Abstract
It remains unclear whether patients with non-small-cell lung cancer (NSCLC) develop brain metastasis during or after standard therapy. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate expression of such markers. A case–control study of patients who were newly diagnosed with NSCLC and who had developed brain metastasis during follow-up was conducted between 2004 and 2009. These patients were compared with a control group of patients who had NSCLC but no evidence of brain metastasis. Immunohistochemical analysis of expression of Ki-67, p53, Bcl-2, Bax, vascular endothelial growth factor, epidermal growth factor receptor, caspase-3, and E-cadherin was conducted. The methylation status of the genes for O6-methylguanine-DNA-methyltransferase, tissue inhibitor of matrix metalloproteinase (TIMP)-2, TIMP-3, and death-associated protein-kinase was also determined, by use of a methylation-specific polymerase chain reaction. A significantly increased risk of developing brain metastasis was associated with the presence of primary tumors with low E-cadherin expression in patients with NSCLC. We also investigated the effects of pioglitazone, a peroxisome proliferator-activated receptor γ-activating drug, in tumor-bearing mouse models. We found that E-cadherin expression was proportional to pioglitazone exposure time. Interestingly, pioglitazone pretreatment before cancer cell inoculation prevented loss of E-cadherin expression and reduced expression of MMP9 and fibronectin, compared with the control group. E-cadherin expression could be a predictor of brain metastasis in patients with NSCLC. Preventive treatment with pioglitazone may be useful for modulating E-cadherin expression.
Similar content being viewed by others
References
Jemal A, Siegal R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics 2008. CA Cancer J Clin 58:71–96
Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM (2001) Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 19:1344–1349
Arnold SM, Young AB, Munn RK, Patchell RA, Nanayakkara N, Markesbery WR (1999) Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis. Clin Cancer Res 5:4028–4033
D’Amico TA, Aloia TA, Moore MB, Conlon DH, Herndon JE 2nd, Kinch MS, Harpole DH Jr (2001) Predicting the sites of metastases from lung cancer using molecular biologic markers. Ann Thorac Surg 72:1144–1148
Milas I, Komaki R, Hachiya T, Bubb RS, Ro JY, Langford L, Sawaya R, Putnam JB, Allen P, Cox JD, McDonnell TJ, Brock W, Hong WK, Roth JA, Milas L (2003) Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small-cell lung cancer and brain metastases. Clin Cancer Res 9:1070–1076
Petersen I, Hidalgo A, Petersen S, Schlüns K, Schewe C, Pacyna-Gengelbach M, Goeze A, Krebber B, Knösel T, Kaufmann O, Szymas J, von Deimling A (2000) Chromosomal imbalances in brain metastases of solid tumors. Brain Pathol 10:395–401
Esteller M, Herman JG (2004) Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 23:1–8
Li H, Lindenmeyer F, Grenet C, Opolon P, Menashi S, Soria C, Yeh P, Perricaudet M, Lu H (2001) AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. Hum Gene Ther 12:515–526
Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK, Bavlin SB, Graff JR (1999) Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 59:798–802
Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A (1995) Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 9:15–30
Thunnissen FB, Schuurbiers OC, den Bakker MA (2006) A critical appraisal of prognostic and predictive factors for common lung cancers. Histopathology 48:779–786
Lee JS, Yoon A, Kalapurakal SK, Ro JY, Lee JJ, Tu N, Hittelman WN, Hong WK (1995) Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor. J Clin Oncol 13:1893–1903
Koomägi R, Volm M (2000) Relationship between the expression of caspase-3 and the clinical outcome of patients with non-small-cell lung cancer. Anticancer Res 20:493–496
Donnem T, Al-Saad S, Al-Shibli K, Delghandi MP, Persson M, Nilsen MN, Busund LT, Bremnes RM (2007) Inverse prognostic impact of angiogenic marker expression in tumor cells versus stromal cells in non small cell lung cancer. Clin Cancer Res 13:6649–6657
Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37:S9–S15
Yilmaz M, Christonfori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28:15–33
Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, Kim PJ, Owen RJ, Lang NP (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25:1476–1481
Choudhary R, Li H, Winn RA, Sorenson AL, Weiser-Evans MC, Nemenoff RA (2010) Peroxisome proliferator-activated receptor-γ inhibits transformed growth of non-small-cell lung cancer cells through selective suppression of snail. Neoplasia 12:224–234
Keshamouni VG, Reddy RC, Arenberg DA, Joel B, Thannickal VJ, Kalemkerian GP, Standiford TJ (2004) Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 23:100–108
Lyon CM, Klinge DM, Do KC, Grimes MJ, Thomas CL, Damiani LA, March TH, Stidley CA, Belinsky SA (2009) Rosiglitazone prevents the progression of preinvasive lung cancer in a murine model. Carcinogenesis 30:2095–2099
Reddy RC, Srirangam A, Reddy K, Chen J, Gangireddy S, Kalemkerian GP, Standiford TJ, Keshamouni VG (2008) Chemotherapeutic drugs induce PPAR-γ expression and show sequence-specific synergy with PPAR-γ ligands in inhibition of non-small-cell lung cancer. Neoplasia 10:597–603
Annicotte JS, Iankova I, Miard S, Fritz V, Sarruf D, Abella A, Berthe ML, Noël D, Pillon A, Iborra F, Dubus P, Maudelonde T, Culine S, Fajas L (2006) Peroxisome proliferator-activated receptor γ regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol Cell Biol 26:7561–7574
Yang SH, Lee KS, Yang HJ, Jeon BH, Lee YS, Nam SW, Chung DS, Lee SW, Hong YK (2011) O(6)-methylguanine-DNA-methyltransferase promoter methylation assessment by microdissection-assisted methylation-specific PCR and high resolution melting analysis in patients with glioblastomas. J Neurooncol 27. doi:10.1007/s11060-011-0668-4
Bubb RS, Komaki R, Hachiya T, Milas I, Ro JY, Langford L, Sawaya R, Putnam JB, Allen P, Cox JD, McDonnell TJ, Brock W, Hong WK, Roth JA, Milas L (2002) Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion. Int J Radiat Oncol Biol Phys 53:1216–1224
Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM, Davis DW, McConkey DJ, Fidler IJ (2000) Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res 60:1453–1459
Hubbs JL, Boyd JA, Hollis D, Chino JP, Saynak M, Kelsey CR (2010) Factors associated with the development of brain metastases: analysis of 975 patients with early stage non-small-cell lung cancer. Cancer 116:5038–5046
Prudkin L, Liu D, Ozburn NC, Sun M, Behrens C, Tang X, Brown KC, Bekele BN, Moran C, Wistuba II (2009) Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol 22:668–678
Leber MF, Efferth T (2009) Molecular principles of cancer invasion and metastasis. Int J Oncol 34:881–895
Shabani HK, Kitange G, Tsunoda K, Anda T, Tokunaga Y, Shibata S, Kaminogo M, Hayashi T, Ayabe H, Iseki M (2003) Immunohistochemical expression of E-cadherin in metastatic brain tumors. Brain Tumor Pathol 20:7–12
Saad AG, Yeap BY, Thunnissen FB, Pinkus GS, Pinkus JL, Loda M, Sugarbaker DJ, Johnson BE, Chirieac LR (2008) Immunohistochemical markers associated with brain metastasis in patients with non-small cell lung carcinoma. Cancer 113:2129–2138
Nernenoff RA (2007) Peroxisome proliferator-activated receptor-gamma in lung cancer: defining specific versus “off-target” effectors. J Thorac Oncol 2:989–992
Reka AK, Kurapati H, Narala VR, Bommer G, Chen J, Standiford TJ, Keshamouni VG (2010) Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition. Mol Cancer Ther 9:3221–3232
Han C, Demetris AJ, Liu Y, Shelhamer JH, Wu T (2004) Transforming growth factor-beta (TGF-beta) activates cytosolic phospholipase A2alpha (cPLA2alpha)-mediated prostaglandin E2 (PGE)2/EP1 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma)/Smad signaling pathways in human liver cancer cells. A novel mechanism for subversion of TGF-beta-induced mitoinhibition. J Biol Chem 279:44344–44354
Davies M, Robinson M, Smith E, Huntley S, Prime S, Paterson I (2005) Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem 95:918–931
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654
Ghosh AK, Bhattacharyya S, Wei J, Kim S, Barak Y, Mori Y, Varga J (2009) Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator. FASEB J 23:2968–2977
Libra M, Scalisi A, Vella N, Clementi S, Sorio R, Stivala F, Spandidos DA, Mazzarino C (2009) Uterine cervical carcinoma: role of matrix metalloproteinases (review). Int J Oncol 34:897–903
Jia D, Yan M, Wang X, Hao X, Liang L, Liu L, Kong H, He X, Li J, Yao M (2010) Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer 10:364
Sauerbeck A, Gao J, Readnower R, Liu M, Pauly JR, Bing G, Sullivan PG (2011) Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp Neurol 227:128–135
Thal SC, Heinemann M, Luh C, Pieter D, Werner C, Engelhard K (2011) Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-γ-independent mechanisms. J Neurotrauma 28:983–993
Burstein HJ, Demetri GD, Mueller E, Sarraf P, Spiegelman BM, Winer EP (2003) Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Res Treat 79:391–397
Yee LD, Williams N, Wen P, Young DC, Lester J, Johnson MV, Farrar WB, Walker MJ, Povoski SP, Suster S, Eng C (2007) Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers. Clin Cancer Res 13:246–252
Girnun GD, Chen L, Silvaggi J, Drapkin R, Chirieac LR, Padera RF, Upadhyay R, Vafai SB, Weissleder R, Mahmood U, Naseri E, Buckley S, Li D, Force J, McNamara K, Demetri G, Spiegelman BM, Wong KK (2008) Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin Cancer Res 14:6478–6486
Shimizu M, Moriwaki H (2008) Synergistic effects of PPARgamma ligands and retinoids in cancer treatment. PPAR Res 2008:181047
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65:9455–9462
Acknowledgments
This work was supported by a National Research Foundation of Korea Grant funded by the Korean Government (2009-0069346). We thank Se Hoon Kim for the analysis of in-vivo experiments.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Yoo, J.Y., Yang, SH., Lee, J.E. et al. E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model. J Neurooncol 109, 219–227 (2012). https://doi.org/10.1007/s11060-012-0890-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-012-0890-8