The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1 alpha in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1 alpha is expanding. Despite that, the understanding of HIF-1 alpha induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1 alpha inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1 alpha signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1 alpha strategies into the clinic.