A role for endothelial-derived matrix metalloproteinase-2 in breast cancer cell transmigration across the endothelial-basement membrane barrier |
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Authors: | Hamed Kargozaran Sarah Y Yuan Jerome W Breslin Katherine D Watson Nathalie Gaudreault Alison Breen Mack H Wu |
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Institution: | (1) Department of Surgery, Division of Research, University of California Davis School of Medicine, 4625 2nd Avenue, Room 3006, Sacramento, CA 95817, USA |
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Abstract: | Invasive cancer cells utilize matrix metalloproteinases (MMPs) to degrade the extracellular matrix and basement membrane in
the process of metastasis. Among multiple members of the MMP family, the gelatinase MMP-2 has been implicated in the development
and dissemination of malignancies. However, the cellular source of MMP-2 and its effect on metastatic extravasation have not
been well characterized. The objective of this study was to test the hypothesis that active MMP-2 derived from endothelial
cells facilitated the transmigration of breast cancer cells across the microvascular barrier. Gelatin zymography was used
to assess latent and active MMP-2 production in conditioned media from MDA-MB-231 human breast cancer cells, human lung microvascular
endothelial cells (HLMVEC) and co-culture of these two cells. Transmigrated cancer cells were measured during MMP-2 knockdown
with siRNA and pharmacological inhibition of MMP activity with OA-HY. The results showed consistent MMP-2 secretion by the
HLMVECs, whereas a low level production was seen in the MDA-MB-231 cells. Inhibition of MMP-2 expression or activity in HLMVECs
significantly attenuated the transmigration of MDA-MB-231 cells across an endothelial monolayer barrier grown on a reconstituted
basement membrane. The data provide evidence supporting a potential role for the endothelial production of MMPs in promoting
cancer cell extravasation. We suggest that the interaction between malignant cells and peritumoral benign tissues including
the vascular endothelium may serve as an important mechanism in the regulation of tumor invasion and metastasis. |
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Keywords: | Breast cancer Metastasis Microvascular barrier |
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