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

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• 作者：Zhongwei Cao¹ ; Bi-Sen Ding¹ ; ^{bid2004@med.cornell.edu" class="auth_mail} ; Peipei Guo¹ ; Sharrell B. Lee¹ ; Jason M. Butler¹ ; Stephanie C. Casey² ; Michael Simons³ ; Wayne Tam⁴ ; Dean W. Felsher² ; Koji Shido¹ ; Arash Rafii¹ ; Joseph M. Scandura⁵ ; Shahin Rafii¹ ; ^{srafii@med.cornell.edu" class="auth_mail}
• 刊名：Cancer Cell
• 出版年：17 March, 2014
• 年：2014
• 卷：25
• 期：3
• 页码：350-365
• 全文大小：7001 K

文摘

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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 E渭-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.