title: Abnormal expression of Endoglin and its receptor complex (TGF-β1 and TGF-β receptor II) as early angiogenic switch indicator in premalignant lesions of the colon mucosa.
abstract: The precise timing of the angiogenic switch in colorectal cancer development is still unclear. The simultaneous expression of Endoglin (CD105), transforming growth factor (TGF)-β1 and TGF-β receptor (R) II were quantified in surgical specimens comprising normal human colon, pre-malignant dysplastic tissue, in situ, and invasive colon cancer specimens, at mRNA and protein levels, respectively by real-time PCR and immunohistochemistry. Serum concentrations of soluble Endoglin and TGF-β1 were evaluated. mRNA and CD105+-microvessel density (MVD) increased significantly in dysplastic colon and carcinoma versus normal tissues; values correlated respectively with dysplasia degree and Dukes' stages. TGF-β1 expression was significantly upregulated in most severe dysplastic adenoma specimens, while TGF-β1 transcript and protein signals were intense in carcinoma, positively-correlated with tumor progression. TGF-β1 RII was overexpressed in adenoma and carcinoma versus normal samples, but unrelated with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent in adenoma and normal tissues; in carcinoma the highest levels were in invasive tumor. Circulating TGF-β1 levels were increased in severe dysplasia and progressed with tumor progression. Correlations between adenoma dysplasia degree and TGF-β RII and CD105+-MVD, and between tumor Dukes' staging and TGF-β1 and CD105+-MVD, were significant. TGF-β1 and Endoglin and TGF-β1 serum levels, TGF-β1 staining and CD105+-MVD were significantly and inversely associated with disease-free survival. TGF-β1 levels were an independent and significant prognostic factor of disease-free survival. These findings suggest active angiogenesis occurs in many pre-malignant colon cases and supports more careful evaluation of different chemopreventive agents.
authors.affiliation: Department of Clinical Physiopathology, University of Turin, I-10126 Torino, Italy. graziella.bellone@unito.it
authors.forename: Graziella
authors.initials: G
authors.lastname: Bellone
authors.forename: Claudia
authors.initials: C
authors.lastname: Gramigni
authors.forename: Barbara
authors.initials: B
authors.lastname: Vizio
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Mauri
authors.forename: Adriana
authors.initials: A
authors.lastname: Prati
authors.forename: Dino
authors.initials: D
authors.lastname: Solerio
authors.forename: Luca
authors.initials: L
authors.lastname: Dughera
authors.forename: Enrico
authors.initials: E
authors.lastname: Ruffini
authors.forename: Guido
authors.initials: G
authors.lastname: Gasparri
authors.forename: Michele
authors.initials: M
authors.lastname: Camandona
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000236:Adenoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000096:biosynthesis* / Q000097:blood; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000071063:Endoglin; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000097:blood; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000097:blood; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000097:blood; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II