Abstract
Hypoxia is an important contributor to the heterogeneity of the microenvironment of solid tumors and is a significant environmental stressor that drives adaptations which are essential for the survival and metastatic capabilities of tumor cells. Critical adaptive mechanisms include altered metabolism, pH regulation, epithelial-mesenchymal transition, angiogenesis, migration/invasion, diminished response to immune cells and resistance to chemotherapy and radiation therapy. In particular, pH regulation by hypoxic tumor cells, through the modulation of cell surface molecules such as extracellular carbonic anhydrases (CAIX and CAXII) and monocarboxylate transporters (MCT-1 and MCT-4) functions to increase cancer cell survival and enhance cell invasion while also contributing to immune evasion. Indeed, CAIX is a vital regulator of hypoxia mediated tumor progression, and targeted inhibition of its function results in reduced tumor growth, metastasis, and cancer stem cell function. However, the integrated contributions of the repertoire of hypoxia-induced effectors of pH regulation for tumor survival and invasion remain to be fully explored and exploited as therapeutic avenues. For example, the clinical use of anti-angiogenic agents has identified a conundrum whereby this treatment increases hypoxia and cancer stem cell components of tumors, and accelerates metastasis. Furthermore, hypoxia results in the infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and Tumor Associated Macrophages (TAMs), and also stimulates the expression of PD-L1 on tumor cells, which collectively suppress T-cell mediated tumor cell killing. Therefore, combinatorial targeting of angiogenesis, the immune system and pH regulation in the context of hypoxia may lead to more effective strategies for curbing tumor progression and therapeutic resistance, thereby increasing therapeutic efficacy and leading to more effective strategies for the treatment of patients with aggressive cancer.
Highlights
The tumor microenvironment (TME) is heterogeneous in its composition and dynamic in its evolution
Hypoxia is a prominent component of the TME of solid cancers and is a result of an imbalance between the increasing demand for oxygen and nutrients by rapidly proliferating tumor cells and an inadequate, dysfunctional blood supply resulting from tumor angiogenesis (Lendahl et al, 2009; Bailey et al, 2012)
These results suggest that combinatorial targeting of MCT1 and MCT4 may be required to elicit a robust therapeutic response
Summary
The tumor microenvironment (TME) is heterogeneous in its composition and dynamic in its evolution. Key pH regulatory components that cancer cells upregulate in hypoxia include membrane-bound, extracellular carbonic anhydrases (CAs), CAIX and CAXII, which maintain an intracellular and extracellular acid-base balance (McDonald et al, 2012; Damaghi et al, 2013; McDonald and Dedhar, 2014), and monocarboxylate transporters (MCTs), especially MCT4, which facilitate lactate extrusion (Marchiq and Pouysségur, 2015) The importance of these factors in regulating pH in hypoxia has resulted in their exploitation as therapeutic targets across a broad spectrum of solid tumors, as discussed below. SLC-0111 Girentuximab (cG250) DTP-348 177 Lu-cG250 AdGMCAIX transduced DC AZD3965
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