Perspectives on Hypoxia Signaling in Tumor Stroma

SIMPLE SUMMARY: Low oxygen tension (hypoxia) caused by high demand of cancer cell proliferation or standard of care therapy is a prevalent feature of solid tumors and is often associated with malignancy. The hypoxia-inducible transcription factor (HIF) family is the critical mediator driving the hypoxia signaling. HIF activity has diverse effects in tumor cells and on tumor stroma, including tumor vasculature, extracellular matrix, fibroblasts and immune cells. In this review, we focus on the effects of HIF in tumor stromal components and discuss essential functions of HIF regulating angiogenesis, collagen deposition and anti-tumor immunity. We also provide a brief overview of the current state of clinical studies targeting tumor hypoxia and provide insights on the limitation of hypoxia-targeted therapies. We believe, with comprehensive knowledge of hypoxia in the tumor microenvironment, challenges of hypoxia-targeted therapies might be better understood and addressed. ABSTRACT: Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, results in tumor cell migration, proliferation, metabolic changes, and resistance to therapy. Additionally, the hypoxic tumor microenvironment impacts multiple cellular and non-cellular compartments in the tumor stroma, including disordered tumor vasculature, homeostasis of ECM. Hypoxia also has a multifaceted and often contradictory influence on immune cell function, which contributes to an immunosuppressive environment. Here, we review the important function of HIF in tumor stromal components and summarize current clinical trials targeting hypoxia. We provide an overview of hypoxia signaling in tumor stroma that might help address some of the challenges associated with hypoxia-targeted therapies.