BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice

Abstract

The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis. In DSS-treated wild-type mice, the preneoplastic lesions which did not eventually evolve to adenomas resided in a colitic microenvironment characterized by a balanced upregulation of both BMP ligands, i.e., Bmp4/7 and BMP inhibitors, such as chordin, noggin, and gremlin-1. In the uPA-deficient tumor-promoting inflammatory microenvironment, however, there was a clear evidence for BMP pathway suppression. By contrast to DSS-treated wild-type controls, the inflammation-associated Bmp4 upregulation was abolished, and the BMP signaling suppression was further enhanced by a particularly high increase of gremlin-1 expression. These findings propose that BMP pathway suppression in colon cancer could be associated with very early stages of the preneoplasia-to-neoplasia sequence of events.

Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

“…A recent report indicated that β-catenin can be inhibited by BMP via SMAD4 to down-regulate the expression of c-myc and Axin2 in microdissected small intestinal adenomas of tamoxifen-treated mice [98]. Another study sufficiently suggests that BMP and WNT appear to be interconnected via the PI3k/Akt pathway [99,100].…”

“…Subsequently, activated p-SMAD 1/5/8 translocates from the cytoplasm to the nucleus by forming a complex with SMAD4, and ultimately, it regulates transcription and expression of target genes such as inhibitor of DNA binding (ID) [96] and CCL15 [97]. Importantly, the BMP pathway is down-regulated in the majority of colon cancer cases [98].…”

Knockdown GREM1 suppresses cell growth, angiogenesis, and epithelial‐mesenchymal transition in colon cancer

“…5,12,13 So we also detected the effect of tumor-secreted GREM1 on the capillary structure formation of HUVEC. 5,12,13 So we also detected the effect of tumor-secreted GREM1 on the capillary structure formation of HUVEC.…”

Prognostic and clinicopathological significance of Hapto and Gremlin1 expression in extrahepatic cholangiocarcinoma

“…Previous studies demonstrated that Gremlin1 is overexpressed in various types of human cancers [26]. It has been reported that Gremlin1 is associated with tumorigenesis of several cancers, including oral cancer, glioma, colorectal cancer, hepatocellular cancer and renal cancer [22,[27][28][29][30][31][32][33].…”