Stromal matrix metalloproteinase-9 (MMP-9) promotes pericyte recruitment in neuroblastoma angiogenesis : a new role for matrix metalloproteinases

Chantrain, Christophe F.
(2005)

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  • Chantrain, Christophe F.UCLouvain
    author
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DeClerck, Yves
 ;
Marbaix, Etienne
Abstract
Neuroblastoma is a highly invasive neural crest derived cancer and the second most common solid tumor in children. Matrix metalloproteinases (MMPs) constitute a family of more than 26 endopeptidases that are able to proteolytically process a growing number of matrix and non-matrix substrates. MMPs are involved at different levels of tumor progression. MMP-2 and MMP-9 are overexpressed in more advanced stages of neuroblastoma. Although MMP-2 is produced by both tumor cells and stromal cells, MMP-9 is only secreted by stromal cells. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Treatment with Prinomastat, a synthetic inhibitor of MMPs, prolonged tumor bearing mice survival, did not affect formation of liver metastases but inhibited intravascular colonization of the lung by the tumor cells. Treatment with Prinomastat reduced neuroblastoma tumor vascularization with the presence of smaller vessels. We examined the contribution of MMP-9 to tumor angiogenesis in immunodeficient MMP-9 deficient mice. We demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, associated with a significant decrease in pericytes present along microvessels. Further investigations revealed that in neuroblastoma tumor, MMP-9 is predominantly expressed by bone marrow-derived leukocytes and that it promotes leukocytes infiltration into the tumor stroma. Taken together, the data show that in neuroblastoma, MMP-9 enhances bone marrow-derived cells infiltration into the tumor microenvironment where they positively contribute to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.
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Chantrain, C. F. (2005). Stromal matrix metalloproteinase-9 (MMP-9) promotes pericyte recruitment in neuroblastoma angiogenesis : a new role for matrix metalloproteinases. https://hdl.handle.net/2078.5/110648