Details

Autor(en) / Beteiligte

• Dutton, Louise R
• Hoare, Owen P
• McCorry, Amy M B
• Redmond, Keara L
• Adam, Noor Eisa
• Canamara, Shannon
• Bingham, Victoria
• Mullan, Paul B
• Lawler, Mark
• Dunne, Philip D
• Brazil, Derek P

Titel

Fibroblast-derived Gremlin1 localises to epithelial cells at the base of the intestinal crypt

Ist Teil von

• Oncotarget, 2019-07, Vol.10 (45), p.4630-4639

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Gremlin1 (GREM1) is a secreted glycoprotein member of the differential screening-selected gene in aberrant neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists, which binds to BMPs preventing their receptor engagement. Previous studies have identified that stage II colorectal cancer (CRC) patients with high levels of gene expression in their tumour tissue have a poorer prognosis. Using a series of and methodologies, we demonstrate that gene expression is significantly higher ( < 0.0001) in CRC consensus molecular subtype 4 (CMS4), compared to the other CMS subtypes and correlates ( < 0.0001) with levels of cancer-associated fibroblasts (CAFs) within the CRC tumour microenvironment (TME). Our optimised immunohistochemistry protocol identified endogenous GREM1 protein expression in both the muscularis mucosa and adjacent colonic crypt bases in mouse intestine, in contrast to RNA expression which was shown to localise specifically to the muscularis mucosa, as determined by hybridisation. Importantly, we demonstrate that cells with high levels of GREM1 expression display low levels of phospho-Smad1/5, consistent with reduced BMP signalling. Taken together, these data highlight a novel paracrine signalling circuit, which involves uptake of mature GREM1 protein by colonic crypt cells following secretion from neighbouring fibroblasts in the TME.