PECAM‐1 and Metastatic Tumor Cell Proliferation

Abstract

PECAM‐1 mediates homophilic and heterophilic ligand binding as well as intracellular signaling. Although endothelial PECAM‐1 has been implicated in metastatic tumor cell proliferation, the mechanism of this involvement is unknown. Mutants of PECAM‐1 in which PECAM‐1‐dependent homophilic binding, heterophilic binding or intracellular signaling had been disabled by targeted mutations were generated, and then expressed in REN cells (an EC surrogate). The resulting cells were then studied in tumor co‐culture assays using B16 melanoma, LOX human melanoma and murine 4T1 breast cancer. For all three tumors, tumor cell proliferation was simulated 2‐4 fold in the presence of cells expressing PECAM‐1, an activity that was lost if homophilic but not heterophilic or intracellular signaling was disabled. Consistent with the presence of a soluble factor, conditioned media (CM) from the co‐culture of REN cells expressing wild type PECAM‐1 stimulated tumor cell proliferation. An antibody array analysis of CM from murine EC/tumor cell co‐cultures identified TIMP1 (a simulator of tumor cell proliferation) as a possible factor whose expression was significantly inhibited by anti‐PECAM‐1 antibody. Consistent with this, we found that TIMP1 was significantly increased in the presence of cells expressing mouse PECAM‐1. This stimulation of TIMP1 expression was lost if homophilic binding was disrupted but was preserved if heterophilic binding or intracellular signaling were disabled. These data suggest that in vivo, endothelial PECAM‐1 regulates metastatic tumor cell proliferation through processes that involve PECAM‐1‐dependent homophilic ligand interactions and the release of endothelial‐derived TIMP1.