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

Jun,Kyong-Hwa; Lee,Jung Eun; Kim,Se Hoon; Jung,Ji-Han; Choi,Hyun‑Joo; Kim,Young  Il; Chin,Hyung-Min; Yang,Seung-Ho

doi:10.3892/or.2015.4191

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

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
View Affiliations

Affiliations: Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea, Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea, Department of Pathology, Yonsei University of College of Medicine, Seoul, Republic of Korea, Department of Hospital Pathology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
Published online on: August 10, 2015 https://doi.org/10.3892/or.2015.4191
Pages: 2047-2053

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Mathers CD, Shibuya K, Boschi-Pinto C, Lopez AD and Murray CJ: Global and regional estimates of cancer mortality and incidence by site: I. Application of regional cancer survival model to estimate cancer mortality distribution by site. BMC Cancer. 2:36–63. 2002. View Article : Google Scholar : PubMed/NCBI
2	Park CH, Song KY and Kim SN: Treatment results for gastric cancer surgery: 12 years' experience at a single institute in Korea. Eur J Surg Oncol. 34:36–41. 2008. View Article : Google Scholar
3	Kim M: Intracranial involvement by metastatic advanced gastric carcinoma. J Neurooncol. 43:59–62. 1999. View Article : Google Scholar : PubMed/NCBI
4	Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K and Massagué J: Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature. 446:765–770. 2007. View Article : Google Scholar : PubMed/NCBI
5	Shiozaki H, Oka H, Inoue M, Tamura S and Monden M: E-cadherin mediated adhesion system in cancer cells. Cancer. 77(Suppl 8): S1605–S1613. 1996. View Article : Google Scholar
6	Ishimine H, Yamakawa N, Sasao M, Tadokoro M, Kami D, Komazaki S, Tokuhara M, Takada H, Ito Y, Kuno S, et al: N-Cadherin is a prospective cell surface marker of human mesenchymal stem cells that have high ability for cardiomyocyte differentiation. Biochem Biophys Res Commun. 438:753–759. 2013. View Article : Google Scholar : PubMed/NCBI
7	Decoster E, Vassal A and Faye G: MSS1, a nuclear-encoded mitochondrial GTPase involved in the expression of COX1 subunit of cytochrome c oxidase. J Mol Biol. 232:79–88. 1993. View Article : Google Scholar : PubMed/NCBI
8	Satake S, Semba S, Matsuda Y, Usami Y, Chiba H, Sawada N, Kasuga M and Yokozaki H: Cdx2 transcription factor regulates claudin-3 and claudin-4 expression during intestinal differentiation of gastric carcinoma. Pathol Int. 58:156–163. 2008. View Article : Google Scholar : PubMed/NCBI
9	Kawamura T, Kusakabe T, Sugino T, Watanabe K, Fukuda T, Nashimoto A, Honma K and Suzuki T: Expression of glucose transporter-1 in human gastric carcinoma: Association with tumor aggressiveness, metastasis, and patient survival. Cancer. 92:634–641. 2001. View Article : Google Scholar : PubMed/NCBI
10	Maher F, Davies-Hill TM, Lysko PG, Henneberry RC and Simpson IA: Expression of two glucose transporters, GLUT1 and GLUT3, in cultured cerebellar neurons: Evidence for neuron-specific expression of GLUT3. Mol Cell Neurosci. 2:351–360. 1991. View Article : Google Scholar : PubMed/NCBI
11	Tang M, Li J, Liu B, Song N, Wang Z and Yin C: Clusterin expression and human testicular seminoma. Med Hypotheses. 81:635–637. 2013. View Article : Google Scholar : PubMed/NCBI
12	Trougakos IP and Gonos ES: Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol. 34:1430–1448. 2002. View Article : Google Scholar : PubMed/NCBI
13	Gerson KD, Maddula VS, Seligmann BE, Shearstone JR, Khan A and Mercurio AM: Effects of β4 integrin expression on microRNA patterns in breast cancer. Biol Open. 1:658–666. 2012. View Article : Google Scholar : PubMed/NCBI
14	Wu J, Liu X and Wang Y: Predictive value of preoperative serum CCL2, CCL18, and VEGF for the patients with gastric cancer. BMC Clin Pathol. 13:15–20. 2013. View Article : Google Scholar : PubMed/NCBI
15	Chen C, Yang JM, Hu TT, Xu TJ, Yan G, Hu SL, Wei W and Xu WP: Prognostic role of human epidermal growth factor receptor in gastric cancer: A systematic review and meta-analysis. Arch Med Res. 44:380–389. 2013. View Article : Google Scholar : PubMed/NCBI
16	Preusser M, Berghoff AS, Ilhan-Mutlu A, Dinhof C, Magerle M, Marosi C, Hejna M, Capper D, Von Deimling A, Schoppmann SF, et al: Brain metastases of gastro-oesophageal cancer: Evaluation of molecules with relevance for targeted therapies. Anticancer Res. 33:1065–1071. 2013.PubMed/NCBI
17	Yamada Y, Yoshida T, Hayashi K, Sekiya T, Yokota J, Hirohashi S, Nakatani K, Nakano H, Sugimura T and Terada M: p53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res. 51:5800–5805. 1991.PubMed/NCBI
18	de Vries AC and Kuipers EJ: Commentary: Metformin use is associated with reduced gastric cancer risk. Aliment Pharmacol Ther. 39:12392014. View Article : Google Scholar : PubMed/NCBI
19	Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, Straus SM, Herings RM and Stricker BH: Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: Results from a large population-based follow-up study. Diabetes Care. 35:119–124. 2012. View Article : Google Scholar :
20	Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, Nomura K, Mimura S, Kobayashi M, Aritomo Y, et al: The anti-diabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther. 11:549–560. 2012. View Article : Google Scholar : PubMed/NCBI
21	Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 14:101–112. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kim LS, Huang S, Lu W, Lev DC and Price JE: Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis. 21:107–118. 2004. View Article : Google Scholar : PubMed/NCBI
23	JuanYin J, Tracy K, Zhang L, Munasinghe J, Shapiro E, Koretsky A and Kelly K: Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model. Clin Exp Metastasis. 26:403–414. 2009. View Article : Google Scholar : PubMed/NCBI
24	Herrlinger U, Wiendl H, Renninger M, Förschler H, Dichgans J and Weller M: Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: Diagnostic and prognostic value. Br J Cancer. 91:219–224. 2004.PubMed/NCBI
25	Gril B, Evans L, Palmieri D and Steeg PS: Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies. Eur J Cancer. 46:1204–1210. 2010. View Article : Google Scholar : PubMed/NCBI
26	Kamikihara T, Ishigami S, Arigami T, Matsumoto M, Okumura H, Uchikado Y, Kita Y, Kurahara H, Kijima Y, Ueno S, et al: Clinical implications of N-cadherin expression in gastric cancer. Pathol Int. 62:161–166. 2012. View Article : Google Scholar : PubMed/NCBI
27	Lee JL, Kang YK, Kim TW, Chang HM, Lee GW, Ryu MH, Kim E, Oh SJ, Lee JH, Kim SB, et al: Leptomeningeal carcinomatosis in gastric cancer. J Neurooncol. 66:167–174. 2004. View Article : Google Scholar : PubMed/NCBI
28	Tomita H, Yasui H, Boku N, Nakasu Y, Mitsuya K, Onozawa Y, Fukutomi A, Yamazaki K, Machida N, Taku K, et al: Leptomeningeal carcinomatosis associated with gastric cancer. Int J Clin Oncol. 17:361–366. 2012. View Article : Google Scholar
29	York JE, Stringer J, Ajani JA, Wildrick DM and Gokaslan ZL: Gastric cancer and metastasis to the brain. Ann Surg Oncol. 6:771–776. 1999. View Article : Google Scholar
30	Kasakura Y, Fujii M, Mochizuki F, Suzuki T and Takahashi T: Clinicopathological study of brain metastasis in gastric cancer patients. Surg Today. 30:485–490. 2000. View Article : Google Scholar : PubMed/NCBI
31	Prudkin L, Liu DD, Ozburn NC, Sun M, Behrens C, Tang X, Brown KC, Bekele BN, Moran C and Wistuba II: Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol. 22:668–678. 2009. View Article : Google Scholar : PubMed/NCBI
32	Yoo JY, Yang SH, Lee JE, Cho DG, Kim HK, Kim SH, Kim IS, Hong JT, Sung JH, Son BC, 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. View Article : Google Scholar : PubMed/NCBI
33	Ishibashi Y, Matsui T, Takeuchi M and Yamagishi S: Metformin inhibits advanced glycation end products (AGEs)-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing AGEs receptor expression via AMP-activated protein kinase. Horm Metab Res. 45:387–390. 2013.
34	Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J and Menendez JA: Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis. Cell Cycle. 9:4461–4468. 2010. View Article : Google Scholar
35	Rattan R, Graham RP, Maguire JL, Giri S and Shridhar V: Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 13:483–491. 2011. View Article : Google Scholar : PubMed/NCBI
36	Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, Allegra M, Giacchero D, Bahadoran P, Bertolotto C, et al: Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol Cancer Ther. 12:1605–1615. 2013. View Article : Google Scholar : PubMed/NCBI