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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-04, Vol.65 (8), p.3200-3208
• Main Authors: JODELE, Sonata, CHANTRAIN, Christophe F, BLAVIER, Laurence, LUTZKO, Carolyn, CROOKS, Gay M, SHIMADA, Hiroyuki, COUSSENS, Lisa M, DECLERCK, Yves A
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Antineoplastic agents; Biological and medical sciences; Bone Marrow Cells - enzymology; Bone Marrow Cells - pathology; Bone Marrow Transplantation; Cell Line, Tumor; Child; Child, Preschool; Humans; Male; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - genetics; Medical sciences; Mice; Mice, Knockout; Neoplasm Transplantation; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - pathology; Neuroblastoma - blood supply; Neuroblastoma - enzymology; Neuroblastoma - pathology; Neurology; Pharmacology. Drug treatments; Transplantation, Heterologous; Tumors of the nervous system. Phacomatoses
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-3770

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.