Thread by @Chrest_brett

In breast cancer, HER2 expression can stimulate glucose uptake (and NADPH production via pentose phosphate pathway & fatty acid oxidation)...which gives more weight to @drg1985 quote, that ⬆️glycolysis is a "consequence of cancer rather than the cause"
ncbi.nlm.nih.gov/pubmed/21508971

Seems like the Warburg effect by itself and a cancer cells use of glucose is insufficient to promote and explain cell replication? Indeed, "the multifaceted roles of oncogenes in metabolism are context-dependent"
2/n

Once again, there seems to be more weight towards looking at oncogenes and tumor suppressors first, perhaps something that Seyfried would disagree with?
3/n

Skimming this paper real quick, ncbi.nlm.nih.gov/pmc/articles/P… , and looking at all of the different gene mutations (ie, "m.10695G>A") ....I have no idea how Seyfried gets the idea that cancer "is not a genetic disease."

4/n

"The word “cancer” encompasses a large variety of diseases that are based on DNA alterations, making it difficult to establish general rules for treating different tumors."

Yes, Mitochondria might be a target for treatment, but that doesn't mean there's no genetic component? 5/n

Unfortunately, Seyfried feeds into a lot of the hoopla and woo - sad. He say's it's a mitochondrial disease....but what is wrong with the mitochondria?....GENETIC MUTATIONS.

6/n

Many factors, including genes and the tumor microenvironment, influence the Warburg effect. The point is that, once again, the pivotal role of oncogenes and tumor suppressor genes gets excluded from the various biased Warburg narratives.

7/n

ncbi.nlm.nih.gov/pubmed/25672512

Once again, "Taken together, while alterations in oncogenes and tumor suppressors drive inappropriate cell proliferation, they also concomitantly rewire and coordinate cellular metabolism to meet the biosynthetic demands of continuous cell division." 8/n
ncbi.nlm.nih.gov/pmc/articles/P…

More evidence that Warburg is secondary - a modifiable consequence & not cause:

"p53-deficient cells exhibit higher rates of glycolysis, more lactate production, & decreased mitochondrial respiration compared with wild-type, suggesting p53 suppresses the Warburg effect." 🤔 9/n

Hmmm, more nuance to the idea that we should decrease glucose? Cancer cells are smart and tricky - they can adapt, thus they can try and mutant to cope with limited glucose.
ncbi.nlm.nih.gov/pmc/articles/P…

10/n

Upregulation of glycolysis in cancer can be a result of gene transcription via highly expressed PFKFB3:

"MK2 promotes ⬆️ gene transcription & allosteric activation of PFKFB3...a key glycolysis-promoting enzyme"

(Stress stimuli = H2O2, UV radiation, growth factors, etc)

11/n

To highlight the role of genes again, here is the general structure of the PFKFB3 gene and protein. It is localized on chromosome 10p15.1.

(Sidenote: HER2 expression can also increase PFKFB3)

This supports at least some role of genetics 🤷‍♂️

12/n

nature.com/articles/sigtr…

Interesting. 😲
This supports, once again, that we shouldn't only be looking at glycolysis with regards to cancer and metabolism.

13/n

Of note, it seems as though transcription factor p53 can suppress PFKFB3.
ncbi.nlm.nih.gov/pmc/articles/P…

14/n

This adds even more nuance to the reliance on the Warburg Effect:
15/n

https://twitter.com/kevinnbass/status/1172325759462957057

We once again see tumor adaptation. Cancer is smart, relying on the keto diet and putting all your faith in the traditional Warburg model might not be...

https://twitter.com/kevinnbass/status/1172298066197544960

16/n

New study! Have not looked deeper into it yet, but the authors "argue that there is not one single oncogenic state, but rather a diverse set of oncogenic states." The Warburg Effect is not as clear cut as we once thought & cancer is not one disease:
sciencedirect.com/science/articl…

17/n

In a different study: Not all cancers response the same to the Warburg Effect and Ketones. In cells, ketones didn't interfere with turnover of glucose & lactate, neither affected cancer cell proliferation, or their sensitivity to chemo or radiation.
ncbi.nlm.nih.gov/pmc/articles/P…

18/n

Incredibly interesting reasons for why some tumor models may have accelerated growth with keto.

The "β-hydroxybutyrate paradox" could explain the contradictory results in the literature concerning the anti-cancer effects of β-OHB...

cancerandmetabolism.biomedcentral.com/articles/10.11…

19/n

On the note of cancer's ability to adapt, the absence of glucose or glutamine may just enable the cancer to upregulate pathways that allow cells to overcome this constraint.

20/n

I haven't read it yet, but a new review highlights the importance of p53 as a metabolic regulator.

21/n

https://twitter.com/MolMetab/status/1186731191266877441

The efficacy of Keto for cancer seems highly tumor dependant and again, based on the cancer's genotype...further supporting a genetic role. As promising as it may sound, evidence in humans is lacking & the evidence we do have is weak and or mixed.

22/n
ncbi.nlm.nih.gov/pubmed/29443693

Example of the challenges of a low carb diet in cancer patients. Compliance is difficult & the diet didn't seem to improve patient mortality. One patient who continued the diet no longer had cancer after 2.5 years...because he had the tumor removed.

23/n

ncbi.nlm.nih.gov/pubmed/27525031

Of note - Not all cancers prefer only glucose:

"While enhanced glycolysis & glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source."
ncbi.nlm.nih.gov/pmc/articles/P…

24/n

Mitochondrial mutations, Myc, and glutamine. And of course, further caveats other than glucose: "Cells also obtain energy through other pathways, such as fatty acid, lactate and ketone oxidation, as well as unidentified sources."

25/n
ncbi.nlm.nih.gov/pmc/articles/P…

Oncogenes can influence the metabolic phenotype. Mechanistically, K-Ras mutations "resulted in a significant decrease in mitochondrial respiration, accompanied by a decrease of mitochondrial transmembrane potential and an increase of ROS generation."

26/n
ncbi.nlm.nih.gov/pmc/articles/P…

Oncogene Myc can stimulate the Warburg Effect. As I've included before, oncogenes can influence the uptake of nutrients. Myc is know to regulate microRNAs. It can transcriptionally repress miR-23a & miR-23b and thus upregulate glutamine catabolism.

ncbi.nlm.nih.gov/pmc/articles/P…

27/n

Considerable interplay between Myc, HIF1, p53 and the Warburg Effect. This "has been described as the ‘triad’ of transcription factors responsible for the glycolytic phenotype in cancer"

ncbi.nlm.nih.gov/pmc/articles/P…

28/n

Example of mutant or inactive p53 and the influence on increased glucose:

29/n

Conclusion is well said. Not all cancer is the same & not all cancer metabolism is the same, nor does it stay one phenotype. Changes to the environment, therapeutic or otherwise, can allow for adaptation & thus an unfavorable environment can provide a selective advantage.

30/n

Support for the obvious metabolic role (and heterogeneity), but not in favor of the glycolytic "switch". Once again, an oversimplification.
nature.com/articles/d4158…

31/n

Example of adaptation with excess & limited glucose. "Importantly, the cellular doubling time of some cancer cell lines remained relatively unchanged, but others showed drastically prolonged doubling times under glucose limitation"
ncbi.nlm.nih.gov/pmc/articles/P…

32/n

This is a perfect highlight that makes the point that dysfunctional mitochondria can be responsible for cancer & pathological states, but it is most likely not the SOLE cause.
33/n

I believe I have stated over and over that cancer is not one disease. "Some prefer aerobic glycolysis, while others prefer oxidative phosphorylation."
34/n

This starts to get at the crux of the argument.
To suggest that somatic mutations do not cause or contribute to cancer & that it's only metabolism & mitochondria is misleading...because there's evidence for mitochondrial DNA somatic mutations & genetics/mutations in general.
35/n

Another study explaining that mitochondria aren't dysfunctional in all cancers:
sciencedirect.com/science/articl…

36/n

37/n

However, contrasting all of this, it seems that abnormal mitochondria are seen in glioblastoma. All of this research by Seyfried is mainly in GBM, thus, the metabolic and morphological characteristics are still tumor specific.
ncbi.nlm.nih.gov/pubmed/31025151

38/n

Dysfunctional mitochondria are not seen in all tumor cells. AND "high glycolytic flux in cancer cells does not mean impairment of OXPHOS."
ncbi.nlm.nih.gov/pmc/articles/P…

39/n

Of note, mutations are indeed one key player in all of this. K-Ras mutations and activation leads to mitochondrial dysfunction.
40/n

Found another 2 case reports showing the opposite of what Keto advocates promote.
41/n

https://twitter.com/Chrest_brett/status/1208651942395703296

In 2005, Seyfried questioned the role of somatic mtDNA mutations in brain cancer. He concluded that the mutations do not likely contribute to brain cancer in mice. In 2018, mtDNA mutations were frequently presented in human brain tumors.

ncbi.nlm.nih.gov/pubmed/29717568
42/n

Of important note, "Twenty-six (57.8%) patients showed ND3 10398A>G mutation in their tumor specimens, in which 26.9% of these mutations were heterozygous mutations." This mutation affects complex 1 and ROS production.
43/n

In 2018 again, "results suggested that somatic mtDNA mutations may cause mitochondrial dysfunction and affect chemoresistance of HCC cells."
ncbi.nlm.nih.gov/pubmed/29463347
44/n

Characteristics of oncocytic (mitochondria-rich) tumors with functional versus defective mitochondria - "those that have mitochondrial defects that are benign, and those where mitochondrial function remains intact that are malignant"
45/n

Wow. "The Oncojanus Paradigm of Respiratory Complex I"

"..mitochondrial respiration is necessary for tumor progression & escape from dormancy of cancer cells..it has been found that the severity of CI dysfunction influences [growth, resistance, etc.]"

ncbi.nlm.nih.gov/pubmed/29735924

"The Warburg hypothesis, postulating that mitochondrial dysfunction in malignant cells forces them to generate energy (ATP) through glycolysis thus appears to be incorrect."
ncbi.nlm.nih.gov/pubmed/22664330

47/n

Starting to read this newer review on the topic. Proponents don't acknowledge this fact....
ncbi.nlm.nih.gov/pubmed/30822194

Mitochondria can accumulate mtDNA mutations & mainly leads to complex I (CI) deficiency; as per the title of the study, "the clonal expansion of mtDNA is associated with tumor formation." In the following study, most of these mutations were somatic.
academic.oup.com/hmg/article/17…

49/n

New review on Warburg:

"The widespread clinical use of (FDG) positron emission tomography contributes to the perception of a glycolytic switch, but this tracer reports glucose uptake without providing any information about glucose’s metabolic fates"
nature.com/articles/s4225…

50/n

"..there is little evidence supporting a glycolytic switch in these tumours. Even when glucose uptake is activated, oxidative metabolism persists in the tumour and may exceed that in adjacent non-malignant tissue."
51/n

"Given the importance of mitochondria in cancer, the oft-cited ‘glycolytic switch’, taken to be synonymous with the Warburg effect, is misleading and probably not very useful as a general concept"

Well done @RJDLab and Nav

52/n

Another conflicting issue with the common Seyfried narrative, "Reduction of fat or fatty acid β oxidation may provide clinical benefit to TNBC patients." Do I think fat causes cancer? No. Just like I don't think sugar causes cancer.
ncbi.nlm.nih.gov/pubmed/26923594
53/n