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

Zhongwei Cao, Bi Sen Ding, Peipei Guo, Sharrell B. Lee, Jason M. Butler, Stephanie C. Casey, Michael Simons, Wayne Tam, Dean W. Felsher, Koji Shido, Arash Rafii, Joseph M. Scandura, Shahin Rafii

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103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)350-365
Number of pages16
JournalCancer Cell
Volume25
Issue number3
DOIs
Publication statusPublished - 17 Mar 2014

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Cao, Z., Ding, B. S., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., Rafii, A., Scandura, J. M., & Rafii, S. (2014). Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell, 25(3), 350-365. https://doi.org/10.1016/j.ccr.2014.02.005