title: 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.
authors.forename: George S
authors.initials: GS
authors.lastname: Karagiannis
authors.forename: Natasha
authors.initials: N
authors.lastname: Musrap
authors.forename: Punit
authors.initials: P
authors.lastname: Saraon
authors.forename: Ann
authors.initials: A
authors.lastname: Treacy
authors.forename: David F
authors.initials: DF
authors.lastname: Schaeffer
authors.forename: Richard
authors.initials: R
authors.lastname: Kirsch
authors.forename: Robert H
authors.initials: RH
authors.lastname: Riddell
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
mesh_terms: D055395:Bone Morphogenetic Protein 1 / Q000235:genetics*; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016207:Cytokines; D018450:Disease Progression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D055395:Bone Morphogenetic Protein 1; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse