Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance

摘要: 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 angiocrine provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 ECs reciprocally induces Notch2-Hey1 LCs. This crosstalk enforces aggressive CD44 + IGF1R CSF1R LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion Fgfr1 or Eμ-Myc model impairing Notch2 signaling mouse human LCs diminished aggressiveness prolonged survival. Thus, targeting FGF4-FGFR1/Jag1-Notch2 loop inhibits enhances chemosensitivity.