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

Int J Oncol. 2010 Nov;37(5):1153-65. doi: 10.3892/ijo_00000767.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenoma / metabolism
  • Adenoma / mortality
  • Adenoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / biosynthesis*
  • Antigens, CD / blood
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / pathology
  • Endoglin
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Protein Serine-Threonine Kinases / blood
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Cell Surface / biosynthesis*
  • Receptors, Cell Surface / blood
  • Receptors, Transforming Growth Factor beta / biosynthesis*
  • Receptors, Transforming Growth Factor beta / blood
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1 / biosynthesis*
  • Transforming Growth Factor beta1 / blood
  • Young Adult

Substances

  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II