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.

Keywords: Islr; Meflin; cancer-associated fibroblast; fibrosis; mesenchymal stromal/stem cell; tumour microenvironment.

FIGURE 1

(A) Structure of Meflin/Islr. It is a glycosylphosphatidylinositol-anchored membrane protein with five leucine-rich repeats (LRRs) flanked by cysteine-rich N- and C-terminal domains and an immunoglobulin (Ig)-like domain. (B) Meflin/Islr is an MSC marker. Meflin is highly expressed in undifferentiated MSCs, whereas its expression is downregulated upon MSC differentiation. A lineage trace experiment showed the possibility that Meflin⁺ MSCs undergo self-renewal, although this has not yet been explicitly proven. Meflin⁺ MSCs may also be involved in the maintenance of heamatopoietic stem cells in the bone marrow.

FIGURE 2

Meflin is a new marker for restraining cancer-associated fibroblast (rCAFs) in pancreatic cancer. Recent evidence showed that Meflin⁺ rCAFs, which suppress the activity of Lox and Lox-mediated collagen remodelling, differentiate into αSMA⁺ pCAFs that are weakly positive or negative for Meflin and promote tissue fibrosis during cancer progression. TGF-β signalling, hypoxia, and stiffness are major factors that induce the phenotypic conversion of CAFs. Conversely, it has been hypothesised that vitamins A and D could reprogram pCAFs to rCAFs.

FIGURE 3

Meflin and Grem1 expression in CAFs regulates stromal BMP signalling involved in tumour progression. The collective evidence from several studies shows that Meflin⁺ rCAFs proliferate in early-stage cancer, in which Meflin may augment stromal BMP signalling that counteracts with TGF-β signalling. In advanced-stage cancer, Grem1⁺ pCAFs may be dominant and suppress BMP signalling to promote cancer progression.