How Cancer Begins
How Cancer Might Arise in Normal Cells
Cancer starts in normal cells. It is generally thought to be a result of DNA damage which contains oncogenic mutations that switch on unrestrained proliferation. As part of this process there is a metabolic change from mitochondrial oxidative phosphorylation to aerobic glycolysis.
What has not been fully considered is the nature (phenotype) of the normal cells which make it possible for cancer to arise in them. To take this into account, I propose a 'seed and soil' hypothesis for the initial changes in carcinogenesis rather than a cataclysmic mutational event afflicting an otherwise normal cell.
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It has been reported that knockdown experiments in mice convincingly show that normal expression of the CDK4 gene is a necessary part of the pre-cancer phenotype. Thus, in at least one case, normal gene expression at the outset of carcinogenesis is necessary for the process to advance.
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There is also a body of evidence that expression of the PKM2 isotype is an important characteristic of cancer cells. Shikonin, a drug derived chemically from lithospermum erythrorhizon, and a specific inhibitor of PKM2 can prevent carcinogenesis in a similar way to that seen with CDK4 knockdown (as reported by Wenjuan Li et al. in the journal Molecular Carcinogenesis in 2014).
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In addition knockdown of PKM2 activity by specific inhibitory RNAs results in apoptosis (Reported by Beibei Chu et al in Molecular Medicine Reports 2015 and several other workers) which implies that apoptosis does not occur in cells which do express the PKM2 isotype. In this case specific knockdown of the PKM2 isotype leaves only expression of PKMI which is presumably responsible for the apoptosis.
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I propose that carcinogenesis starts by an episode of DNA damage in normal tissue cells that express the PKM2 isotype rather than the PKMI, and that internal evolution selects these transformed cells to give rise to a tumour that is composed homogeneously of PKM2 positive cells.
So why do I believe cancer starts by DNA damage including at least one oncogenic mutation in PKM2 cells?
It is because these are the cells where CDK4-NKR may potentially act to turn down ATP production and prevent apoptosis. DNA damage occurring in PKMI cells, if it caused malignant transformation, would lead to marked apoptosis powered by the abundant ATP supplied by mitochondrial oxidative phosphorylation. (This amount of ATP would be too much to be modulable by CDK4-NKR). In addition PKM2 and not PKMI is the target of CDK4-NKR.
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Thus in my 'seed and soil' hypothesis of malignant transformation 'soil' is composed of normal cells with normal CDK4-NKR, which at the same time express the PKM2 isotype.
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The seed is DNA damage which includes at least one oncogenic mutation that will switch on cell division.
Avoiding Apoptosis
CDK4 is the cyclin dependent kinase which is upregulated at the start of cell division and joins with cyclin D to form an active holoenzyme which phosphorylates the retinoblastoma protein leading to upregulation of all the downstream proteins needed to carry out cell division. Once this process starts a multiplicity of other genes influencing cell cycle progression are switched on, including cyclin dependent kinase 2 and cyclin dependent kinase 1.
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It is only CDK4, however, that is important for carcinogenesis because only CDK4 has the NKR region containing the amino acid sequence PRGPRP that can down- regulate PKM2 and keep ATP low enough to avoid the apoptosis which is the cell's crisis response to DNA damage.
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The effect of impaired DNA repair genes as happens with BRACA which has over three thousand five hundred dysfunctional germline mutations, would be to increase the probability of DNA damage. This would also be expected to occur sooner, explaining the early onset of familial tumours such as breast cancer. Similar arguments would apply to other germline mutations which predispose to cancer.
The effect of the down regulation of PKM2 by CDK4-NKR would be expected to allow the cumulative sequential mutations in the absence of apoptosis which can explain the occurrence of aneuploidy which is one of the signatures of cancer.