Requirement of CXCL12-CXCR7 signaling for CD20(-) CD138(-) double-negative population in lymphoplasmacytic lymphoma

Lab Invest. 2016 May;96(5):517-25. doi: 10.1038/labinvest.2016.28. Epub 2016 Feb 15.

Abstract

Cancer cells with tumorigenic potential are limited to a small subpopulation known as cancer-initiating cells (CICs). Recently we investigated a candidate of CICs of lymphoplasmacytic lymphoma (LPL), which is positive for both B-cell marker CD20 and plasma-cell marker CD138. We reported that the subpopulation of CD20(-) CD138(-) phenotype, in which both markers were negative was a candidate of CICs in LPL using LPL cell line, MWCL-1. CICs are known to be plastic under stressed condition, in which non-CICs are changed to CICs. In the present study, we investigated the plasticity of CICs of LPL, and found that hypoxia induced the conversion of CD20(+) CD138(-) to CD20(-) CD138(-) phenotype. We then searched for markers preferentially expressed in CD20(-) CD138(-) subpopulation, and the chemokine receptor CXCR7 was isolated. When cultured with CXCL12, a ligand of CXCR7, the number of CD20(-) CD138(-) cells increased in a time- and dose-dependent manner. In addition, hypoxia enhanced the expression level of CXCL12 in MWCL-1. In clinical samples of LPL, a few tumor cells expressed CXCR7, in which CD20 expression was not detected. These results indicated that hypoxia and CXCL12-CXCR7 axis appeared to be advantageous microenvironments to CD20(-) CD138(-) cells.

MeSH terms

  • Aged
  • Antigens, CD20 / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Cell Line, Tumor
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / pathology
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism*
  • Signal Transduction
  • Syndecan-1 / metabolism
  • Tumor Microenvironment / immunology
  • Up-Regulation
  • Waldenstrom Macroglobulinemia / genetics
  • Waldenstrom Macroglobulinemia / immunology*
  • Waldenstrom Macroglobulinemia / pathology

Substances

  • ACKR3 protein, human
  • Antigens, CD20
  • Biomarkers, Tumor
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Receptors, CXCR
  • SDC1 protein, human
  • Syndecan-1