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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3361-3368
NEOPLASIA
Enforced expression of tissue inhibitor of matrix
metalloproteinase-3 affects functional capillary morphogenesis and
inhibits tumor growth in a murine tumor model
William W. Spurbeck,
Catherine Y. C. Ng,
Ted S. Strom,
Elio F. Vanin, and
Andrew M. Davidoff
From the Departments of Surgery and
Hematology/Oncology, St Jude Children's Research Hospital, and the
Department of Surgery, University of Tennessee College of Medicine,
Memphis, TN.
Homeostasis of the extracellular matrix is a delicate balance
between degradation and remodeling, the balance being maintained by the interaction of activated matrix metalloproteinases (MMPs) and
specific tissue inhibitors of matrix metalloproteinases (TIMPs). Up-regulation of MMP activity, favoring proteolytic degradation of the
basement membrane and extracellular matrix, has been linked to
tumor growth and metastasis, as well as tumor-associated angiogenesis, whereas inhibition of MMP activity appears to restrict these processes. We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit
angiogenesis in vivo. Growth of both histologic types of
gene-modified tumor cells in severe combined
immunodeficiency (SCID) mice was significantly restricted when
compared with controls. Grossly, these tumors were small and had few
feeding vessels. Histologic evaluation revealed that although tumors
overexpressing TIMP-3 had an increased number of CD31+
endothelial cells, these endothelial cells had not formed functional tubules, as evidenced by decreased vessel continuity and minimal pericyte recruitment. This effect appears to be mediated, in part, by
decreased expression of vascular endothelial (VE)-cadherin by
endothelial cells in the presence of TIMP-3 as seen both in an in vitro
assay and in TIMP-3-overexpressing tumors. Taken together, these
results demonstrate that overexpression of TIMP-3 can inhibit angiogenesis and associated tumor growth, and that the
antiangiogenic effects of TIMP-3 appear to be mediated
through the inhibition of functional capillary morphogenesis.
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