Angiogenesis in Cancer: A Tragedy of Commons
Cancer is the result of evolution within the tumor microenvironment. Natural selection selects for cells capable of efficient nutrient uptake. Cancer cells achieve this by overexpressing angiogenic factors (VEGF) that induce the formation of blood vessels that carry nutrients to the tumor. Traditionally, angiogenesis has been viewed as a cooperative phenomenon resulting in the evolution of free-loaders. Using a game theoretic framework, we model VEGF production as an evolutionary strategy and show that the over-production of VEGF is the result of a tragedy of commons.
A cell’s investment in VEGF depends on the degree to which it aids its nutrient uptake. If higher production of VEGF leads to higher nutrient uptake, then cells are incentivized to produce VEGF. If nutrients are equally divided within a given neighborhood, an individual cell’s incentive to produce VEGF decreases. Our simulations predict that cancer cells produce 100 times more VEGF than typically seen in normal cells, and what would be their collective team optimum. This means that VEGF production by a cancer cell aims to co-opt nutrients from neighboring cells resulting in an evolutionary arms race. Increasing the number of cancer cells in a fixed neighborhood results in lower per-cell VEGF production while exacerbating the tragedy of the commons collectively. Next, we simulate anti-angiogenesis therapy and find that in response to therapy, cells adopt a low VEGF production strategy that continues to sustain growth in the cancer population. This results in evolutionary rescue. These results are in line with clinical observations. Our model challenges the existing paradigm of angiogenesis as a cooperative activity and provides novel insights into therapy in a clinical setting.