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

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 E?-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.

SUBMITTER: Cao Z

PROVIDER: S-EPMC4017921 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Cao Zhongwei Z Ding Bi-Sen BS Guo Peipei P Lee Sharrell B SB Butler Jason M JM Casey Stephanie C SC Simons Michael M Tam Wayne W Felsher Dean W DW Shido Koji K Rafii Arash A Scandura Joseph M JM Rafii Shahin S

Cancer cell 20140301 3

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 enforc ...[more]

PMID: 24651014

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

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

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