Hypoxia Signaling in Cancer: From Basics to Clinical Practice

Abstract

Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.

A novel hypoxia-driven gene signature that can predict the prognosis of hepatocellular carcinoma

“…Hypoxia is an important characteristic of solid tumors. During the progression of solid tumors, hypoxic areas spontaneously form in the interior of solid tumors due to the development of a malformed vascular system [ 5 , 6 ]. A hypoxic microenvironment is important for mediating the increase in proto-oncogene expression levels in HCC cells and for promoting angiogenesis, cell metastasis, and proliferation [ 7 ].…”

Hypoxia induces radioresistance, epithelial‑mesenchymal transition, cancer stem cell‑like phenotype and changes in genes possessing multiple biological functions in head and neck squamous cell carcinoma

“…Several studies have indicated that hypoxia is associated with cancer progression and the development of resistance to chemotherapy and radiotherapy ( 30 – 32 ). Oxygenation status of head and neck tumors appears to be important, as hypoxic tumors exhibit a poorer response to surgery and radiotherapy ( 33 , 34 ).…”

The role of the metabolite cargo of extracellular vesicles in tumor progression

“…It is also important to note that cancer changes cell metabolism. Typical metabolic conditions in the TME include hypoxia, starvation, and acidosis [ 133 , 138 ]. The metabolic rewiring alters the secretion rate and metabolite content of cancer-derived EVs as well, but this cargo remains poorly characterized.…”