Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

Abstract

SUMMARY Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…In addition to the importance of Arf6 in tumour angiogenesis, it has been reported that Arf6 activation in cancer cells is required for cancer invasion and metastasis 50 . Recent preclinical studies have suggested that anti-angiogenic therapy may promote cancer invasion and metastasis by inducing hypoxia of cancer cells, suggesting that effective cancer therapeutic approaches should involve both inhibition of tumour angiogenesis and cancer invasion/metastasis 51,52 . The critical roles of Arf6 in both tumour vascularization and cancer cell invasiveness/metastasis provide a new cancer therapeutic opportunity.…”

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

“…However, although antitumoural effects and survival benefit are often evident, relapse to progressive tumour growth has been recently reported, reflecting multiple mechanisms of adaptation to anti-angiogenic therapies. 25,26 In this context, D133p53 may have a critical role by stimulating angiogenesis through pathways involving several angiogenic factors distinct from VEGF. Thus, targeting D133p53 may have a strong impact in cancer therapeutics.…”

Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

“…These treatments effectively inhibit tumor progression through deprivation of oxygen and nutrition from the tumor microenvironment, but cannot block metastasis of RCC cells. Moreover, there is growing evidence that antiangiogenic therapies can accelerate invasion and metastasis by making the tumor microenvironment more fertile (4,5).…”