The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer

Abstract

BACKGROUND.Transforming growth factor β (TGFβ) is important in colorectal cancer (CRC) progression. Bone morphogenetic proteins (BMPs), a subgroup within the TGFβ superfamily, recently also have been implicated in CRC, but their precise role in CRC has yet to be investigated.METHODS.The authors used a tissue microarray and immunohistochemistry of BMP receptors and signal transduction elements in adenomas and CRC specimens to elucidate the role of BMP signaling in CRC carcinogenesis.RESULTS.The adenoma specimens expressed all 3 BMP receptors (BMPRs) (BMPR type 1a [BMPR1a], BMPR1b, and BMPR2) and expressed SMAD family member 4 (SMAD4); and 20 of 22 adenomas (90.9%) exhibited active BMP signaling, as determined by nuclear phosphorylated SMAD1,5,8 (pSMAD1,5,8) expression. In contrast, pSMAD1,5,8 nuclear staining was present in 5 CRC specimens (22.7%) but was lost in 17 CRC specimens (77.3%; cancer vs adenoma; P < .0001). The earliest loss of pSMAD1,5,8 nuclear staining was detected in regions of high‐grade dysplasia/carcinoma in situ within adenomas. CRCs showed frequent loss of BMPR2 (P < .0001) and SMAD4 (P < .01) compared with adenomas. Negative expression of BMPR2 was observed more frequently in earlier stage cancers (Dukes stage B) than in advanced cancers (Dukes stage C; P < .05).CONCLUSIONS.Taken together, the current results indicated that loss of BMP signaling correlates tightly with progression of adenomas to cancer and occurs relatively early during cancer progression. Cancer 2008. © 2007 American Cancer Society.

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

“…Our results are further confirmed by the observation that in addition to loss of P53, SMAD4 inactivation plays a key role in late stages of CRC, such as migration and metastatic outgrowth potential. SMAD4 inactivation appeared to block differentiation, which is in line with previous findings where SMAD4 loss was associated with cell spreading, liver metastasis, and a poor disease prognosis (2,(20)(21)(22)(23). Together, our study depicts metastasis as an extremely inefficient process where at least four genetic alterations are required for tumor cells to seed and grow out at distant sites independently of stem cell niche factors.…”

Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin?

“…SMAD1, SMAD5, and SMAD8 serve as substrates for BMP receptors, which have been suggested to play a role in tumor progression, although a possible role in STS remains to be clarified. 47 The 18q22 region associated with favorable prognosis harbors CDH7, which has been implicated in tumor progression in human melanoma, and the loci for cadherin-19 and cadherin-20 are located nearby. 48 One could speculate that deletion of the 18q22 region could compromise cadherin-mediated tumor growth and invasion.…”

Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia

“…Highly expressed in this group of patients with the worst outcome were genes (BMPR1B, CTGF [CCN2], TTYH2, IGJ, PON2, CD73, CDC42EP3, TSPAN7, and SEMA6A) involved in adaptive cell signaling responses to transforming growth factor ␤, stem cell function, B-cell development and differentiation, and the regulation of tumor growth. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] These highest risk cases lacked expression of the genes (NR4A3, BTG3, RGS1, and RGS2) whose relatively high expression characterized the ALL cases with the best outcome. Not surprisingly, given that all cases with an activated kinase signature were assigned to the highest risk group with the combined classifier, 6 of the genes associated with our kinase signature (BMPR1B, ECM1, IGJ, PON2, SEMA6A, and TSPAN7) were contained within our gene expression classifier for RFS.…”