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

Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
Cancer cell (Impact Factor: 23.52). 04/2009; 15(3):232-9. DOI: 10.1016/j.ccr.2009.01.021
Source: PubMed


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.

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    • "Metastasis is further enabled due to the poor structural integrity of the tumor blood vessels and pathological angiogenesis-associated tumor hypoxia. Recently, anti-angiogenic therapy has been reported to cause an increased metastatic phenotype, possibly via elevated tumor hypoxia and hypoxia-induced epithelial to mesenchymal transition (EMT) [80] [81] [82]. Anti-angiogenic therapy may however also increase the metastatic potential of tumor cells through adaptive resistance pathways not associated with hypoxia [83], indicating that antiangiogenic therapy-induced changes in the tumor phenotype may lead to a more aggressive disease through a number of different mechanisms. "
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    • "This may affect not only the efficacy of the therapy but also the putative development of resistance. Relating to the studies by Paez-Ribes et al. (2009) and Ebos et al. (2009) "
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