Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction

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.

Hypoxia and acidosis: immune suppressors and therapeutic targets

“…For example, carbonic anhydrase IX (CA‐IX) controls intracellular and extracellular acid–base balance to maintain survival and is a key regulator of extracellular acidity. As a catalyser of reversible hydration of CO 2 to bicarbonate and protons at the extracellular surface, inhibition of the catalytic activity of CA‐IX can manipulate its role in pH regulation . Lactate overproduction is another hallmark of cancer that is associated with acidity and can impact a cell's ability to regulate its pH in the face of acidity .…”

“…In contrast to the belief that stromal cells use only glucose as an energy source, it was demonstrated that they also can use cancer‐cell‐derived lactate, which is transported into cells primarily with MCT‐1 . There is a strong effort to target MCTs, and these approaches may be combined with immune therapies by virtue of their effects on pH regulation . Targeting lactate metabolism is another promising approach for the modulation of tumour pH.…”

“…Hypoxia can be simply identified as lack of oxygen, which is a consequence of increasing oxygen requirement by proliferating cancer cells and dysfunctional and insufficient blood supply resulting from tumour angiogenesis. 10 As normal oxygen pressure varies between different tissues, there is not a fixed level to define hypoxia or degree of hypoxia. For instance, normoxia is a partial pressure (pO 2 ) of 21% in the lungs, 13% in arterial blood and 5% in the human liver.…”

Role of liver ICAM-1 in metastasis

“…Additionally, these proteins may also act as signaling molecules to modulate the local microenvironment, creating a pro-metastatic environment, and trigger an angiogenic and desmoplastic response via a complex reciprocal dialogue between the tumor cells and the cells of the colonized organ (15,16). In addition to the tissue cells, immune populations recruited from the circulation during metastasis formation are also involved in generating a favorable environment for metastatic growth (17,18). Therefore, determining the role of adhesion molecules during the different stages of this process remains a major goal for our understanding of the metastatic cascade.…”

Role of the Hypoxia-Inducible Factor in Periodontal Inflammation

“…This is made possible by a cellular HIF system. Cellular hypoxia, or a lower than "normal" concentration of O 2 in cells, occurs commonly and could induce signiicant changes, immediate or delayed, on cellular processes, including cell growth and apoptosis, cell proliferation and survival, pH regulation and energy metabolism, cell migration, matrix and barrier function, angiogenesis, and vasomotor regulation [8][9][10][11][12][13]. These biological processes involve active responses by the body to secure an additional oxygen supply via circulation.…”