Intratumoral hypoxia (reduced O availability) is a common finding in human cancer and leads to increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes that contribute to angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition, motility, invasion, metastasis, cancer stem cell maintenance, immune evasion, and resistance to chemotherapy and radiation therapy. Conventional anticancer therapies target well-oxygenated and proliferating cancer cells, whereas there are no approved therapies that target hypoxic cancer cells, despite growing clinical and experimental evidence indicating that intratumoral hypoxia is a critical microenvironmental factor driving cancer progression. In this review, our current understanding of the consequences of HIF activity and the translational potential of targeting HIFs for cancer therapy are discussed.

Most cases of breast cancer mortality are due to vascular metastasis. Breast cancer cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor activity (HIF) in breast cancer cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of breast cancer cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of breast cancer cells to ECs. Interference with HIF, ANGPTL4, or L1CAM expression inhibits vascular metastasis of breast cancer cells to the lungs.