Targeting hypoxia in tumor: a new promising therapeutic strategy
Low oxygen condition (hypoxia) is considered a hallmark of rapidly growing solid tumors. The presence of hypoxia renders tumor cells resistant to conventional chemo- and radio-therapy selecting a more malignant and invasive phenotype, and playing a negative role in patient prognosis. This commentary wishes to recognize the 2019 Nobel Prize in Medicine awarded to three physicians-scientists, Prof. William G. Kaelin Jr., Prof. Sir Peter J. Ratcliffe, and Prof. Gregg L. Semenza, for their discovery of the mechanisms mediating cell ability to sense and adapt to changes in oxygen availability. Their studies established the basis for our understanding of the role of hypoxia in a variety of diseases, including anemia, renal failure, cardiovascular disease, metabolic diseases, and cancer, paving the way for new promising therapeutic strategies through the development of drugs that can either activate or block the oxygen-sensing machinery.
KeywordsHypoxia HIF Oxygen sensing VHL Angiogenesis VEGF Cancer Metastasis
Factor inhibiting HIF-1
Hypoxia Inducible Factor-1
Hypoxia response elements
HIF-1 plays important roles in critical aspects of cancer biology, including angiogenesis, regulation of glucose and energy metabolism, epithelial-to-mesenchymal transition, invasion, and metastasis, and stem cell maintenance, thus allowing tumor cells to proliferate and survive under hypoxic conditions. These discoveries provided proof-of-principle that inhibition of HIF-1 activity may represent a novel strategy for the therapy not only of cancer but also for other diseases characterized by impaired oxygenation such as anemia, coronary artery disease, obstructive pulmonary diseases, chronic ischemic cardiomyopathy, inflammatory synovitis, atherosclerosis, systemic sclerosis, etc. [8, 9].
Over the last two decades, to bridge basic science to the clinical situation, dozens of putative small molecule HIF inhibitors that directly or indirectly downregulate HIF-1α have been identified and are currently tested in clinical trials for various forms of cancer . Several HIF prolyl hydroxylase inhibitors, that prevent VHL from binding to HIF-1α, have also been developed and are now in late-stage clinical trials in disease in which HIF signaling is beneficial, e.g. to augment endogenous EPO production for the treatment of renal-based anemia. Such drugs are also being investigated for the treatment of circulatory diseases and for the protection against ischemic injury, inflammatory diseases, other than as anticancer molecules.
Hypoxia is considered a driving force of tumor progression and a negative prognostic factor. The finding of HIF as the main regulator of transcriptional responses to changes in oxygen levels have far-reaching implications, opening up new avenues for the development of new promising therapeutic strategies targeting the HIF-signaling pathway. In this regard, Journal of Experimental & Clinical Cancer Research is announcing a special issue to highlight significant advances on the understanding of the impact of hypoxia on tumor progression and treatment efficacy.
We thank all the people in the lab for critical discussion.
All authors were involved in conceptualization, writing and revising of the manuscript. All authors read and approved the final version of the manuscript.
The research within the realm of this manuscript is funded in G.D. lab by and Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 2015 16742) and by Fondi Ateneo; in M.C.B. lab by Ministry of Health (Ricerca Finalizzata RF-2016-02361048) and by AIRC (IG 2015 17459); in D.D.B. lab by AIRC (IG 2016 18560).
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The authors declare that they have no competing interests.
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