The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinaae-9 dependent

Sonata Jodele, Christophe F. Chantrain, Laurence Blavier, Carolyn Lutzko, Gay M. Crooks, Hiroyuki Shimada, Lisa M. Coussens, Yves A. DeClerck

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

The contribution of the tumor stroma to cancer progression has been increasingly recognized. We had previously shown that in human neuroblastoma tumors orthotopically implanted in immunodeficient mice, stromal-derived matrix metalloproteinase-9 (MMP-9) contributes to the formation of a mature vasculature by promoting pericyte recruitment along endothelial cells. Here we show that MMP-9 is predominantly expressed by bone marrow-derived CD45-positive leukocytes. Using a series of bone marrow transplantation experiments in MMP-9+/+ and MMP-9-/- mice xenotransplanted with human neuroblastoma tumors, we show that bone marrow-derived MMP-9 is critical for the recruitment of leukocytes from bone marrow into the tumor stroma and for the integration of bone marrow-derived endothelial cells into the tumor vasculature. Expression of MMP-9 by bone marrow-derived cells in the tumor stroma is also critical for the formation of a mature vasculature and coverage of endothelial cells with pericytes. Furthermore, in primary human neuroblastoma tumor specimens of unfavorable histology, we observed a higher level of tumor infiltration with MMP-9 expressing phagocytic cells and a higher degree of coverage of endothelial cells by pericytes when compared with tumor specimens with a favorable histology. Taken together, the data show that in neuroblastoma, MMP-9 plays a critical role in the recruitment of bone marrow-derived cells to the tumor microenvironment where they positively contribute to angiogenesis and tumor progression.

Original languageEnglish (US)
Pages (from-to)3200-3208
Number of pages9
JournalCancer Research
Volume65
Issue number8
DOIs
StatePublished - Apr 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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