J Lung Cancer.  2012 Jun;11(1):38-44. 10.6058/jlc.2012.11.1.38.

Expression of Transforming Growth Factor beta1 and Cadherins in Lung Adenocarcinoma

• Park SY
• Yoo J

• KMID: 2199875
• DOI: http://doi.org/10.6058/jlc.2012.11.1.38

Abstract

PURPOSE
There is evidence supporting the concept of tumor progression from pulmonary adenocarcinoma in situ (formerly bronchioloalveolar carcinoma, BAC) to adenocarcinoma with varying degrees of invasion. The aim of this study was to investigate the role of transforming growth factor beta1 (TGFbeta1) in tumor invasiveness in lung adenocarcinoma, and to determine the potential relationships between its expression and immunophenotypes of cell adhesion molecules.
MATERIALS AND METHODS
Tumor samples from adenocarcinoma in situ (n=13), minimally invasive adenocarcinoma (formerly BAC with < or =5 mm invasion, n=2), and lepidic predominant invasive adenocarcinoma (formerly mixed adenocarcinoma showing non-mucinous BAC features with >5 mm invasion, n=25) were examined for the expression of TGFbeta1, E-cadherin, N-cadherin, and H-cadherin proteins using immunohistochemistry.
RESULTS
Of a total of 40 cases, 25 (63%) were positive for TGFbeta1. The frequency of immunoreactivity in patients with adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma was 23% (3/13), 50% (1/2), and 84% (21/25), respectively (p=0.001). TGFbeta1 correlated with T classification (p=0.006) and stage (p=0.001). Loss of E-cadherin expression was more frequently observed in invasive adenocarcinomas than in adenocarcinomas in situ (p=0.034). E-cadherin expression inversely correlated with T classification (p=0.009). TGFbeta1 expression showed a statistically significant correlation with H-cadherin expression (p=0.040), but not with E-cadherin expression (p=0.752).
CONCLUSION
These results suggest that TGFbeta1 and E-cadherin may play an important role in invasive progression of lung adenocarcinoma through regulating epithelial-to-mesenchymal transition.

Keyword

Transforming growth factor beta1; Cadherins; Adenocarcinoma

MeSH Terms

Adenocarcinoma
Adenocarcinoma, Bronchiolo-Alveolar
Cadherins
Cell Adhesion
Humans
Lung
Lung Neoplasms
Proteins
Transforming Growth Factor beta1
Transforming Growth Factors
Adenocarcinoma
Cadherins
Lung Neoplasms
Proteins
Transforming Growth Factor beta1
Transforming Growth Factors

Figure

• 

  Fig. 1 Immunohistochemistry for transforming growth factor β1 showing cytoplasmic positivity (A), E-cadherin showing predominantly membranous reactivity (B), N-cadherin showing membranous and cytoplasmic staining (C), and H-cadherin showing cytoplasmic reactivity (D) (×100).

Reference

1. Colvy TV, Noguchi M, Henschke C, et al. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, editors. Adenocarcinoma. World Health Organization classification of tumours: pathology and genetics of tumours of the lung, pleura, thymus and heart. 2004. Lyon: IARC Press;35–44.

2. Laskin JJ, Sandler AB, Johnson DH. Redefining bronchioloalveolar carcinoma. Semin Oncol. 2005. 32:329–335.

3. Aoyagi Y, Yokose T, Minami Y, et al. Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma. Cancer Res. 2001. 61:7950–7954.

4. Sarkaria IS, Pham D, Ghossein RA, et al. SCCRO expression correlates with invasive progression in bronchioloalveolar carcinoma. Ann Thorac Surg. 2004. 78:1734–1741.

5. Yang Y, Dukhanina O, Tang B, et al. Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects. J Clin Invest. 2002. 109:1607–1615.

6. Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005. 23:2078–2093.

7. Hasegawa Y, Takanashi S, Kanehira Y, Tsushima T, Imai T, Okumura K. Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer. 2001. 91:964–971.

8. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009. 138:645–659.

9. Maitah MY, Ali S, Ahmad A, Gadgeel S, Sarkar FH. Upregulation of sonic hedgehog contributes to TGF-β1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One. 2011. 6:e16068.

10. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/americna thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011. 6:244–285.

11. Saito H, Tsujutani S, Oka S, et al. The expression of transforming growth factor-β1 is significantly correlated with expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma. Cancer. 1999. 86:1455–1462.

12. Kashiwagi S, Yashiro M, Takashima T, et al. Significance of E-cadherin expression in triple-negative breast cancer. Br J Cancer. 2010. 103:249–255.

13. Grinberg-Rashi H, Ofek E, Perelman M, et al. The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res. 2009. 15:1755–1761.

14. Muraoka-Cook RS, Kurukawa H, Koh Y, et al. Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res. 2004. 64:9002–9011.

15. Santibañez JF, Quintanilla M, Bernabeu C. TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011. 121:233–251.

16. Toonkel RL, Borczuk AC, Powell CA. TGF-β signaling pathway in lung adenocarcinoma invasion. J Thorac Oncol. 2010. 5:153–157.

17. Bandyopadhyay A, Agyin JK, Wang L, et al. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res. 2006. 66:6714–6721.

18. Nam JS, Terabe M, Mamura M, et al. An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 2008. 68:3835–3843.

19. Zhong Z, Carroll KD, Policarpio D, et al. Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells. Clin Cancer Res. 2010. 16:1191–1205.

20. Guzinska-Ustymowicz K, Kemona A. Transforming growth factor beta can be a parameter of aggressiveness of pT1 colorectal cancer. World J Gastroenterol. 2005. 11:1193–1195.

21. Deckers M, van Dinther M, Buijs J, et al. The tumor suppressor Smad4 is required for transforming growth factor β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 2006. 66:2202–2209.

22. Bremnes RM, Veve R, Hirsch FR, Franklin WA. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002. 36:115–124.

23. Hong RH, Choi DY, Lim SC, Suh CH, Kee KH, Lee MJ. The differential expressions of the epithelial-mesenchymal transition regulator, Slug and the cell adhesion molecule, E-cadherin in colorectal adenocarcinoma. Korean J Pathol. 2008. 42:351–357.

24. Maret D, Gruzglin E, Sadr MS, et al. Surface expression of precursor N-cadherin promotes tumor cell invasion. Neoplasia. 2010. 12:1066–1080.

25. Philippova M, Ivanov D, Joshi MB, et al. Identification of proteins associating with glycosylphosphatidylinositol-anchored T-cadherin on the surface of vascular endothelial cells: role for Grp78/BiP in T-cadherin-dependent cell survival. Mol Cell Biol. 2008. 28:4004–4017.

26. Riou P, Saffroy R, Chenailler C, et al. Expression of T-cadherin in tumor cells influences invasive potential of human hepatocellular carcinoma. FASEB J. 2006. 20:2291–2301.