Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma

Abstract

Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer-associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α-smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica-Masson staining. We also analyzed the expression of mesenchymal stromal cell-and fibroblast-expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer-restraining CAFs and differ from αSMA-positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF + CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…CAFs are able to remodel ECM by the production of several ECM-related proteins (e.g., integrins) that mediate the crosstalk with tumor cells and promote local invasion and metastatic spread [ 64 ]. These spindle-like cells are also found in mesothelioma tissue, associated with pro-tumor functions, such as stromal remodeling and tumor invasion, and are correlated with poor prognosis [ 65 ]. Ohara et al proposed a mechanism by which fibroblasts participate to pleural fibrosis in the early mesothelioma phases in response to ROS production by frustrated macrophages.…”

Bioinformatics Analysis of ISLR in Pan-Cancer and its Correlation with Tumor Immunity

“…Although ISLR was discovered as early as 1997, it has not been fully studied in tumors. Some studies have reported that ISLR plays an important role in tumor progression in CAFs, such as colorectal cancer, pancreatic cancer, and malignant pleural stromal tumors [7,23,24]. This means that ISLR may play a role in the TME, which is one of the reasons why we conducted this research on the role of ISLR in pan-cancer and tumor immunity.…”

A Panel of Emerging EMT Genes Identified in Malignant Mesothelioma

“…Using surgical specimens of epithelioid MPM, the authors evaluated the clinicopathological significance of αSMA expression, the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry. They showed that the expression of αSMA and CTGF in CAFs correlated with poor prognosis in epithelioid subtype MESO patients 40 .…”