Potential importance of protease activated receptor (PAR)-1 expression in the tumor stroma of non-small-cell lung cancer

Abstract

BackgroundProtease activated receptor (PAR)-1 expression is increased in a variety of tumor cells. In preclinical models, tumor cell PAR-1 appeared to be involved in the regulation of lung tumor growth and metastasis; however the role of PAR-1 in the lung tumor microenvironment, which is emerging as a key compartment in driving cancer progression, remained to be explored.MethodsIn the present study, PAR-1 gene expression was determined in lung tissue from patients with non-small-cell lung cancer (NSCLC) using a combination of publicly available RNA microarray datasets and in house-made tissue microarrays including tumor biopsies of 94 patients with NSCLC (40 cases of adenocarcinoma, 42 cases of squamous cell carcinoma and 12 cases of other type of NSCLC at different stages).ResultsPAR-1 gene expression strongly correlated with tumor stromal markers (i.e. macrophage, endothelial cells and (myo) fibroblast markers) but not with epithelial cell markers. Immunohistochemical analysis confirmed the presence of PAR-1 in the tumor stroma and showed that PAR-1 expression was significantly upregulated in malignant tissue compared with normal lung tissue. The overexpression of PAR-1 in tumor stroma of NSCLC appeared to be independent from tumor type, tumor stage, histopathological differentiation status, disease progression and patient survival.ConclusionOverall, our data provide evidence that PAR-1 in NSCLC is mainly expressed on cells that constitute the pulmonary tumor microenvironment, including vascular endothelial cells, macrophages and stromal fibroblasts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3081-3) contains supplementary material, which is available to authorized users.

Antithrombotic Agents and Cancer

“…Beyond platelets and malignant cells, the expression of PAR-1 is detected in fibroblasts, macrophages, and endothelial cells, which represent the principal cell types of the tumor microenvironment deeply involved in cancer cell seeding and growth [ 107 ].…”

Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer

“…The serum levels of PAR-1 might have a diagnostic value in lung cancer patients [ 91 ]. PAR-1 in NSCLC (Non-small cell lung cancer) is mainly expressed in cells that constitute the tumor microenvironment, including vascular endothelial cells, macrophages and stromal fibroblasts [ 92 ].…”

Effect of chimeric antigen receptor T cells against protease-activated receptor 1 for treating pancreatic cancer

“…Rather than being specific to tumor cells, PAR1 is expressed by the surrounding stroma that consists of endothelial cells, fibroblasts, and macrophages. Activation of stromal cell-associated PAR1 expression in the TME leads to increased vascular permeability, ECM production, and cytokine secretion, thereby promoting tumorigenesis [ 18 , 52 ]. In this study, we developed PAR1-targeted CAR-T cells using third-generation CARs containing additional signaling domains, including CD28, CD137 (4-1BB), and CD3ζ (CD247), to augment activation of cytokine production and a tumor-eradication ability [ 38 , 53 ].…”