Skip to main content
Top
Published in: Tumor Biology 4/2012

01-08-2012 | Research Article

Prognostic significance of transforming growth factor beta (TGF-β) signaling axis molecules and E-cadherin in colorectal cancer

Authors: Pavlos Lampropoulos, Adamantia Zizi-Sermpetzoglou, Spyros Rizos, Alkiviadis Kostakis, Nikolaos Nikiteas, Athanasios G. Papavassiliou

Published in: Tumor Biology | Issue 4/2012

Login to get access

Abstract

The transforming growth factor beta (TGF-β) signaling pathway has been considered both a tumor suppressor and a cancer promoter. Additionally, downregulation of cell adhesion molecules such as E-cadherin plays an important role in the metastatic potential of colorectal cancer (CRC). The aim of the present study was to evaluate TGF-β, TGF-β type I receptor (TGF-βR1), TGF-β type II receptor (TGF-βR2), Smad4, pSmad2/3, and E-cadherin expression in colorectal carcinoma and to correlate the obtained data with other standard prognostic parameters, such as disease stage, metastases, and patient survival. TGF-β, TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin expression was evaluated immunohistochemically in 195 unrelated CRC specimens and the results subjected to various statistical analyses. TGF-β was expressed in 71.28%, TGF-βR1 in 61.0%, TGF-βR2 in 54.4%, Smad4 in 61.5%, pSmad2/3 in 71.3%, and E-cadherin in 50.26% of the colorectal carcinoma samples tested. The correlation of immunoexpression with the clinicopathological parameters of CRC revealed that the high expression of TGF-β and low expression of TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin were correlated with tumor–node–metastasis (TNM) stage of disease. High TGF-β expression and low TGF-βR1, TGF-βR2, Smad4, and pSmad2/3 expression were also correlated with lymph node metastasis. The Kaplan–Meier survival curves demonstrated a clear association of cancer-specific overall survival with high TGF-β, as well as low TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin expression. Our results suggest that TGF-β, TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin are closely related to TNM stage of CRC. Moreover, TGF-β, TGF-βR2, Smad4, pSmad2/3, and E-cadherin emerge as valuable independent biomarkers of prognosis in CRC patients.
Literature
1.
go back to reference Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81.PubMed Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81.PubMed
2.
go back to reference Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.PubMed Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.PubMed
3.
go back to reference Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998;95:737–40.PubMed Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998;95:737–40.PubMed
4.
go back to reference Miyazono K, ten Dijke P, Heldin CH. TGF-beta signaling by Smad proteins. Adv Immunol. 2000;75:115–57.PubMed Miyazono K, ten Dijke P, Heldin CH. TGF-beta signaling by Smad proteins. Adv Immunol. 2000;75:115–57.PubMed
5.
go back to reference Akhurst RJ, Derynck R. TGF-beta signaling in cancer -a double- edged sword. Trends Cell Biol. 2001;11:S44–51.PubMed Akhurst RJ, Derynck R. TGF-beta signaling in cancer -a double- edged sword. Trends Cell Biol. 2001;11:S44–51.PubMed
6.
go back to reference Beach JR, Hussey GS, Miller TE, et al. Myosin II isoform switching mediates invasiveness after TGF-β-induced epithelial-mesenchymal transition. Proc Natl Acad Sci USA. 2011;108:17991–6.PubMedPubMedCentral Beach JR, Hussey GS, Miller TE, et al. Myosin II isoform switching mediates invasiveness after TGF-β-induced epithelial-mesenchymal transition. Proc Natl Acad Sci USA. 2011;108:17991–6.PubMedPubMedCentral
7.
go back to reference Sylvie J, Ellen C, Kris V. The role of Wnt in cell signaling and cell adhesion during early vertebrate development. Front Biosci. 2011;17:2352–66. Sylvie J, Ellen C, Kris V. The role of Wnt in cell signaling and cell adhesion during early vertebrate development. Front Biosci. 2011;17:2352–66.
8.
go back to reference Meulmeester E, Ten Dijke P. The dynamic roles of TGF-β in cancer. J Pathol. 2011;223:205–18.PubMed Meulmeester E, Ten Dijke P. The dynamic roles of TGF-β in cancer. J Pathol. 2011;223:205–18.PubMed
9.
go back to reference Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198:11–26.PubMed Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198:11–26.PubMed
10.
go back to reference Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87:992–1005.PubMed Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87:992–1005.PubMed
11.
go back to reference Kinsella AR, Green B, Lepts GC, Hill CL, Bowie G, Taylor BA. The role of the cell-cell adhesion molecule E-cadherin in large bowel tumour cell invasion and metastasis. Br J Cancer. 1993;67:904–9.PubMedPubMedCentral Kinsella AR, Green B, Lepts GC, Hill CL, Bowie G, Taylor BA. The role of the cell-cell adhesion molecule E-cadherin in large bowel tumour cell invasion and metastasis. Br J Cancer. 1993;67:904–9.PubMedPubMedCentral
12.
go back to reference Hugh TJ, Dillon SA, Taylor BA, Pignatelli M, Poston GJ, Kinsella AR. Cadherin-catenin expression in primary colorectal cancer: a survival analysis. Br J Cancer. 1999;80:1046–51.PubMedPubMedCentral Hugh TJ, Dillon SA, Taylor BA, Pignatelli M, Poston GJ, Kinsella AR. Cadherin-catenin expression in primary colorectal cancer: a survival analysis. Br J Cancer. 1999;80:1046–51.PubMedPubMedCentral
13.
go back to reference Dorudi S, Hanby AM, Poulsom R, Northover J, Hart IR. Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. Br J Cancer. 1995;71:614–6.PubMedPubMedCentral Dorudi S, Hanby AM, Poulsom R, Northover J, Hart IR. Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. Br J Cancer. 1995;71:614–6.PubMedPubMedCentral
14.
go back to reference Karamitopoulou E, Zlobec I, Patsouris E, Peros G, Lugli A. Loss of E-cadherin independently predicts the lymph node status in colorectal cancer. Pathology. 2011;43:133–7.PubMed Karamitopoulou E, Zlobec I, Patsouris E, Peros G, Lugli A. Loss of E-cadherin independently predicts the lymph node status in colorectal cancer. Pathology. 2011;43:133–7.PubMed
15.
go back to reference Ikeguchi M, Taniguchi T, Makino M, Kaibara N. Reduced E-cadherin expression and enlargement of cancer nuclei strongly correlate with hematogenic metastasis in colorectal adenocarcinoma. Scand J Gastroenterol. 2000;35:839–46.PubMed Ikeguchi M, Taniguchi T, Makino M, Kaibara N. Reduced E-cadherin expression and enlargement of cancer nuclei strongly correlate with hematogenic metastasis in colorectal adenocarcinoma. Scand J Gastroenterol. 2000;35:839–46.PubMed
16.
go back to reference Sobin LH, Wittenkind C. TNM classification of malignant tumors. 6th ed. New York: Wiley; 2002. Internatrional Union Against cancer. Sobin LH, Wittenkind C. TNM classification of malignant tumors. 6th ed. New York: Wiley; 2002. Internatrional Union Against cancer.
17.
go back to reference Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res. 2002;8:1838–42.PubMed Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res. 2002;8:1838–42.PubMed
18.
go back to reference Saito H, Tsujitani S, Oka S, et al. The expression of transforming growth factor-beta1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma. Cancer. 1999;86:1455–62.PubMed Saito H, Tsujitani S, Oka S, et al. The expression of transforming growth factor-beta1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma. Cancer. 1999;86:1455–62.PubMed
19.
go back to reference Kinugasa S, Abe S, Tachibana M, et al. Overexpression of transforming growth factor-beta1 in scirrhous carcinoma of the stomach correlates with decreased survival. Oncology. 1998;55:582–7.PubMed Kinugasa S, Abe S, Tachibana M, et al. Overexpression of transforming growth factor-beta1 in scirrhous carcinoma of the stomach correlates with decreased survival. Oncology. 1998;55:582–7.PubMed
20.
go back to reference Wu ZY, Zhan WH, Li JH, et al. Expression of E-cadherin in gastric carcinoma and its correlation with lymph node micrometastasis. World J Gastroenterol. 2005;11:3139–43.PubMedPubMedCentral Wu ZY, Zhan WH, Li JH, et al. Expression of E-cadherin in gastric carcinoma and its correlation with lymph node micrometastasis. World J Gastroenterol. 2005;11:3139–43.PubMedPubMedCentral
21.
go back to reference Yu C, Liu Y, Huang D, et al. TGF-β1 mediates epithelial to mesenchymal transition via the TGF-β/Smad pathway in squamous cell carcinoma of the head and neck. Oncol Rep. 2011;25:1581–7.PubMed Yu C, Liu Y, Huang D, et al. TGF-β1 mediates epithelial to mesenchymal transition via the TGF-β/Smad pathway in squamous cell carcinoma of the head and neck. Oncol Rep. 2011;25:1581–7.PubMed
22.
go back to reference Kim AN, Jeon WK, Lim KH, Lee HY, Kim WJ, Kim BC. Fyn mediates transforming growth factor-beta1-induced down-regulation of E-cadherin in human A549 lung cancer cells. Biochem Biophys Res Commun. 2011;407:181–4.PubMed Kim AN, Jeon WK, Lim KH, Lee HY, Kim WJ, Kim BC. Fyn mediates transforming growth factor-beta1-induced down-regulation of E-cadherin in human A549 lung cancer cells. Biochem Biophys Res Commun. 2011;407:181–4.PubMed
23.
go back to reference Xu Z, Jiang Y, Steed H, Davidge S, Fu Y. TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochem Biophys Res Commun. 2010;401:376–81.PubMed Xu Z, Jiang Y, Steed H, Davidge S, Fu Y. TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochem Biophys Res Commun. 2010;401:376–81.PubMed
24.
go back to reference Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010;29:6485–98.PubMedPubMedCentral Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010;29:6485–98.PubMedPubMedCentral
25.
go back to reference Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005;6:56.PubMedPubMedCentral Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005;6:56.PubMedPubMedCentral
26.
go back to reference Kim JH, Jang YS, Eom KS, et al. Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci. 2007;22:898–904.PubMedPubMedCentral Kim JH, Jang YS, Eom KS, et al. Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci. 2007;22:898–904.PubMedPubMedCentral
27.
go back to reference Wieser R. The transforming growth factor-beta signaling pathway in tumorigenesis. Curr Opin Oncol. 2001;13:70–7.PubMed Wieser R. The transforming growth factor-beta signaling pathway in tumorigenesis. Curr Opin Oncol. 2001;13:70–7.PubMed
28.
go back to reference Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–52.PubMed Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–52.PubMed
29.
go back to reference Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82:85–91.PubMed Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82:85–91.PubMed
30.
go back to reference Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev. 1995;4:549–54.PubMed Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev. 1995;4:549–54.PubMed
31.
go back to reference Tsushima H, Kawata S, Tamura S, et al. High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression. Gastroenterology. 1996;110:375–82.PubMed Tsushima H, Kawata S, Tamura S, et al. High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression. Gastroenterology. 1996;110:375–82.PubMed
32.
go back to reference Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Ferreira VM, Lopes CS. Association of E-cadherin and beta-catenin immunoexpression with clinicopathologic features in primary ovarian carcinomas. Hum Pathol. 2004;35:663–9.PubMed Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Ferreira VM, Lopes CS. Association of E-cadherin and beta-catenin immunoexpression with clinicopathologic features in primary ovarian carcinomas. Hum Pathol. 2004;35:663–9.PubMed
33.
go back to reference Zhao XJ, Li H, Chen H, et al. Expression of e-cadherin and beta-catenin in human esophageal squamous cell carcinoma: relationships with prognosis. World J Gastroenterol. 2003;9:225–32.PubMedPubMedCentral Zhao XJ, Li H, Chen H, et al. Expression of e-cadherin and beta-catenin in human esophageal squamous cell carcinoma: relationships with prognosis. World J Gastroenterol. 2003;9:225–32.PubMedPubMedCentral
34.
go back to reference Mialhe A, Louis J, Montlevier S, et al. Expression of E-cadherin and alpha-, beta- and gamma-catenins in human bladder carcinomas: are they good prognostic factors? Invasion Metastasis. 1997;17:124–37.PubMed Mialhe A, Louis J, Montlevier S, et al. Expression of E-cadherin and alpha-, beta- and gamma-catenins in human bladder carcinomas: are they good prognostic factors? Invasion Metastasis. 1997;17:124–37.PubMed
35.
go back to reference Pignatelli M, Ansari TW, Gunter P, et al. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J Pathol. 1994;174:243–8.PubMed Pignatelli M, Ansari TW, Gunter P, et al. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J Pathol. 1994;174:243–8.PubMed
36.
go back to reference Bukholm IK, Nesland JM, Kåresen R, Jacobsen U, Børresen-Dale AL. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol. 1998;185:262–6.PubMed Bukholm IK, Nesland JM, Kåresen R, Jacobsen U, Børresen-Dale AL. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol. 1998;185:262–6.PubMed
37.
go back to reference Zolota V, Batistatou A, Tsamandas AC, Iliopoulos G, Scopa CD, Bonikos DS. Immunohistochemical expression of TGF-beta1, p21WAF1, p53, Ki67, and angiogenesis in gastric carcinomas: a clinicopathologic study. Int J Gastrointest Cancer. 2002;32:83–9.PubMed Zolota V, Batistatou A, Tsamandas AC, Iliopoulos G, Scopa CD, Bonikos DS. Immunohistochemical expression of TGF-beta1, p21WAF1, p53, Ki67, and angiogenesis in gastric carcinomas: a clinicopathologic study. Int J Gastrointest Cancer. 2002;32:83–9.PubMed
38.
go back to reference Tsamandas AC, Kardamakis D, Ravazoula P, et al. The potential role of TGFbeta1, TGFbeta2 and TGFbeta3 protein expression in colorectal carcinomas. Correlation with classic histopathologic factors and patient survival. Strahlenther Onkol. 2004;180:201–8.PubMed Tsamandas AC, Kardamakis D, Ravazoula P, et al. The potential role of TGFbeta1, TGFbeta2 and TGFbeta3 protein expression in colorectal carcinomas. Correlation with classic histopathologic factors and patient survival. Strahlenther Onkol. 2004;180:201–8.PubMed
39.
go back to reference Royce SG, Alsop K, Haydon A, et al. The role of SMAD4 in early-onset colorectal cancer. Colorectal Dis. 2010;12:213–9.PubMed Royce SG, Alsop K, Haydon A, et al. The role of SMAD4 in early-onset colorectal cancer. Colorectal Dis. 2010;12:213–9.PubMed
40.
go back to reference Xu Y, Pasche B. TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 2007;16:R14–20.PubMed Xu Y, Pasche B. TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 2007;16:R14–20.PubMed
41.
go back to reference Wang J, Sun L, Myeroff L, et al. Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem. 1995;270:22044–9.PubMed Wang J, Sun L, Myeroff L, et al. Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem. 1995;270:22044–9.PubMed
42.
go back to reference Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 1999;59:5678–82.PubMed Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 1999;59:5678–82.PubMed
43.
go back to reference Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003;306:799–804.PubMed Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003;306:799–804.PubMed
44.
go back to reference Eppert K, Scherer SW, Ozcelik H, et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell. 1996;86:543–52.PubMed Eppert K, Scherer SW, Ozcelik H, et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell. 1996;86:543–52.PubMed
Metadata
Title
Prognostic significance of transforming growth factor beta (TGF-β) signaling axis molecules and E-cadherin in colorectal cancer
Authors
Pavlos Lampropoulos
Adamantia Zizi-Sermpetzoglou
Spyros Rizos
Alkiviadis Kostakis
Nikolaos Nikiteas
Athanasios G. Papavassiliou
Publication date
01-08-2012
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2012
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-012-0333-3

Other articles of this Issue 4/2012

Tumor Biology 4/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine