Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models

• DOI: 10.3892/or.2015.4191
• Publication Date: 2015-08-10T04:16:28Z
• Authors: KYONG-HWA JUN; JUNG EUN LEE; SE HOON KIM; JI-HAN JUNG; HYUN-JOO CHOI; YOUNG IL KIM; HYUNG-MIN CHIN; SEUNG-HO YANG
• Keywords: Adult; Male; Vascular Endothelial Growth Factor A; 0301 basic medicine; Epithelial-Mesenchymal Transition; 610; Brain Neoplasms/drug therapy; Cell Line; Neoplastic/drug effects; Mice; 03 medical and health sciences; Antigens, CD; Stomach Neoplasms; Metformin/pharmacology; Cell Line, Tumor; 80 and over; Brain Neoplasms/metabolism*; Animals; Humans; CD/metabolism*; Antigens; Metformin/administration & dosage*; Aged; Aged, 80 and over; Tumor; Brain Neoplasms; Cadherins/metabolism*; Stomach Neoplasms/pathology; Middle Aged; Cadherins; Xenograft Model Antitumor Assays; Metformin; 3. Good health; Gene Expression Regulation, Neoplastic; Gene Expression Regulation; Case-Control Studies; Brain Neoplasms/pathology; Stomach Neoplasms/drug therapy; Female; Brain Neoplasms/secondary*; Epithelial-Mesenchymal Transition/drug effects; Vascular Endothelial Growth Factor A/metabolism*; Stomach Neoplasms/metabolism*

Gastric cancer is the second most common cause of cancer-related death worldwide. Although brain metastasis is a rare complication of gastric cancer, no standard therapy for gastric cancer brain metastasis has been established. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate such markers. A case-control study of patients newly diagnosed with gastric cancer who had developed brain metastasis during follow-up, was conducted. These patients were compared with patients who had advanced gastric cancer but no evidence of brain metastasis. Immunohistochemistry was used to analyze the expression of E-cadherin, N-cadherin, MSS1, claudin-3, claudin-4, Glut1, clusterin, ITGB4, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and p53. The expression of VEGF tended to be higher in the case group (33.3 vs. 0%, p=0.055). Median survival was significantly correlated with vascular invasion (12 vs. 33 months, p=0.008) and N-cadherin expression (36 vs. 12 months, p=0.027). We also investigated the effects of metformin in tumor-bearing mouse models. VEGF expression was decreased and E-cadherin increased in the metformin‑treated group when compared with the control group. The expression of the mesenchymal marker MMP9 was decreased in the metformin-treated group. Brain metastasis of advanced gastric cancer was associated with the expression of VEGF. Metformin treatment may be useful for modulating the metastatic capacity by reducing VEGF expression and blocking epithelial-to-mesenchymal transition.