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

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.

Constructing cancer patient-specific and group-specific gene networks with multi-omics data

“…Among the top 10 genes with a high average Δ PCC in lung adenocarcinoma (LUAD), several genes such as CLDN18, ADAMTS8, PECAM1 and SFTPA1 have been known to be associated with LUAD in previous studies [ 31 – 33 ]. No direct relation of NSUN2 and SLC39A8 with lung squamous cell carcinoma (LUSC) has been known so far.…”

Interactive Verification Analysis of Multiple Sequencing Data for Identifying Potential Biomarker of Lung Adenocarcinoma

“…Many studies had reported that CDH5 expression is associated with multiple tumors [ 43 , 44 ], such as gastric cancer and breast cancer, but the relationship between CDH5 and LUAD is still to be determined. PECAM1 is a multifunctional cell adhesion molecule involved in numerous physiologic processes within the vasculature; Abraham et al found that the activity of PECAM1 appears to be associated with the tumor microenvironment and tumor cell proliferation [ 45 ]; Kuang et al demonstrated that PECAM1 could be a potential prognostic factor and therapeutic target in NSCLC [ 46 ]. The von Willebrand factor (VWF) is a multimeric glycoprotein and plays an essential role in mediating platelet-tumor cell interactions [ 47 ].…”

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

“…Many clinic trails have mentioned a worn that metformin could reduce the platelets which affluent express PECAM-1 on its surface. Herein, we put forward a hypothesis, and metformin could involve in PECAM-1 regulation, which can further affect cisplatin resistance for irradiated cells [19].…”