Hypoxia and Tumors

Human solid tumors are invariably less well-oxygenated than the normal tissues from which they arose. The cellular response to insufficient tissue oxygenation, or hypoxia, is mainly mediated by the hypoxia-inducible factor (HIF) family of transcription factors. These regulate the expression of multiple genes involved in processes that drive the adaptation and progression of cancer cells, as suggested by experimental and clinical data form various tumor types.

Hypoxia leads to resistance to radiotherapy and anticancer chemotherapy, increases angiogenesis and vasculogenesis predisposing to tumor metastases, and contributes to altered metabolism and genomic instability. Tumor hypoxia profoundly changes the interaction and cross-talk of cancer cells with the surrounding tumor microenvironment, leading also to immune-resistance and immune-suppression, which help tumor cells to escape from immune surveillance.

Therefore, given its central role in tumor progression and resistance to therapies, tumor hypoxia is considered a valid target to be exploited in oncology. Several approaches for targeting hypoxic tumor cells have been proposed in recent years, including hypoxia-activated prodrugs, gene therapy, recombinant anaerobic bacteria, specific targeting of HIFs, or targeting pathways important in hypoxic cells such as the mTOR and UPR (unfolded protein response) pathways. Better understanding of hypoxic phenomenon and dissecting out the hypoxia-inducible responses and signaling pathways will grant numerous novel targets in the near future.

The purpose of this thematic series, published in Journal of Experimental & Clinical Cancer Research, is to highlight significant findings and advances in our understanding of the role of the tumor hypoxia in cancer biology and therapy, in light of the 2019 Nobel Prize in Medicine awarded to William G. Kaelin Jr., Sir Peter J. Radcliff and Gregg G. Semenza, whose discoveries contributed to a great understanding to the cell adaptation to reduced oxygen availability.

Keywords: Hypoxia, HIF, Angiogenesis, Invasion and Metastasis, Immune response, Metabolic reprogramming, Microenvironment, Innovative therapies.