The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent.
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.
Jodele
Sonata
S
Division of Hematology-Oncology, University of Southern California and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Chantrain
Christophe F
CF
Blavier
Laurence
L
Lutzko
Carolyn
C
Crooks
Gay M
GM
Shimada
Hiroyuki
H
Coussens
Lisa M
LM
Declerck
Yves A
YA
D000293:Adolescent; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D014183:Transplantation, Heterologous
D020780:Matrix Metalloproteinase 9