Eph-B2/Ephrin-B2 interaction plays a major role in the adhesion and proliferation of Waldenstrom's macroglobulinemia

Feda Azab, Abdel Kareem Azab, Patricia Maiso, Teresa Calimeri, Ludmila Flores, Yang Liu, Phong Quang, Aldo M. Roccaro, Antonio Sacco, Hai T. Ngo, Yong Zhang, Brittany L. Morgan, Ruben D. Carrasco, Irene M. Ghobrial

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Purpose: The ephrin receptors (Eph) are found in a wide range of cancers and correlate with metastasis. In this study, we characterized the role of Eph-B2 receptor in the interaction of Waldenstrom's macroglobulinemia (WM) cells with the bone marrow microenvironment. Experimental Design: We screened the activity of different receptor tyrosine kinases in WM patients and found that Eph-B2 was overexpressed compared with control. Also, we tested the expression of ephrin-B2 ligand on endothelial cells and bone marrow stromal cells (BMSC) isolated from WM patients. We then tested the role of Eph-B2/Ephrin-B2 interaction in the adhesion of WM cells to endothelial cells and BMSCs; the cell signaling induced by the coculture in both the WM cells and the endothelial cells; WM cell proliferation, apoptosis, and cell cycle in vitro and tumor progression in vivo; and in angiogenesis. Results: Eph-B2 receptor was found to be activated in WM patients compared with control, with a 5-fold increase in CD19+ WM cells, and activated cell adhesion signaling, including focal adhesion kinase, Src, P130, paxillin, and cofilin, but decreased WM cell chemotaxis. Ephrin-B2 ligand was highly expressed on endothelial cells and BMSCs isolated from WM patients and on human umbilical vein endothelial cells and induced signaling in the endothelial cells promoting adhesion and angiogenesis. Blocking of ephrin-B2 or Eph-B2 inhibited adhesion, cytoskeletal signaling, proliferation, and cell cycle in WM cells, which was induced by coculture with endothelial cells and decreased WM tumor progression in vivo. Conclusion: Ephrin-B2/Eph-B2 axis regulates adhesion, proliferation, cell cycle, and tumor progression in vivo through the interaction of WM with the cells in the bone marrow microenvironment.

Original languageEnglish (US)
Pages (from-to)91-104
Number of pages14
JournalClinical Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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