Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer

Int J Colorectal Dis. 2010 May;25(5):591-9. doi: 10.1007/s00384-010-0906-9. Epub 2010 Feb 18.

Abstract

Aim: In the current study, we investigated the expression of TGF-beta1, its receptor TGFbetaRII, and the signaling proteins Smad4 and Smad7 in colorectal cancer tissue in relation to infiltration with antigen-presenting cells and some clinical and pathologic parameters of disease progression in patients with colorectal cancer (CRC).

Materials and methods: The immunohistochemical expression of TGF-beta1, TGFbetaRII, Smad4, Smad7, HLA-DR antigen, CD1a, CD83, and CD68 was evaluated in 142 patients (50 females and 92 males) with CRC, followed-up for 6-8 years period.

Results: In our study, 127 (89.4%) out of 142 colorectal cancers displayed cytoplasmic TGF-beta1 immunoreactivity. Common-mediator Smad4 was detected in the tumor cytoplasm in 124 cancers (79.5%) and inhibitory Smad7 immunostaining was observed in 110 (77.4%) tumor specimens. TGFbetaRII was expressed on tumor cell membranes in 119 (76.3%) of the cancers. The increased TGF-beta1 expression in tumor cytoplasm was related to low CD68(+)- and CD83(+)-cell infiltration in tumor tissues. Patients with TGF-beta1 overexpression had worse prognosis after surgical therapy compared to those with low expression of TGF-beta1. The observed association was more pronounced for the patients in T1-T2 stage (p = 0.0015).

Conclusions: The expression of TGF-beta1, its receptor TGFbetaRII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens. Our results suggest that TGF-beta1 production by tumor cells may affect the tumor environment via suppression of tumor-infiltrating immune cells and probably contributes to tumor cells aggressiveness through autocrine activation of Smad signaling.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigen-Presenting Cells / metabolism
  • Antigen-Presenting Cells / pathology
  • Cell Count
  • Cell Membrane / metabolism
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Disease Progression
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Smad4 Protein / metabolism*
  • Smad7 Protein / metabolism*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Neoplasm Proteins
  • Receptors, Transforming Growth Factor beta
  • SMAD4 protein, human
  • SMAD7 protein, human
  • Smad4 Protein
  • Smad7 Protein
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II