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

Cancer Cell. 2014 Mar 17;25(3):350-65. doi: 10.1016/j.ccr.2014.02.005.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Burkitt Lymphoma / genetics
  • Burkitt Lymphoma / metabolism*
  • Burkitt Lymphoma / pathology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Endothelial Cells / metabolism
  • Enzyme Activation
  • Fibroblast Growth Factor 4 / metabolism*
  • Genes, myc
  • Humans
  • Hyaluronan Receptors / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Receptor, Notch2 / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction / genetics
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Fibroblast Growth Factor 4
  • Hey1 protein, mouse
  • Hyaluronan Receptors
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptor, Notch2
  • Serrate-Jagged Proteins
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, IGF Type 1
  • Receptor, Macrophage Colony-Stimulating Factor

Associated data

  • GEO/GSE46368