Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin‐1

Abstract

The cancer invasion front (CIF), a spatially-recognized area due to the frequent presence of peritumoral desmoplastic reaction, represents a cancer site where many hallmarks of cancer metastasis occur. It is now strongly suggested that the desmoplastic microenvironment holds crucial information for determining tumor development and progression. Despite extensive research on tumor-host cell interactions at CIFs, the exact paracrine molecular network that is hardwired into the proteome of the stromal and cancer subpopulations remains partially understood. Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of a desmoplastic coculture model system of colorectal cancer progression. We discovered a group of bone morphogenetic protein (BMP) antagonists that coordinates major biological programs in CIFs, including cell proliferation, invasion, migration and differentiation processes. Using a mathematical model of cancer cell progression, coupled to in vitro cell migration assays, we demonstrated that the prominent BMP antagonist gremlin-1 (GREM1) may trigger motility of cancer cell cohorts. Our data collectively demonstrate that the desmoplastic CIFs deploy a microenvironmental signature, based on BMP antagonism, in order to regulate the motogenic fates of cancer cell cohorts invading the adjacent stroma.

RETRACTED: LncRNA PVT1 Facilitates Tumorigenesis and Progression of Glioma via Regulation of MiR-128-3p/GREM1 Axis and BMP Signaling Pathway

“…GREM1, known as a BMP antagonist containing cystein knots and typically forming homo-and heterodimers, exerts an inhibitory effect by directly binding to BMP dimers, preventing their interaction with BMP receptors, as well as blocking BMP secretion and increasing extracellular BMP endocytosis [49,50]. GREM1 has been reported to play a role in cancer oncogenesis [51], and its expression is significantly upregulated, which may trigger the motility of cancer cell cohorts [52] and the activation of BMP downstream signaling [32]. Furthermore, many previous researches have demonstrated that BMP expressions are elevated in gliomas, especially BMP2 and BMP4 [32], which are regulated by GREM1 [53].…”

Identification of critical TF-miRNA-mRNA regulation loops for colorectal cancer metastasis

“…Biological processes, related to cell proliferation and differentiation, were significantly enriched, which is consistent with previous studies (Arndt et al, 2009, Karagiannis et al, 2013. BMP4 was found in most of the GO terms.…”

Association between polymorphisms at the GREM1 locus and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population

“…The difference might be due to the role of GREM1 in the regulation of cell proliferation and its anti-apoptotic function (Sneddon et al, 2006;Maciel et al, 2008). Overexpression of GREM1 in desmoplastic cocultures of CRC impairs BMP2/7 signaling and promotes tumor cell motility and proliferation (Maciel at al., 2008;Karagiannis et al, 2013). During embryogenesis, GREM1-mediated increased cell proliferation and/or reduced apoptosis could promote the proper oral tissue development and prevent oral cleft formation.…”