Abstract
Hypoxia is a common feature of solid tumors, which controls multiple aspects of cancer progression. One important function of hypoxia and the hypoxia-inducible factors (HIF) is the maintenance of cancer stem-like cells (CSC), a population of tumor cells that possess stem cell-like properties and drives tumor growth. Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here, we show that glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found that these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacologic inactivation of HSP90 inhibited the increase in HIF levels and abolished the self-renewal and tumorigenic properties of CSCs induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors. Cancer Res; 76(19); 5845-56. ©2016 AACR.
Highlights
Growing tumors often outpace their blood supply generating a hypoxic microenvironment
Acidosis increases hypoxia-inducible factors (HIF) function and the cancer stem-like cells (CSC) phenotype We were interested in analyzing to what extent metabolic parameters of the hypoxic tumor microenvironment other than pO2 may regulate HIF levels and function in glioblastoma
We show that two key characteristics of the tumor microenvironment, hypoxia and acidosis, synergize to potentiate HIF activity and HIF-dependent functions through complementary and additive mechanisms
Summary
Growing tumors often outpace their blood supply generating a hypoxic microenvironment. HIF abundance is tightly regulated by the prolyl hydroxylase domain (PHD) proteins. PHDs use O2 to hydroxylate HIFs [2, 3], which enables binding of the VHL protein, a component of an E3 ubiquitin ligase complex that catalyzes HIF1/2a ubiquitination and degradation. One of the primary effects of hypoxia is the induction of a metabolic shift from oxidative phosphorylation to glycolysis, with lactic acid as the end product [4]. This is accompanied by the upregulation of carbonic anhydrases, transporters for lactate, Hþ, HCO3À, and other ions, leading to a net acidification of the extracellular tumor environment [5, 6]. A decreased pH is a characteristic feature of many tumor types and a number of studies have started to delineate critical functions of the acidic extracellular
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