Hartman Institute for Therapeutic Organ Regeneration

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

TitleAngiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Publication TypeJournal Article
Year of Publication2014
AuthorsCao Z, Ding B-S, Guo P, Lee SB, Butler JM, Casey SC, Simons M, Tam W, Felsher DW, Shido K, Rafii A, Scandura JM, Rafii S
JournalCancer Cell
Volume25
Issue3
Pagination350-65
Date Published2014 Mar 17
ISSN1878-3686
KeywordsAnimals, Burkitt Lymphoma, Calcium-Binding Proteins, Cell Cycle Proteins, Cell Proliferation, Drug Resistance, Neoplasm, Endothelial Cells, Enzyme Activation, Fibroblast Growth Factor 4, Genes, myc, Humans, Hyaluronan Receptors, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Membrane Proteins, Mice, Mice, Transgenic, Neoplasm Invasiveness, Receptor, Fibroblast Growth Factor, Type 1, Receptor, IGF Type 1, Receptor, Macrophage Colony-Stimulating Factor, Receptor, Notch2, RNA Interference, RNA, Small Interfering, Serrate-Jagged Proteins, Signal Transduction, Tumor Cells, Cultured, Up-Regulation
Abstract

<p>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.</p>

DOI10.1016/j.ccr.2014.02.005
Alternate JournalCancer Cell
PubMed ID24651014
PubMed Central IDPMC4017921
Grant ListCA163167 / CA / NCI NIH HHS / United States
R21 CA159175 / CA / NCI NIH HHS / United States
R01 HL084619 / HL / NHLBI NIH HHS / United States
R01HL097797 / HL / NHLBI NIH HHS / United States
HL055748 / HL / NHLBI NIH HHS / United States
HL119872 / HL / NHLBI NIH HHS / United States
R01 HL055748 / HL / NHLBI NIH HHS / United States
U54CA163167 / CA / NCI NIH HHS / United States
R01HL119872 / HL / NHLBI NIH HHS / United States
R01 HL119872 / HL / NHLBI NIH HHS / United States
CA159175 / CA / NCI NIH HHS / United States
RC2 HL101846 / HL / NHLBI NIH HHS / United States
RC2HL101846 / HL / NHLBI NIH HHS / United States
U54 CA163167 / CA / NCI NIH HHS / United States
R01 DK095039 / DK / NIDDK NIH HHS / United States
F32 CA177139 / CA / NCI NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States

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