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

By John M. L. Ebos, Christina R. Lee, W. Cruz-Muñoz, G. Bjarnason, J. Christensen, R. Kerbel. Cancer Cell, 2009

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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.

Subfields: Biotechnology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/3657fe8f0cb745f18714d00389789bb09e2dcb2d

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Citations in the corpus

The therapeutic promise of the cancer stem cell concept. (2010, background): “found in a mouse model of breast cancer that, despite inhibitory effects of the VEGFR tyrosine kinase inhibitor sunitinib on established primary tumor growth, administration of sunitinib prior to or shortly after tumor cell inoculation resulted in accelerated tumor metastasis and decreased survival ”
Hypoxia and hypoxia-inducible factors (HIFs): master regulators of metastasis (2010, background): “increased invasiveness and metastasis of tumor cells in preclinical models (55, 56), because these drugs induced”
Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 (2009, background): “angiogenesis might, in the long run, induce angiogenesis as a rebound phenomenon and have been demonstrated in preclinical studies to induce tumour progression and metastases [17–19].”
Hypoxia-induced angiogenesis: good and evil. (2011, result): “A second study observed similar results in mouse xenograft models of breast cancer and melanoma.(94) Intratumoral hypoxia was drastically increased as a result of impaired angiogenesis.”
Ten years of anti-vascular endothelial growth factor therapy (2016, background): “Also, preclinical studies testing high doses of VEGFR RTKIs have reported increased tumour aggressiveness and metastasis 130 .”
Molecular mechanisms and clinical applications of angiogenesis (2011, background): “Moreover, questions have begun to arise about whether anti-angiogenic therapy causes cancer cells to become more malignan”
Metronomic chemotherapy: new rationale for new directions (2010, background): “More surprisingly, two recent animal studies revealed that VEGF-targeted anti-angiogenic drugs, while inhibiting primary tumor growth, could promote tumor invasiveness and metastasis”
Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, neutral): “However, the provocative observation that VEGF-targeting anti-angiogenic compounds paradoxically increase metastatic propensity in murine models has provided a cautionary tale regarding the possibly unanticipated effects on metastases of these agents (Ebos et al., 2009; Pàez-Ribes et al., 2009).”
Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. (2011, background): “However, antiangiogenic treatments targeting the VEGF pathway rarely induce durable tumor responses, both in mice and patients with cancer (Bergers and Hanahan, 2008), and may also favor metastasis in selected tumor models (Ebos et al., 2009; Paez-Ribes et al., 2009).”
Antiangiogenic therapy: impact on invasion, disease progression, and metastasis (2011, background): “The first finding comes from two preclinical studies showing that the benefits from VEGF-pathway-inhibitor monotherapy can depend on disease stage and treatment circumstances and can, in certain settings, be offset by increased aggressive invasiveness and augmented metastatic potential”
Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “VEGF receptor tyrosine kinase inhibitors, which induce tumor hypoxia by blocking vascularization, have been reported to increase metastasis in mouse models (Ebos et al., 2009), which may be mediated by HIF-1.”
Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. (2011, methodology): “6D; Table 1), on primary breast tumor growth by using a highly metastatic variant of the MDA-MB-231 cell line (27).”