title: Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts.
abstract: Bone morphogenetic proteins (BMPs) are a group of growth factors with dual functions in cancer development and progression. Recently, certain tumor-promoting roles have been identified for selected antagonists/inhibitors (BMPIs) of this developmental pathway. A recent focus on the implication of BMP in colorectal cancer progression has emerged, mainly due to the presence of inactivating mutations in several members of the canonical signaling cascade. However, the detailed expression profiles of BMPIs remain largely unknown. Based on our previous work, whereby three specific BMPIs, gremlin-1 (GREM1), high-temperature requirement A3 (HTRA3) and follistatin (FST) were collectively overexpressed in desmoplastic cocultures of colorectal cancer (CRC), here, we undertook an immunohistochemical approach to describe the patterns of their expression in CRC patients. Two major characteristics described the BMPI expression signature: First, the synchronous and coordinated stromal and epithelial overexpression of individual BMPIs in desmoplastic lesions, which demonstrated that all three of them contribute to increasing levels of BMP antagonism in such areas. Second, the presence of microenvironmental polarity in the BMPI pattern of expression, which was indicated through the preferential expression of HTRA3 in the stromal, and the parallel FST/GREM1 expression in the epithelial component of the investigated sections. In addition, expression of HTRA3 in the epithelial compartment of the tumors demonstrated a significant predictive power to discriminate between tumor-budding-bearing and tumor-budding-free desmoplastic microenvironments. Together, these findings contribute to the understanding of signaling dynamics of BMP antagonism in the colorectal cancer desmoplastic invasion front.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: George S
authors.initials: GS
authors.lastname: Karagiannis
authors.affiliation: MC Pathology, The Laboratory, Charlemont Clinic, Charlemont Mall, Dublin, Ireland.
authors.forename: Ann
authors.initials: A
authors.lastname: Treacy
authors.affiliation: Zane Cohen Clinical Research Centre, Mount Sinai Hospital, Toronto, Canada; Division of General Surgery, Mount Sinai Hospital, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Messenger
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine, St Michael's Hospital, Toronto, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Grin
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Kirsch
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Riddell
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada. Electronic address: ediamandis@mtsinai.on.ca.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019485:Bone Morphogenetic Proteins / Q000032:analysis*; D015331:Cohort Studies; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D038681:Follistatin / Q000032:analysis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D012007:Rectum / Q000473:pathology*; D012697:Serine Endopeptidases / Q000032:analysis*
chemical_list: D019485:Bone Morphogenetic Proteins; D038681:Follistatin; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C474013:HTRA3 protein, human; D012697:Serine Endopeptidases
keywords: Bone morphogenetic protein antagonists; Cancer-associated fibroblasts; Colorectal cancer; Follistatin; Gremlin-1; High-temperature requirement-A3; Tumor budding