This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jodele, S. Articles by DeClerck, Y. A. Search for Related Content PubMed PubMed Citation Articles by Jodele, S. Articles by DeClerck, Y. A.

The Contribution of Bone Marrow–Derived Cells to the Tumor Vasculature in Neuroblastoma Is Matrix Metalloproteinase-9 Dependent

Divisions of ¹ Hematology-Oncology and ² Research Immunology and Bone Marrow Transplantation, Departments of Pediatrics and Biochemistry and Molecular Biology and ³ Pathology, Keck School of Medicine, University of Southern California and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California; ⁴ Department of Pathology and Cancer Research Institute, University of California San Francisco, San Francisco, California; and ⁵ Department of Pediatrics, Catholic University of Louvain Medical School, Brussels, Belgium

Requests for reprints: Yves A. DeClerck, Division of Hematology-Oncology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-669-5648; Fax: 323-664-9455; E-mail: declerck{at}hsc.usc.edu.

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.

This article has been cited by other articles:

				S. Takagi, S. Simizu, and H. Osada RECK Negatively Regulates Matrix Metalloproteinase-9 Transcription Cancer Res., February 15, 2009; 69(4): 1502 - 1508. [Abstract] [Full Text] [PDF]

				Q. Hao, J. Liu, R. Pappu, H. Su, R. Rola, R. A. Gabriel, C. Z. Lee, W. L. Young, and G.-Y. Yang Contribution of Bone Marrow-Derived Cells Associated With Brain Angiogenesis Is Primarily Through CD69+ Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2151 - 2157. [Abstract] [Full Text] [PDF]

				R. Miller, V. Cirulli, G. R. Diaferia, S. Ninniri, G. Hardiman, B. E. Torbett, R. Benezra, and L. Crisa Switching-On Survival and Repair Response Programs in Islet Transplants by Bone Marrow-Derived Vasculogenic Cells Diabetes, September 1, 2008; 57(9): 2402 - 2412. [Abstract] [Full Text] [PDF]

				K. Reddy, Z. Zhou, K. Schadler, S.-F. Jia, and E. S. Kleinerman Bone Marrow Subsets Differentiate into Endothelial Cells and Pericytes Contributing to Ewing's Tumor Vessels Mol. Cancer Res., June 1, 2008; 6(6): 929 - 936. [Abstract] [Full Text] [PDF]

				M. Gerg, C. Kopitz, S. Schaten, A. Tschukes, C. Kahlert, M. Stangl, C. W. Hann von Weyhern, B. L.D.M. Brucher, D. R. Edwards, K. Brand, et al. Distinct Functionality of Tumor Cell-Derived Gelatinases during Formation of Liver Metastases Mol. Cancer Res., March 1, 2008; 6(3): 341 - 351. [Abstract] [Full Text] [PDF]

				Y. Y. Mahller, S. S. Vaikunth, M. C. Ripberger, W. H. Baird, Y. Saeki, J. A. Cancelas, T. M. Crombleholme, and T. P. Cripe Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors Cancer Res., February 15, 2008; 68(4): 1170 - 1179. [Abstract] [Full Text] [PDF]

				C. Melani, S. Sangaletti, F. M. Barazzetta, Z. Werb, and M. P. Colombo Amino-Biphosphonate Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma Cancer Res., December 1, 2007; 67(23): 11438 - 11446. [Abstract] [Full Text] [PDF]

				H. Li, X. Fan, R. C. Kovi, Y. Jo, B. Moquin, R. Konz, C. Stoicov, E. Kurt-Jones, S. R. Grossman, S. Lyle, et al. Spontaneous Expression of Embryonic Factors and p53 Point Mutations in Aged Mesenchymal Stem Cells: A Model of Age-Related Tumorigenesis In Mice Cancer Res., November 15, 2007; 67(22): 10889 - 10898. [Abstract] [Full Text] [PDF]

				C. Lamagna and G. Bergers The bone marrow constitutes a reservoir of pericyte progenitors J. Leukoc. Biol., October 1, 2006; 80(4): 677 - 681. [Abstract] [Full Text] [PDF]

				R. R. Nair, J. Solway, and D. D. Boyd Expression Cloning Identifies Transgelin (SM22) as a Novel Repressor of 92-kDa Type IV Collagenase (MMP-9) Expression J. Biol. Chem., September 8, 2006; 281(36): 26424 - 26436. [Abstract] [Full Text] [PDF]

				S. Ge, G. M. Crooks, G. McNamara, and X. Wang Fluorescent Immunohistochemistry and In Situ Hybridization Analysis of Mouse Pancreas Using Low-power Antigen-retrieval Technique J. Histochem. Cytochem., July 1, 2006; 54(7): 843 - 847. [Abstract] [Full Text] [PDF]

				V. Chabottaux, N. E. Sounni, C. J. Pennington, W. R. English, F. van den Brule, S. Blacher, C. Gilles, C. Munaut, E. Maquoi, C. Lopez-Otin, et al. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res., May 15, 2006; 66(10): 5165 - 5172. [Abstract] [Full Text] [PDF]

				V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax Pericellular Proteases in Angiogenesis and Vasculogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 716 - 728. [Abstract] [Full Text] [PDF]

				L. Blavier, A. Lazaryev, F. Dorey, G. M. Shackleford, and Y. A. DeClerck Matrix metalloproteinases play an active role in wnt1-induced mammary tumorigenesis. Cancer Res., March 1, 2006; 66(5): 2691 - 2699. [Abstract] [Full Text] [PDF]

				E. I. Deryugina, A. Zijlstra, J. J. Partridge, T. A. Kupriyanova, M. A. Madsen, T. Papagiannakopoulos, and J. P. Quigley Unexpected Effect of Matrix Metalloproteinase Down-Regulation on Vascular Intravasation and Metastasis of Human Fibrosarcoma Cells Selected In vivo for High Rates of Dissemination Cancer Res., December 1, 2005; 65(23): 10959 - 10969. [Abstract] [Full Text] [PDF]