MY CRITIQUE OF THE PDF EPIGENETICS IN CANCER and the EPIGENETIC COMMUNITY IN GENERAL. I was surprised to find in it this statement it puts epigenetics at the very heart of cancer biology as if purely spontaneous alterations in methylation are solely responsible for cancer, surely a huge bias imposed by the epigenetics researcher. This idea seems to be reinforced by the heterogeneity of cancer cells, as if diversity indicates spontaneity or randomness. Genetic mutations are alleged to be SECONDARY to altered methylation which renders certain hot spots vulnerable to mutation. No mention whatsoever in the paper is made to the HIFs which respond to hypoxia by inducing all of the attributes of cancer. HIFs IN CANCER PROGRESSION. (Semenza. PDF Attachment) This is from an excellent paper on hypoxia, with several exceptions. The text in brackets is mine. HIFs play key roles in many crucial aspects of cancer biology including 1. angiogenesis, (the growth of blood vessels to accommodate the growth of a tumour) 2. stem cell maintenance, (preventing the cell from fully differentiating to a mature cell going onto terminal differentiation, ie apoptosis or cell suicide) 3. metabolic reprogramming (from oxidative metabolism to non oxidative fermentation of glucose), 4. autocrine growth factor signalling (self signalling rather than paracrine {from cells next door}, juxtacrine {close by}, or endocrine {distant} signalling, 5. epithelial-mesenchymal transition or EMT (not limited to a single or monolayer of cells, eg those lining a milk duct), 6. invasion (of surrounding tissue), 7. metastasis (cells moving into nearby bloodvessels then circulating to set up a secondary tumor at a a distant site), and 8. resistance to radiation therapy and chemotherapy. Yet to quote the paper Epigenetics in Cancer. “Cancer is usually viewed as a complex group of multiple disorders that are mostly driven by somatic mutation and that involve the accretion of ten proposed properties: enhanced proliferation, growth suppressor evasion, anti-apoptosis, replicative immortality, angiogenesis, inflammation, altered metabolism, genomic instability and metastasis signalling117. We suggest that epigenetic disruption lies at the heart of all of these processes and that mutations enable and collaborate in these disruptions” As the HIFs appear to be transcription factors for methyltransferases, then I would suggest that HYPOXIA plays the primary role in the induction and progression of cancer, the HIFs the secondary and with epigenetic changes to a large extent instigating genetic changes, including mutations, last.. ncbi.nlm.nih.gov/pubmed/22266372 mcb.asm.org/content/31/16/3339 HETEROGENEITY IN CANCER CELLS. As there appears to be overwhelming evidence that oxygen tension is the primary differentiation factor in cells then I would suggest that it is the oxygen gradient between the those cells closest to the blood vessels having the greatest O2 tension and thus being the least dedifferentiated and those in the most distal or in the most hypoxic zone being the most dedifferenyiated. PLURIPOTENCY. Loss of methylation at pluripotency loci. Once again this statement implies spontaneous dysregulation. I would suggest that this phenomenon is is any thing but dysregulation but is simply the cell in question dedifferentiating to become increasingly a blastocyst phenotype and thus pluripotent undergoing phased alterations in methylation as it proceeds backwards. CONCLUSION. By ignoring all other aspects of biology the epigeneticists view is hopelessly skewed in favor of, well, epigenetics to the exclusion of everything else, biochemistry, endocrinology, hematology, general physiology, etc. etc. etc. Research for the sake of the researcher. If the HYPOXIA results from STRESS induced vasoconstriction, then the stress can be dealt with by the patient, eg biofeedback or meditation of some kind, paying bills, getting rid of religion, getting a divorce etc. No funding from pharmaceutical companies or NH&MRC. Perhaps this explains your reticence to give me membership of the AEA or reply to all of my other emails. I thought that it was solely lack of courtesy and ignorance of anything other than molecular biology. Forgive me for being so naive.
Posted on: Sat, 25 Oct 2014 12:21:21 +0000
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