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- W4296032087 abstract "Clinical cancers are typically spatially and temporally heterogeneous, containing multiple microenvironmental habitats and diverse phenotypes and/or genotypes, which can interact through resource competition and direct or indirect interference. A common intratumoral evolutionary pathway, probably initiated as adaptation to hypoxia , leads to the “Warburg phenotype” which maintains high glycolytic rates and acid production, even in normoxic conditions. Since individual cancer cells are the unit of Darwinian selection, intraspecific competition dominates intratumoral evolution. Thus, elements of the Warburg phenotype become key “strategies” in competition with cancer cell populations that retain the metabolism of the parental normal cells. Here we model the complex interactions of cell populations with Warburg and parental phenotypes as they compete for access to vasculature, while subject to direct interference by Warburg-related acidosis. In this competitive environment, vasculature delivers nutrients, removes acid and necrotic detritus, and responds to signaling molecules (VEGF and TNF- α ). The model is built in a nested fashion and growth parameters are derived from monolayer, spheroid, and xenograft experiments on prostate cancer. The resulting model of in vivo tumor growth reaches a steady state, displaying linear growth and coexistence of both glycolytic and parental phenotypes consistent with experimental observations. The model predicts that increasing tumor pH sufficiently early can arrest the development of the glycolytic phenotype, while decreasing tumor pH accelerates this evolution and increases VEGF production. The model’s predicted dual effects of VEGF blockers in decreasing tumor growth while increasing the glycolytic fraction of tumor cells has potential implications for optimizing angiogenic inhibitors. • A math model of monolayer, spheroid, and xenograft prostate cancer is presented. • The model incorporates angiogenesis, Warburg glycolysis, TNF-alpha, and VEGF. • Simulated early buffer therapy can prevent an aggressive, glycolytic phenotype. • Simulated decreases in pH accelerate evolution toward glycolysis and elevate VEGF. • Simulated anti-VEGF therapy slows tumor growth, but leads to more aggressive tumors." @default.
- W4296032087 created "2022-09-17" @default.
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- W4296032087 date "2022-10-01" @default.
- W4296032087 modified "2023-09-28" @default.
- W4296032087 title "A simulation of parental and glycolytic tumor phenotype competition predicts observed responses to pH changes and increased glycolysis after anti-VEGF therapy" @default.
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- W4296032087 doi "https://doi.org/10.1016/j.mbs.2022.108909" @default.
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