E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model

• Published in: Journal of neuro-oncology 2012-09, Vol.109 (2), p.219-227
• Main Authors: Yoo, Jin Young, Yang, Seung-Ho, Lee, Jung Eun, Cho, Deog Gon, Kim, Hoon Kyo, Kim, Sung Hwan, Kim, Il Sup, Hong, Jae Taek, Sung, Jae Hoon, Son, Byung Chul, Lee, Sang Won
• Format: Article
• Language: English
• Subjects: Aged; Animal models; Animals; Bcl-2 protein; biomarkers; Brain; Brain - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Cadherins - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspase 3 - metabolism; Caspase-3; Cell Line, Tumor; Disease Models, Animal; DNA methylation; DNA Modification Methylases - metabolism; DNA Repair Enzymes - metabolism; E-Cadherin; Epidermal growth factor receptors; Female; Fibronectin; Follow-Up Studies; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Inoculation; Laboratory Investigation; Lung cancer; Lung Neoplasms - pathology; Magnetic Resonance Imaging; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9 - metabolism; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Nude; Middle Aged; Neurology; Oncogene Proteins - metabolism; Oncology; p53 protein; pioglitazone; Polymerase chain reaction; Receptor, Epidermal Growth Factor - metabolism; Retrospective Studies; Statistics, Nonparametric; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Tumor Suppressor Proteins - metabolism; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-012-0890-8

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 O 6 -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.