Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia.
Carcinomas are comprised of transformed epithelial cells that are supported in their growth by a dedicated neovasculature. How the genetic milieu of the epithelial compartment influences tumor angiogenesis is largely unexplored. Drugs targeted to mutant cancer genes may act not only on tumor cells but also, directly or indirectly, on the surrounding stroma. We investigated the role of the BRAF(V600E) oncogene in tumor/vessel crosstalk and analyzed the effect of the BRAF inhibitor PLX4720 on tumor angiogenesis. Knock-in of the BRAF(V600E) allele into the genome of human epithelial cells triggered their angiogenic response. In cancer cells harboring oncogenic BRAF, the inhibitor PLX4720 switches off the ERK pathway and inhibits the expression of proangiogenic molecules. In tumor xenografts harboring the BRAF(V600E), PLX4720 extensively modifies the vascular network causing abrogation of hypoxia. Overall, our results provide a functional link between oncogenic BRAF and angiogenesis. Furthermore, they indicate how the tumor vasculature can be "indirectly" besieged through targeting of a genetic lesion to which the cancer cells are addicted.
Laboratory of Vascular Oncology,  Institute for Cancer Research and Treatment, 10060 Turin,  Italy.
Alessia
A
Bottos
Miriam
M
Martini
Federica
F
Di Nicolantonio
Valentina
V
Comunanza
Federica
F
Maione
Alberto
A
Minassi
Giovanni
G
Appendino
Federico
F
Bussolino
Alberto
A
Bardelli
D000483:Alleles; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D043925:Angiogenesis Inducing Agents; D061067:Antibodies, Monoclonal, Humanized; D054697:Cytostatic Agents; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; D000068258:Bevacizumab; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf