Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis

Abstract

Fibroblasts synthesise the extracellular matrix (ECM) such as collagen and elastin, the excessive accumulation of which can lead to fibrosis and organ dysfunction under pathological conditions. Cancer-associated fibroblasts (CAFs) are major constituents of the tumour microenvironment (TME) that accompany the desmoplastic reaction responsible for anti-cancer treatment resistance. Thus, it is important to dissect the roles of CAFs in the TME to develop new therapeutic strategies for refractory cancers. Recent progress in the studies of CAF biology suggests that the functions of CAFs are complicated and that they are composed of functionally distinct populations, including cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We recently identified a new cell surface marker for rCAFs in pancreatic and colon cancers, designated as Meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue)/Islr (immunoglobulin super family containing leucine-rich repeat). Based on the distribution of Meflin/Islr-positive cells, we also considered it a specific candidate marker for mesenchymal stroma/stem cells. Meflin/Islr-positive CAFs have been shown to suppress cancer progression by being involved in regulating collagen structures and BMP signalling in the TME. This review describes the function of Meflin/Islr in cancer fibrosis as well as in cardiac and lung fibrosis and its potential in the development of new cancer therapeutics.

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

“…Our group recently focused on another protein, Meflin, which is specifically expressed in CAFs in both human and mouse PDAC [ 26 , 28 , 29 , 38 ]. It is a glycosyl-phosphatidylinositol-anchored protein encoded by the gene immunoglobulin superfamily containing leucine-rich repeats ( ISLR ), which is also secreted into media containing cultured fibroblasts [ 29 , 39 ].…”

Spheroid Formation and Peritoneal Metastasis in Ovarian Cancer: The Role of Stromal and Immune Components

“…Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression. CAFs enhance cancer cell proliferation [ 54 ], angiogenesis and lymphangiogenesis [ 55 ], ECM remodeling, immune cell recruitment [ 56 ], invasion and metastasis via cytokine and chemokine secretion [ 57 , 58 , 59 , 60 , 61 , 62 ]. CAFs are a highly heterogeneous subpopulation of stromal cells in TME, originating from different precursors, including resident tissue fibroblasts, bone marrow mesenchymal stem cells, hematopoietic stem cells, epithelial cells and endothelial cells [ 63 , 64 , 65 ].…”

Clinical Application Perspectives of Lung Cancers 3D Tumor Microenvironment Models for In Vitro Cultures

“…Tumor cells are responsible for recruiting stromal cells (myofibroblasts) and immune cells to initiate multi-stage progression. Fibroblasts are involved in extracellular matrix formation due to the synthesis of structural proteins, e.g., integrins, collagen, or elastin [45,46]. Cho et al showed the myofibroblast impact on fibronectin remodeling through paracrine communication with tumors [47]., A fibroblast subtype crucial for tumor progression include cancer associated fibroblasts (CAFs) developed from myofibroblasts.…”

“…Nevertheless, high tumor mutational burden, which is typical for smokers, is connected with better "visibility" of tumors for immune cells [64]. Tumor-infiltrated immune cells may include cancer-infiltrated cytotoxic T cells (CTLs), memory T cells (CD 45 RO + ), regulatory T cells (CD4 + CD25 + ), tumor-infiltrated macrophages type M1 and/or M2, and dendritic cells. The infiltration location may appear in the tumor core or its marginal side.…”