Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis For Cancer Therapy

Significance: Hypoxia is emerging as a crucial regulator of the tumor microenvironment; it governs the metastatic potential of multiple primary cancers. It is also potentially involved in the regulation of tumorigenesis, tumor metabolism, and proangiogenic activity.Recent Advances: A wealth of clinical data across a wide range of cancer types has revealed strong correlations between hypoxia or the overexpression of hypoxia-inducible transcription factors and the rates of distant metastases and poor prognoses. Hypoxia-inducible factor (HIF)-1 alpha, one of the key regulatory molecules of the HIF-1 signaling pathways, is involved in multiple crucial steps in the metastatic cascade.Critical Issues: Here, we present recent findings on the roles of the HIF-1 complex in tumor metastasis and highlight the potential of HIF-1 alpha as a target for abrogating tumor metastasis. Moreover, we systematically describe the regulatory role of HIF-1 at each step of the metastatic cascade. Finally, we present the most recent advances in potential pharmacological interventions and the development of specific HIF-1 inhibitors for blocking tumor metastasis.Future Directions: Well-designed clinical trials are urgently needed to validate the anti-metastatic activity of HIF-1 inhibitors discovered in preclinical models.