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Cancer Cell. 2014 Mar 17;25(3):350-65. doi: 10.1016/j.ccr.2014.02.005.

Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.

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  • 1Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 2Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: bid2004@med.cornell.edu.
  • 3Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 5Department of Pathology, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 7Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: srafii@med.cornell.edu.

Abstract

Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24651014
[PubMed - indexed for MEDLINE]
PMCID:
PMC4017921
Free PMC Article

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