title: Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors.
abstract: Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met.
  
  
  CONCLUSIONS
  This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis.
authors.affiliation: Comprehensive Cancer Center, Department of Anatomy, University of California-San Francisco (UCSF), San Francisco, CA 94143-0452, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.forename: Toshina
authors.initials: T
authors.lastname: Ishiguro-Oonuma
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Naylor
authors.forename: Casey W
authors.initials: CW
authors.lastname: Williamson
authors.forename: Vikash
authors.initials: V
authors.lastname: Bhagwandin
authors.forename: Sebastien P
authors.initials: SP
authors.lastname: Tabruyn
authors.forename: Weon-Kyoo
authors.initials: WK
authors.lastname: You
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000813:Anilides; D057134:Antibodies, Neutralizing; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C558660:cabozantinib; D019859:Proto-Oncogene Proteins c-met