Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia

Alessia Bottos, Miriam Martini, Federica Di Nicolantonio, Valentina Comunanza, Federica Maione, Alberto Minassi, Giovanni Appendino, Federico Bussolino, Alberto Bardelli

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number6
DOIs
Publication statusPublished - Feb 7 2012

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Protein-Serine-Threonine Kinases
Neoplasms
Epithelial Cells
Hypoxia
MAP Kinase Signaling System
Neoplasm Genes
Human Genome
Oncogenes
Heterografts
Blood Vessels
Alleles
Carcinoma
Growth
Pharmaceutical Preparations

Keywords

  • Personalized medicine
  • Targeted therapy
  • Tumor suppressor gene

ASJC Scopus subject areas

  • General

Cite this

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AU - Bottos, Alessia

AU - Martini, Miriam

AU - Di Nicolantonio, Federica

AU - Comunanza, Valentina

AU - Maione, Federica

AU - Minassi, Alberto

AU - Appendino, Giovanni

AU - Bussolino, Federico

AU - Bardelli, Alberto

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