress of the tumor and this is actually another theoretical as to why ketosis could be beneficial. Essentially, oxidative stress pays a really important role in tumors. Elevated levels actually promote the tumors growth and progressive capacity but it also used to overproduce oxidative stress in response to things like radiation therapy so it’s a little bit of a double edge sword for tumors. Its very complicated but we know that ketosis has the potential to impact the oxidative stress level within the tumor and because the vast majority of the pre-clinical research currently suggests that often ketogenic diets have a inhibitory effect on tumor growth, we think that this is another promising avenue to at least explore and see if this is impacting, in certain cancers, the therapeutic response.

19:59 ENHANCING ANTI-tumor  IMMUNITY

Another potential mechanism is actually by enhancing anti-tumor immunity. So our immune system has normal potential and capability to suppress tumor origination and tumor growth and when the immune system kind of loses control of that system is when that tumor can kind of evade the immune system and grow into a cancerous lesion. There’s a lot of research right now in immunotherapies for cancer trying to develop ways to basically aid our own immune systems capacity to fight the tumor. Now another really incredible piece of work  from Dr.Scheck a few years ago was showing that in the context of a mouse glioma model, a mouse brain tumor model, these animals that were put on a ketogenic diet basically had improved anti-tumor immunity. So we saw that basically the immune system cells were better able to detect and attack the tumor and the tumor wasn’t quite as capable at suppressing the immune systems response onto the tumor. So in that model it actually seen that this is a really important part of the story because when you knocked out that capacity you didn’t see that same level of therapeutic effect of the ketogenic diet.21:26 IMPACT ON THE WHOLE PHYSIOLOGY   

Another potential mechanism that people are studying is not necessarily impact on tumor directly or tumor growth, but actually the impact on the whole physiology. Ketosis is known to be a muscle sparing effect. Evolutionary it was very important for us to be able to access our stored body fat, because that’s where we keep most of our calories, and make these water soluble ketone molecules that can cross the blood brain barrier to feed the brain during starvation. Because if the brain was required to rely on glucose, we don’t have a whole lot stored in our bodies, we have glycogen, maybe a couple days worth possibly, of glycogen available that could be used to fuel the brain if it HAD to have glucose only and then we would really have to start breaking down our muscles . so you probably know that about half of our protein can be converted into glucose. So if we DIDN’T have this capability of making ketones to fuel the brain during starvation we would have to break down our muscle protein and that would be very negative, even in the short term within a couple weeks you could probably see cardio respiratory muscle failure in response. But thankfully we are able to convert our stored fat into ketones which then fuels the brain in those situations. So probably because of this evolutionary adaptation to utilizing ketones in a catabolic state, in a situation where we need to stop breaking down muscle, there are now some evidence that ketosis itself may actually prevent this, so ketones may be a signaling mechanism can potentially prevent muscle breakdown, or possibly-again in a catabolic state- actually promote muscle synthesis. So this is relevant to cancer because in late stage cancer you often see cachexia , this is wasting of muscle and fat , muscle is really the most important thing that we’re worried about. And cachexia is a direct contributor to morbidity and mortality. So its interesting that ketosis could have a beneficial impact on the whole systems physiology to preserve muscle mass.

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