Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression

Abstract

Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

CD34 + mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury

“…Grem1 is overexpressed in carcinomaassociated fibroblasts of several human carcinomas, including colon carcinomas, and promotes tumor cell proliferation (42).…”

Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma

“…On the other hand, Van Vlodrop et al (1) reported that methylation of the promoter region of Gremlin was associated with higher tumor grade, higher tumor stage, reduced MVD and shorter survival time in patients with CCRCC. Karagiannis et al (16) showed that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression. Yan et al (17) reported that Gremlin1-overexpressing cells display increased growth and tumor formation abilities.…”

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

“…However, these findings should not be interpreted to conclude that cases of poor prognosis have a larger population of CSCs. Gremlin 1 was found to be secreted from stromal cancer-associated fibroblast (CAFs) in colon cancer and its expression was localized to invasion fronts (24)(25)(26). On the other hand, Gremlin 1 was found to be secreted by CSCs in glioblastoma and was thought to prevent CSCs from differentiating by antagonizing the effects ofBMPs (27,28).…”

“…BMPs are members of the transforming growth factor (TGF)-β superfamily and play an essential role during development and differentiation while Gremlin 1 is also related to differentiation in combination with BMPs and its dysregulation results in developmental diseases (20)(21)(22)(23). Gremlin 1 is overexpressed in various types of human cancers (24)(25)(26). Recently several studies have demonstrated that CSCs prevent the BMP differentiating effect by secreting Gremlin 1 in glioblastoma, suggesting that Gremlin 1 plays a role in maintenance of CSC properties (27,28).…”