Clinical & Experimental Metastasis

, Volume 24, Issue 7, pp 495–502 | Cite as

A role for endothelial-derived matrix metalloproteinase-2 in breast cancer cell transmigration across the endothelial-basement membrane barrier

  • Hamed Kargozaran
  • Sarah Y. Yuan
  • Jerome W. Breslin
  • Katherine D. Watson
  • Nathalie Gaudreault
  • Alison Breen
  • Mack H. Wu
Research Paper

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.

Keywords

Breast cancer Metastasis Microvascular barrier 

Notes

Acknowledgement

This work was supported by the NIH grants HL073324, HL061507, and HL084542.

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Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  • Hamed Kargozaran
    • 1
  • Sarah Y. Yuan
    • 1
  • Jerome W. Breslin
    • 1
  • Katherine D. Watson
    • 1
  • Nathalie Gaudreault
    • 1
  • Alison Breen
    • 1
  • Mack H. Wu
    • 1
  1. 1.Department of Surgery, Division of ResearchUniversity of California Davis School of MedicineSacramentoUSA

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