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

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

Authors :
Arash Rafii
Dean W. Felsher
Stephanie C. Casey
Michael Simons
Wayne Tam
Shahin Rafii
Zhongwei Cao
Jason M. Butler
Sharrell Lee
Koji Shido
Joseph M. Scandura
Peipei Guo
Bi-Sen Ding
Source :
Cancer cell. 25(3)
Publication Year :
2013

Abstract

Summary 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.

Details

ISSN :
18783686
Volume :
25
Issue :
3
Database :
OpenAIRE
Journal :
Cancer cell
Accession number :
edsair.doi.dedup.....46732376a42b5c80c0d0373e81dd4ffc