KRAS and cancer: Mutated K-RAS and p53, expression of COX-2, and hypoxia inducible factor 1 (HIF-1) induced by hypoxia from high tumor cell density might all contribute to VEGF-VEGFR activity alteration, resulting in cancer growth and migration.178–181 The proangiogenic effects of VEGF-VEGFR are important both in local sites supporting tumor progression and migration and in metastatic sites for neovascularization to support cancer survival and growth; therefore, anti-VEGF/VEGFR therapy might be developed to target both steps in tumor metastasis.