Cancer and ketogenic diets

[JonDoeUK]

Hypoxia is a critical hallmark of solid tumors and involves enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis. Hyperbaric oxygen (HBO) treatment has for centuries been used to improve or cure disorders involving hypoxia and ischemia, by enhancing the amount of dissolved oxygen in the plasma and thereby increasing O2 delivery to the tissue. Studies on HBO and cancer have up to recently focused on whether enhanced oxygen acts as a cancer promoter or not. As oxygen is believed to be required for all the major processes of wound healing, one feared that the effects of HBO would be applicable to cancer tissue as well and promote cancer growth. Furthermore, one also feared that exposing patients who had been treated for cancer, to HBO, would lead to recurrence. Nevertheless, two systematic reviews on HBO and cancer have concluded that the use of HBO in patients with malignancies is considered safe. To supplement the previous reviews, we have summarized the work performed on HBO and cancer in the period 2004–2012. Based on the present as well as previous reviews, there is no evidence indicating that HBO neither acts as a stimulator of tumor growth nor as an enhancer of recurrence. On the other hand, there is evidence that implies that HBO might have tumor-inhibitory effects in certain cancer subtypes, and we thus strongly believe that we need to expand our knowledge on the effect and the mechanisms behind tumor oxygenation. Hyperbaric oxygen therapy and cancer

[Hveragerthi]

Originally Posted by JonDoeUK

Dr Thomas Seyfried, Boston College cancer researcher

I know about this study. The study has serious problems. I wrote a letter to the editor of the journal regarding the flaws in the study. I discussed these flaws with Dr. Richard Veech at the NIH, who concurred with my concerns.

Unfortunately, these types of studies will occasionally appear in the literature mainly because the reviews, who know about molecular biology, are unfamiliar with the old literature on energy metabolism.

Here’s Dr. Seyfried’s letter that never got published in the journal:

October 20, 2010
Dr. M.V. Blagosklonny
Editor-in-Chief, Cell Cycle
Roswell Park Cancer Institute
Buffalo, NY

Dear Dr. Blagosklonny,

I am writing in reference to an article that appeared in the September 1 issue of Cell Cycle by Bonuccelli, et al., entitled: “Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism”.

The authors have made serious errors in their data interpretation and the conclusions of their article. There is no evidence in the biochemical literature that ketone bodies can be made from pyruvate in fibroblasts. It is common knowledge in biochemistry that ketone bodies are derived from fatty acid beta-oxidation in liver mitochondria. This information is also presented in the cited articles from Veech and co-workers.

The authors present evidence showing that the ketone body 3-hydroxy-butyrate does not enhance lung metastasis (Fig. 4A), yet the paper title indicates that ketones fuel tumor growth and metastasis. The paper title and abstract are therefore misleading.

Furthermore, no evidence was presented in the paper showing that the MDA-MB-231 cells can survive using only L-lactate or ketone bodies as metabolic fuels. While the authors recommend that it may be unwise to use lactate-containing i.v. solutions in cancer patients, the authors should also recognize that lactate is metabolized to glucose in the liver through the Cori cycle. It is well documented that glucose can stimulate tumor growth. No information was provided on food intake or body weights of the treated and control mice. No information was presented on blood glucose or ketone levels in the tumor bearing mice used in the study. It is difficult to assess the effects of drug injections without this information. Finally, no evidence was presented showing that OxPhos is operational in the MDA-MB-231 tumor cells. Gene expression profiles do not provide the required biochemical and physiological evidence for establishing operational OxPhos in tumor cells.

Unfortunately, the author’s provide misinformation. Such information will cause confusion in the field. I am surprised that the reviewers of this paper did not mention these issues in their critique, as some of the evidence and statements presented contradict basic principles of biochemistry as specified in any general textbook on the subject. If further evidence is needed to support my concerns, I would suggest contacting Drs. Richard Veech, Theodore B. VanItallie and Jong Rho.

Sincerely,
Thomas N. Seyfried, Ph.D.

Do Ketones Fuel Cancer? The Low-Carb Experts Respond « Jimmy Moore's Livin' La Vida Low Carb Blog


Also The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer

And a different view of Dr. Seyfried's work:

Ketogenic diet does not “beat chemo for almost all cancers” « Science-Based Medicine

So who is right? Does it really matter considering the fact that as pointed out before glucose IS NOT the only fuel for cancer cells? For example, cancer cells can use amino acids supplied in high amounts by the ketogenic diet. So will simply reducing glucose intake stop cancer? I doubt it.


And that is not the only study claiming ketones are used as a cancer cell fuel source. What about:

Cell Cycle. 2010 Sep 1;9(17):3485-505. doi: 10.4161/cc.9.17.12721.
The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.





Cell Cycle. 2012 Jun 15;11(12):2285-302. doi: 10.4161/cc.20718. Epub 2012 Jun 15.
Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production.





Cancer Biol Ther. 2011 Dec 15;12(12):1101-13. doi: 10.4161/cbt.12.12.18703. Epub 2011 Dec 15.
Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth.





Cell Cycle. 2012 Nov 1;11(21):3956-63. doi: 10.4161/cc.22136. Epub 2012 Sep 19.
Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells.



All of these studies discuss the use of ketones to fuel cancer growth.


And in:


Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and Metastasis via Oxidative Stress, Mitophagy, and Aerobic Glycolysis

The study states "Note that in this model, autophagicglycolytic fibroblasts secrete both recycled and high-energy nutrients (such as ketone bodies and L-lactate, as well as glutamine). Then, cancer cells use these nutrients to fuel oxidative mitochondrial metabolism, to generate large amounts of ATP and protect themselves against apoptosis.


So here is a study also claiming that cancer fibroblasts do in fact secrete ketones, which Dr. Seyfried denies. So Dr. Seyfried is right and the rest of the world is wrong? Or is it Dr. Seyfried is wrong? Seems the evidence is leaning to the later.

[Hveragerthi]

Originally Posted by JonDoeUK

Hypoxia is a critical hallmark of solid tumors and involves enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis.

Not quite true. Studies have proven that malignant tumors have not only well oxygenated regions but hypoxic regions as well. So hypoxia IS NOT a hallmark of solid tumors. In fact, from your link you supplied for a review, not a study:

"Solid tumors often contain areas subjected to acute or chronic hypoxia [1],"

The part of the quote that says "areas" shows that tumors are not completely hypoxic as I pointed out.

As far as cell survival this is an association, not a cause. It is the internal alkalinity of cancer cells that promote their survival. Alkalinity induces hypoxia primarily by inhibiting oxygen release from hemoglobin. As I said though, not all sections of solid tumors are hypoxic. Some areas are well oxygenated, which is why studies have shown that cancer cells derive at least 50% of their energy production from oxidative phosphorylation (OxPHos), which is oxygen dependent.

Angiogenesis is stimulated initially by a lack of oxygen diffusion during the initial tumor growth. When diffusion can no longer bring oxygen to the center of the tumor (anoxia, not hypoxia) the center of the tumor dies leading to the release of angiogenic growth factors such as insulin growth factor and vascular endothelial growth factor. The role of angiogenesis is to INCREASE the oxygen availability to the cancer cells promoting their growth and survival.

Glycolysis is once again driven by the high internal alkaline pH of cancer cells, not the hypoxia. By the way glycolysis can occur in the presence or absence of oxygen.

Alkalinity driving cancer cell growth and malignant transformation:

Role of the Intracellular pH in the Metabolic Switch Between Oxidative Phosphorylaiton and Aerobic Glycolysis-Relavance to Cancer. Cancer 2011;2(3):WMC001716

Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEBJ 2000 Nov;14(14):2185-97

Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proc Natl Acad Sci USA 1990 October; 87(19): 7414–7418

31P NMR analysis of intracellular pH of Swiss Mouse 3T3 cells: effects of extracellular Na+ and K+ and mitogenic stimulation. J Membr Biol 1986;94(1):55-64

Extracellular Na+ and initiation of DNA synthesis: role of intracellular pH and K+. J Cell Biol 1984 Mar;98(3):1082-9



Metastases has NOTHING to do with hypoxia. Metastases is the result of proteolytic enzymes such as hyaluronidase, which breaks down hyaluronic acid allowing cancer cells to spread. These enzymes are acid dependent and are therefore activated by the acidic hydrogen ions excreted by the cancer cells to maintain their internal alkalinity.

Originally Posted by JonDoeUK

Hyperbaric oxygen (HBO) treatment has for centuries been used to improve or cure disorders involving hypoxia and ischemia, by enhancing the amount of dissolved oxygen in the plasma and thereby increasing O2 delivery to the tissue.

But not cancer since cancer cells are highly reliant on oxygen and have a higher affinity for oxygen than healthy cells:

Reliance of cancer cells on oxygen:

Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect. PLoS One 2009 Sep 15;4(9):e7033

Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim Biophys Acta 2011 Jun;1807(6):552-61

Comparison of Metabolic Pathways between Cancer Cells and Stromal Cells in Colorectal Carcinomas: a Metabolic Survival Role for Tumor-Associated Stroma. Cancer Res January 15, 2006 66;632

Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res June 1, 2004 64; 3892



That cancer growth is inhibited by low oxygen levels an die in the absence of oxygen:

Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS One 2009 Sep 15;4(9):e7033

Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment. Cancer Res 2005 Apr 15;65(8):3171-8

Relationship between oxygen and glucose consumption by transplanted tumors in vivo. Cancer Res 1967 Jun;27(6):1041-52



Death of cancer cells by lack of oxygen and angiogensis stimulation to increase the growth rate of tumors by increasing oxygen levels to the tumor:

Computational models of VEGF-associated angiogenic processes in cancer. Math Med Biol 2012 Mar;29(1):85-94

Blood Flow, Oxygen Consumption, and Tissue Oxygenation of Human Breast Cancer Xenografts in Nude Rats. Cancer Res 47, 3496-3503, July 1,1987

A Mathematical Model for the Diffusion of Tumour Angiogenesis Factor into the Surrounding Host. Tissue Math Med Biol (1991) 8 (3): 191-220

The History of Tumour Angiogenesis as a Therapeutic Target. University of Toronto Medical Journal Vol 87, No 1 (2009)


The higher affinity for oxygen by cancer cells than healthy cells:

Utilization of Oxygen by Transplanted Tumors in Vivo. Cancer Res 1967;27:1020-1030

Growth-related changes of oxygen consumption rates of tumor cells grown in vitro and in vivo. J Cell Physiol 1989 Jan;138(1):183-91


In addition hyperbaric oxygen therapy (HBOT) stimulates angiogenesis. This is one of the ways it helps to heal certain conditions. In cancer treatment though one goal is to BLOCK angiogenesis, not promote it. Even the link you provided points out the role of oxygen for inducing angiogenesis:

"As oxygen is believed to be required for all the major processes involved in wound healing, including resistance to infection, activation of fibroblasts, collagen deposition, angiogenesis, and epithelization [14]"

Originally Posted by JonDoeUK

Studies on HBO and cancer have up to recently focused on whether enhanced oxygen acts as a cancer promoter or not. As oxygen is believed to be required for all the major processes of wound healing, one feared that the effects of HBO would be applicable to cancer tissue as well and promote cancer growth.

Yes it does as I have already pointed out several times.

Originally Posted by JonDoeUK

Furthermore, one also feared that exposing patients who had been treated for cancer, to HBO, would lead to recurrence. Nevertheless, two systematic reviews on HBO and cancer have concluded that the use of HBO in patients with malignancies is considered safe. To supplement the previous reviews, we have summarized the work performed on HBO and cancer in the period 2004–2012. Based on the present as well as previous reviews, there is no evidence indicating that HBO neither acts as a stimulator of tumor growth nor as an enhancer of recurrence. On the other hand, there is evidence that implies that HBO might have tumor-inhibitory effects in certain cancer subtypes, and we thus strongly believe that we need to expand our knowledge on the effect and the mechanisms behind tumor oxygenation. Hyperbaric oxygen therapy and cancer

Also from your link you provided:

"The studies performed on HBO and cancer are complex due to a wide range of experimental designs and
treatment regimes."

And

"Studies of apoptosis in neoplasms treated with HBO are limited. Two in vitro studies on mammary and oral cancer cells, respectively, showed no change in apoptosis after HBO [18, 19].

So they have limited studies, in fact two studies that were conducted in Petri dishes, not in actual human studies. Petri dish studies do not always correlate to what actually happens in the body since the Petri dish does not have a metabolism. And the results were no change in apoptosis in cancer cells.

And

"However, the picture is complex, and mechanistic studies are required before any final conclusions can be drawn."

I am not going to list all the problems with posting this link as evidence, but the point is that they state throughout the link that the research results for different tests were conflicting. Therefore, it is to early to be reaching conclusions on such limited evidence.