Abstract
Aim
In the current study, we investigated the expression of TGF-β1, its receptor TGFβRII, 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-β1, TGFβRII, 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-β1 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. TGFβRII was expressed on tumor cell membranes in 119 (76.3%) of the cancers. The increased TGF-β1 expression in tumor cytoplasm was related to low CD68+- and CD83+-cell infiltration in tumor tissues. Patients with TGF-β1 overexpression had worse prognosis after surgical therapy compared to those with low expression of TGF-β1. The observed association was more pronounced for the patients in T1–T2 stage (p = 0.0015).
Conclusions
The expression of TGF-β1, its receptor TGFβRII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens. Our results suggest that TGF-β1 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.
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References
Baker K, Chong G, Foulkes WD, Jass JR (2006) Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes. Histopathology 49:371–380
Korchynskyi O, Landstrom M, Stoika R, Funa K, Heldin C-H, ten Dijke P, Souchelnytskyi S (1999) Expression of Smad proteins in human colorectal cancer. Int J Cancer 82:197–202
Elliot RL, Blobe GC (2005) Role of transforming growth factor beta in human cancer. J Clin Oncol 23:2078–2093
Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A (2007) TGF-beta receptor downregulation in tumor-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer 7:156–166
Xu Y, Pashe B (2007) TGF-β signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet 16(SPEC1):R14-R20. doi:10.1093/hmg/dd1486
Heldin C-H, Miyazono K, ten Duke P (1997) TGF- β signaling from cell membrane to nucleus via Smad proteins. Nature 390:465–471
Derynck R, Feng X-H (1997) TGF- β receptor signaling. Biochim Biophys Acta 1333:F105–F150
Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T (1999) Transforming growth factor β1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 59:3379–3386
Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A (1995) High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev 4:549–554
Robson H, Anderson E, James RD, Schofield PF (1996) Transforming growth factor beta 1 expression in human colorectal tumors: an independent prognostic marker in a subgroup of poor prognosis patients. Br J Cancer 74:753–758
Shibahara T, Si-Tahar M, Shaw SK, Madara JL (2000) Adhesion molecules expressed on homing lymphocytes in model intestinal epithelia. Gastroenterology 118:289–298
Reinacher-Schick A, Baldus SE, Romdhana B, Landsberg S, Zapatka M, Monig SP, Holscher AH, Dienes HP, Schmiegel W, Schwarte-Waldhoff I (2004) Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas. J Pathol 202:412–420
Bates RC, Mercurio AM (2005) The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther 4:365–370
Talmadge JE, Donkor M, Scholar E (2007) Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metast Rev 26:373–400
NakayamaY NN, Minagawa N, Inoue Y, Katsuki T, Onitsuka K, Sako T, Hirata K, Nagata N, Itoh H (2002) Relationships between tumor-associated macrophages and clinicopathological factors in patients with colorectal cancer. Anticancer Res 22:4291–4296
Shurin MR, Shurin GV, Lokshin A, Yurkovetsky Z, Gutkin DW, Chatta G, Zhong H, Han B, Ferris RL (2006) Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev 25:333–356
Miygawa S, Soeda J, Takagi S, Miwa S, Ichikawa E, Noike T (2004) Prognostic significance of mature dendritic cells and factors associated with their accumulation in metastatic liver tumors from colorectal cancer. Hum Pathol 35:1392–1396
Gulubova М, Manolova I, Cirovski G, Sivrev D (2008) Recruitment of dendritic cells in human liver with metastases. Clin Exp Metast 25:777–785
UICC. TNM Classification of Malignant Tumours 6th ed (2002) In: Sobin LH, Wittekind Ch (eds) Wiley-Liss, New York
Kioshima T, Kobayashi I, Matsuo K, Ishibashi Y, Miyoshi A, Akashi Y, Sakai H (1998) Immunohistochemical localization of laminin, collagen type IV and heparan sulfate proteoglycan in human colorectal adenocarcinoma: correlation with local invasive pattern and lymph node metastasis. Acta Histochem Cytochem 31:39–47
Gulubova M, Vlaykova T (2006) Immunohistochemical assessment of fibronectin and tenascin and their integrin receptors alpha5beta1 and alpha9beta1 in gastric and colorectal cancers with lymph node and liver metastases. Acta Histochem 108:25–35
Guzinska-Ustymowicz K, Kemona A (2005) Transforming growth factor beta can be a parameter of aggressiveness of pT1 colorectal cancer. World J Gastroenterol 11:1193–1195
Von Rahden BHA, Stein HJ, Feith M, Puhringer F, Theisen J, Siewert R, Sarbia M (2006) Overexpression of TGF-β1 in esophageal (Barrett’s) adenocarcinoma is associated with advanced stage of disease and poor prognosis. Mol Carcinog 45:786–794
Lu Y, Wu L-Q, Li C-S, Wang S-G, Han B (2008) Expression of transforming growth factors in hepatocellular carcinoma and its relations with clinicopathological parameters and prognosis. Hepatobiliary Pancreat Dis Int 7:174–178
Park YN, Chae KJ, Oh B-K, Choi J, Choi KS, Park C (2004) Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-β. Hepato-Gastroenterol 51:396–400
Picon A, Gold LI, Wang J, Cohen A, Friedman E (1998) A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor β1. Cancer Epidemiol Biomark Prev 7:497–504
Chang H-L, Gillett N, Figari I, Lopez A, Palladino M, Derynck R (1993) Increased transforming growth factor β expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells. Cancer Res 53:4391–4398
Shim KS, Kim KH, Han WS, Park EB (1999) Elevated serum levels of transforming growth factor- β1 in patients with colorectal carcinoma. Cancer 85:554–561
Gold L, Saxena B, Mittalk K, Marmor M, Goswami S, Nactigal L, Kork M, Demopoulos R (1994) Increased expression of transforming growth factor β isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action. Cancer Res 54:2347–2358
Gorsch S, Memoli V, Stukel T, Gold L, Arrick B (1992) Immunohistochemical staining for transforming growth factor β1 associates with disease progression in human breast cancer. Cancer Res 52:6949–6952
Bellone G, Carbone A, Tibaudi D, Mauri F, Ferrero I, Smirne C, Suman F, Rivetti C, Migliaretti G, Camandona M, Palestro G, Emanuelli G, Rodeck U (2001) Differential expression of transforming growth factors- β1, -β2 and -β3 in human colon carcinoma. Eur J Cancer 37:224–233
Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin J-P, Hemminki A, Schwartz S, Aaltonen L, Arango D (2005) Smad4 as a prognostic marker in colorectal cancer. Clin Cancer Res 11:2606–2611
Isaksson-Mettavainio M, Palmqvist R, Forssell J, Stenling R, Oberg A (2006) Smad4/DPC4 expression and prognosis in human colorectal cancer. Anticancer 26:507–510
Javelaud D, Delmas V, Moller M, Sextius P, Andre J, Menashi S, Larue L, Mauviel A (2005) Stable verexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo. Oncogene 24:7624–7629
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338
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Gulubova, M., Manolova, I., Ananiev, J. et al. Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer. Int J Colorectal Dis 25, 591–599 (2010). https://doi.org/10.1007/s00384-010-0906-9
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DOI: https://doi.org/10.1007/s00384-010-0906-9