Abstract
Several major risk factors for cancer involve vascular oversupply of energy to affected tissues. These include obesity, diabetes and chronic inflammation. Here, we propose a potential mechanistic explanation for the association between energy oversupply and cancer risk, which we call the metabolic cancer suppression hypothesis: We hypothesize that oncogenesis is normally suppressed by organismal physiology that regulates and strictly limits normal energy supply to somatic cells, and that this protection is removed by abnormal oversupply of energy. We evaluate this hypothesis using a computational model of somatic cell evolution to simulate experimental manipulation of the vascular energy supply to a tissue. The model simulates the evolutionary dynamics of somatic cells during oncogenesis. In our simulation experiment, we found that under plausible biological assumptions, elevated energy supply to a tissue led to the evolution of elevated energy uptake by somatic cells, leading to the rapid evolution of both defining traits of cancer cells: hyperproliferation, and tissue invasion. Our results support the hypothesis of metabolic cancer suppression, suggesting that vascular oversupply of energetic resources to somatic cells removes normal energetic limitations on cell proliferation, and that this accelerates cellular evolution toward cancer. Various predictions of this hypothesis are amenable to empirical testing, and have promising implications for translational research toward clinical cancer prevention.
Highlights
Background and objectivesSeveral major risk factors for cancer involve vascular oversupply of energy to affected tissues
We undertake here to formalize this hypothesis in a computational model to study its dynamics and to evaluate how well it conforms with the principles of clonal evolution by natural selection, and with recognized patterns in cancer epidemiology
We propose the metabolic cancer suppression hypothesis as a potential mechanistic explanation for the association between cancer risk and vascular oversupply of energy to tissues, which is present in each of the four conditions listed in Supplementary Table S1
Summary
It is generally accepted that cancer develops through somatic mutation and clonal selection, but selection is more difficult to observe. Several major risk factors for cancer involve vascular oversupply of energy to affected tissues (Supplementary Table S1) Each of these four factors is strongly associated with cancer risk, causal mechanisms have generally not been demonstrated. The hypothesis is that dysregulated oversupply of energetic resources to somatic cells abrogates the normal metabolic cancer suppression created through organismal limitation of tissue energy supply, and thereby accelerates cellular evolution toward cancer. A previous in silico model showed that greater cell access to energy can increase selection for mutations supporting hyperproliferation and cell motility [8] This suggested the possibility that energy excess might be the common microenvironmental mechanism underlying multiple cancer risk factors that apparently involve supply of energy resources to affected tissues (Supplementary Table S1). Chronic systemic low-grade inflammation, termed ‘metaflammation’, may reportedly account for as much as 90% of all human cancer [29] or even as much as 95% [30]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
