Evolutionary Consequences of Natural Selection Acting on the Angiogenic Switch in Cancer

Of the many problems in cancer treatment remains the design of therapeutics that can manage treatment-resistant tumors. Despite the use of increasingly sophisticated combinations of chemotherapeutic cocktails, radiation, and surgical resection to counter natural selection, many tumors still evolve towards greater malignancy. Therefore, treatment regimes that harness natural selection, rather than attempting to avoid it, may offer improved clinical outcomes. Previous tissue-specific mathematical models suggest the hypothesis that tumors can evolve tumors, or “hypertumors.” Hypertumors are an evolutionarily favored parasitic focus of proliferative cells growing on an existing tumor, arising when a mutant clone transfers ATP allocation from angiogenesis growth factor secretion to proliferation. Here we show that a cellular-energetics model supports the hypertumor hypothesis, but also suggests the possibility of runaway selection on angiogenesis factor secretion, leading to massive vascular hyperplasia. Experimental evidence from existing literature suggests total intracellular adenylate concentration is regulated primarily by de novo synthesis and irreversible destruction of AMP. However, adenylate concentrations of all three species adenylate—ATP, ADP and AMP— are adjusted homeostatically to regulate energy charge. As a result, the model suggests cells respond to increasing ATP hydrolysis by increasing total adenylate. Under physiologically relevant circumstances, this phenomenon can cause cells to increase ATP concentration, and in turn, proliferation rate, when genes for angiogenesis factor secretion are upregulated. Therefore, angiogenic clones are also more proliferative, and selection as a result favors unlimited angiogenesis. This result suggests that tumors are damaged by forcing them into an evolutionary spiral leading to an unstable hypervascular state. Alternatively, since vascularization supports delivery of chemotherapy, this phenomenon appears to be associated with the efficacy of vascular regulators like Avastin.