TY - JOUR
T1 - The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer
AU - Kodach, Liudmila L.
AU - Bleuming, Sylvia A.
AU - Musler, Alex R.
AU - Peppelenbosch, Maikel P.
AU - Hommes, Daniel W.
AU - Van Den Brink, Gijs R.
AU - Van Noesel, Carel J.M.
AU - Offerhaus, G. Johan A.
AU - Hardwick, James C.H.
PY - 2008/1/15
Y1 - 2008/1/15
N2 - 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 SMAD 1,5,8 (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.
AB - 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 SMAD 1,5,8 (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.
UR - http://www.scopus.com/inward/record.url?scp=38049029612&partnerID=8YFLogxK
U2 - 10.1002/cncr.23160
DO - 10.1002/cncr.23160
M3 - Article
C2 - 18008360
AN - SCOPUS:38049029612
SN - 0008-543X
VL - 112
SP - 300
EP - 306
JO - Cancer
JF - Cancer
IS - 2
ER -
