Involvement of TIMP-1 in PECAM-1-mediated tumor dissemination

Abraham,Valsamma; Cao,Gaoyuan; Parambath,Andrew; Lawal,Fareedah; Handumrongkul,Chakkrapong; Debs,Robert; DeLisser,Horace  M.

doi:10.3892/ijo.2018.4422

Involvement of TIMP-1 in PECAM-1-mediated tumor dissemination

Authors:
- Valsamma Abraham
- Gaoyuan Cao
- Andrew Parambath
- Fareedah Lawal
- Chakkrapong Handumrongkul
- Robert Debs
- Horace M. DeLisser
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Affiliations: Pulmonary, Allergy and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA, Rutgers Institute for Translational Medicine and Science, Child Health Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA, California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA
Published online on: May 25, 2018 https://doi.org/10.3892/ijo.2018.4422
Pages: 488-502
Copyright: © Abraham et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Platelet endothelial cell adhesion molecule‑1 (PECAM‑1) is expressed on the vascular endothelium and has been implicated in the late progression of metastatic tumors. The activity of PECAM‑1 appears to be mediated by modulation of the tumor microenvironment (TME) and promotion of tumor cell proliferation, rather than through the stimulation of tumor angiogenesis. The present study aimed to extend those initial findings by indicating that the presence of functional PECAM‑1 on the endothelium promotes a proliferative tumor cell phenotype in vivo, as well as in tumor cell (B16‑F10 melanoma and 4T1 breast cancer cell lines) co‑culture assays with mouse endothelial cells (ECs) or a surrogate EC line (REN‑MP). The pro‑proliferative effects were mediated by soluble endothelial‑derived factors that were dependent on PECAM‑1 homophilic ligand interactions, but which were independent of PECAM‑1‑dependent signaling. Further analysis of the conditioned media obtained from tumor/EC and tumor/REN‑MP co‑cultures identified TIMP metallopeptidase inhibitor‑1 (TIMP‑1) as a PECAM‑1‑regulated factor, the targeting of which in the tumor cell/REN‑MP system inhibited tumor cell proliferation. In addition, TIMP‑1 expression was decreased in metastatic tumors from the lungs of PECAM‑1‑null mice, thus providing evidence of the in vivo significance of co‑culture studies. Taken together, these studies indicated that endothelial PECAM‑1, through PECAM‑1‑dependent homophilic binding interactions, may induce release of TIMP‑1 from the endothelium into the TME, thus leading to increased tumor cell proliferation.

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