Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer

In the current study, we investigated the expression of TGF-beta 1, its receptor TGF beta RII, 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). The immunohistochemical expression of TGF-beta 1, TGF beta RII, 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. In our study, 127 (89.4%) out of 142 colorectal cancers displayed cytoplasmic TGF-beta 1 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. TGF beta RII was expressed on tumor cell membranes in 119 (76.3%) of the cancers. The increased TGF-beta 1 expression in tumor cytoplasm was related to low CD68(+)- and CD83(+)-cell infiltration in tumor tissues. Patients with TGF-beta 1 overexpression had worse prognosis after surgical therapy compared to those with low expression of TGF-beta 1. The observed association was more pronounced for the patients in T1-T2 stage (p = 0.0015). The expression of TGF-beta 1, its receptor TGF beta RII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens. Our results suggest that TGF-beta 1 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.