HGF/c-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis

Cancer Lett. 2012 Jul 1;320(1):48-55. doi: 10.1016/j.canlet.2012.01.026. Epub 2012 Jan 21.


Recent studies in several tumor models indicated that treatment with angiogenic inhibitors may trigger induction of metastasis to other organs. Here we investigated modes of resistance and invasion in several tumor cell lines including 4T1 (breast), H460 (lung) and Colo205 (colorectal) using sunitinib at doses comparable to clinically utilized regimen. In comparison with vehicle-treated tumors, sunitinib increased metastasis to lung in 4T1 tumors and to peritoneal lymph node in Colo205 tumors. However, the same treatment did not induce invasiveness in H460 tumors, further suggesting that accelerating metastasis during treatment with angiogenic inhibitors is tumor cell-type dependent. Interestingly, Crizotinib (a dual inhibitor of c-Met and ALK pathways) as single agent or in combination with sunitinib reduced metastasis in all models tested suggesting a role for c-Met/HGF pathway in intrinsic- or sunitinib-induced-metastasis. Moreover, ELISA data showed that while c-Met is highly enriched in tumor cells, HGF is secreted mainly by the stroma (mouse HGF) suggesting a paracrine fashion for c-Met pathway activation in the tumors. In conclusion, our findings indicate that sunitinib-induced metastasis is tumor cell-type dependent and further supports a rationale for combination of anti-angiogenics and c-Met inhibition in the clinic.

MeSH terms

  • Angiogenesis Inhibitors / adverse effects*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Colorectal Neoplasms / blood supply
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Indoles / adverse effects*
  • Indoles / therapeutic use
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Lymphatic Metastasis
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / drug therapy
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyrroles / adverse effects*
  • Pyrroles / therapeutic use
  • Signal Transduction / drug effects
  • Sunitinib


  • Angiogenesis Inhibitors
  • Indoles
  • Pyrroles
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Sunitinib