In brief, tissue hypoxia and certain molecular alterations (e.g., mutations in oncogenes such as ERBB2 and suppressors such as VHL and PTEN) contribute to the overexpression of HIF-1α in tumor cells, which in turn leads to tumor metastasis, treatment failure, and high mortality37,78, 79, 80, 81 (Fig. 4). This evidence concerns the gene VHL and neoplasm.