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


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.
Gulubova
Maya
M
Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, 11 Armeiska Str, 6000, Stara Zagora, Bulgaria. decan@mf.uni-sz.bg
Manolova
Irena
I
Ananiev
Julian
J
Julianov
Alexander
A
Yovchev
Yovcho
Y
Peeva
Katya
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; C497806:SMAD7 protein, human; D051901:Smad4 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II