title: The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer.
abstract: BACKGROUND
  Transforming growth factor beta (TGFbeta) is important in colorectal cancer (CRC) progression. Bone morphogenetic proteins (BMPs), a subgroup within the TGFbeta 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.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Liudmila L
authors.initials: LL
authors.lastname: Kodach
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Bleuming
authors.forename: Alex R
authors.initials: AR
authors.lastname: Musler
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: James C H
authors.initials: JC
authors.lastname: Hardwick
mesh_terms: D000236:Adenoma / Q000209:etiology*; D000368:Aged; D000369:Aged, 80 and over; D052004:Bone Morphogenetic Protein Receptors / Q000032:analysis; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D003110:Colonic Neoplasms / Q000209:etiology*; D015179:Colorectal Neoplasms / Q000209:etiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000032:analysis
chemical_list: D019485:Bone Morphogenetic Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D052004:Bone Morphogenetic Protein Receptors