Department of Integrative Oncology, British Columbia Cancer Research Centre Vancouver, BC, Canada.
Department of Integrative Oncology, British Columbia Cancer Research CentreVancouver, BC, Canada; Department of Biochemistry and Molecular Biology, University of British ColumbiaVancouver, BC, Canada.
Front Cell Dev Biol. 2016 Mar 31;4:27. doi: 10.3389/fcell.2016.00027. eCollection 2016.
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.
缺氧是实体瘤微环境异质性的重要贡献者，也是一种重要的环境应激源，它驱动了肿瘤细胞生存和转移能力所必需的适应性改变。关键的适应机制包括改变代谢、pH 值调节、上皮-间充质转化、血管生成、迁移/侵袭、对免疫细胞的反应减弱以及对化疗和放疗的耐药性。特别是，缺氧肿瘤细胞通过调节细胞表面分子，如细胞外碳酸酐酶（CAIX 和 CAXII）和单羧酸转运蛋白（MCT-1 和 MCT-4）来调节 pH 值，从而增加癌细胞的存活并增强细胞侵袭，同时也有助于免疫逃逸。事实上，CAIX 是缺氧介导的肿瘤进展的重要调节剂，靶向抑制其功能可导致肿瘤生长、转移和癌症干细胞功能减少。然而，pH 值调节的缺氧诱导效应器对肿瘤生存和侵袭的综合贡献仍有待充分探索和利用作为治疗途径。例如，抗血管生成药物的临床应用已经确定了一个难题，即这种治疗方法会增加肿瘤的缺氧和癌症干细胞成分，并加速转移。此外，缺氧会导致髓系来源的抑制细胞（MDSCs）、调节性 T 细胞（Treg）和肿瘤相关巨噬细胞（TAMs）的浸润，同时还会刺激肿瘤细胞表达 PD-L1，这些细胞共同抑制 T 细胞介导的肿瘤细胞杀伤。因此，在缺氧的情况下联合靶向血管生成、免疫系统和 pH 值调节可能会导致更有效的遏制肿瘤进展和治疗耐药性的策略，从而提高治疗效果，并为治疗侵袭性癌症患者提供更有效的策略。
