Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies

Abstract

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.

Keywords: angiogenesis; hypoxia; microenvironment; normalization; signatures; tumor suppressors; vessel.

Figure 1

Alleviation of tumor hypoxia by vascular normalization reprograms the tumor microenvironment. Hypoxia in the tumor microenvironment promotes tumor angiogenesis and abnormal vascularization through the activation of HIF-1α and downstream effector genes, such as VEGF-A, while inhibiting the tumor suppressor PTEN. This is coupled by enhanced immune suppression, the release of proinflammatory molecules, as well as the promotion of invasion and metastasis. The alleviation of tumor hypoxia through vascular normalization enhances tumor perfusion, leading to the degradation of HIF-1α and restoration of PTEN activity. The reestablishment of normal oxygenation additionally counteracts tumor growth through the revitalization of the immune response.