Prognostic value and association of Lauren classification with VEGF and VEGFR‑2 expression in gastric cancer

Li,Xiayi; Zhu,Xueru; Wang,Yiwei; Wang,Ruifen; Wang,Lifeng; Zhu,Mei‑Ling; Zheng,Leizhen

doi:10.3892/ol.2019.10820

Prognostic value and association of Lauren classification with VEGF and VEGFR‑2 expression in gastric cancer

Authors:
- Xiayi Li
- Xueru Zhu
- Yiwei Wang
- Ruifen Wang
- Lifeng Wang
- Mei‑Ling Zhu
- Leizhen Zheng
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Affiliations: Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China, Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
Published online on: September 6, 2019 https://doi.org/10.3892/ol.2019.10820
Pages: 4891-4899
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gastric cancer (GC) is one of the most common malignant tumors in the world. As anti‑angiogenic therapy shows efficacy in the treatment of GC, but only works in certain patients, the identification of potential beneficiaries are urgently required in order to apply appropriate treatments. The Lauren classification demonstrates numerous differences in etiology, epidemiology and pathology; however, the association between Lauren classification and pro‑angiogenic factors remains unclear. The present study aimed to investigate the clinicopathological factors associated with Lauren classification and the prognostic significance of Lauren classification and vascular endothelial growth factor (VEGF) and VEGF receptor‑2 (VEGFR‑2) expression in GC. Paraffin‑embedded GC tissues and clinical information of 255 patients with GC were collected. The clinicopathological factors associated with Lauren classification were evaluated by Logistic regression analysis. Kaplan‑Meier survival and Cox regression analyses were used to examine the prognostic significance of Lauren classification and of VEGF and VEGFR‑2 expression in patients with GC. The results demonstrated that there was no association between Lauren classification and VEGF and VEGFR‑2 expression. Furthermore, results from survival analysis demonstrated that Lauren classification (P=0.001) and Tumor‑Node‑Metastasis stage (stage II, P=0.002; stage III, P<0.001) were independent prognostic factors in GC. Following subgroup analysis based on Tumor‑Node‑Metastasis stage, Lauren classification was demonstrated to be an independent prognostic factor in patients with stage III GC (P=0.010) but not in patients with stage I or II GC. Furthermore, VEGFR‑2 overexpression was an independent predictor of survival in intestinal‑type GC (P=0.040) but not in diffuse‑type GC. Taken together, these results indicate that Lauren classification may serve as an independent prognostic factor for patients with GC. In addition, although the expression of VEGF and VEGFR‑2 was not associated with Lauren classification, VEGFR‑2 overexpression may be considered as an independent prognostic factor in intestinal‑type GC.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Lauren P: The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a Histo-clinical classification. Acta Pathol Microbiol Scand. 64:31–49. 1965. View Article : Google Scholar : PubMed/NCBI
4	Qiu MZ, Cai MY, Zhang DS, Wang ZQ, Wang DS, Li YH and Xu RH: Clinicopathological characteristics and prognostic analysis of Lauren classification in gastric adenocarcinoma in China. J Transl Med. 11:582013. View Article : Google Scholar : PubMed/NCBI
5	Gong EJ, Lee JY, Bae SE, Park YS, Choi KD, Song HJ, Lee GH, Jung HY, Jeong WJ, Cheon GJ, et al: Characteristics of non-cardia gastric cancer with a high serum anti-Helicobacter pylori IgG titer and its association with diffuse-type histology. PLoS One. 13:e01952642018. View Article : Google Scholar : PubMed/NCBI
6	Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, Tsuneyama K and Takano Y: Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: An immunostaining study on the tissue microarray. J Clin Pathol. 60:273–277. 2007. View Article : Google Scholar : PubMed/NCBI
7	Min L, Zhao Y, Zhu S, Qiu X, Cheng R, Xing J, Shao L, Guo S and Zhang S: Integrated analysis identifies molecular signatures and specific prognostic factors for different gastric cancer subtypes. Transl Oncol. 10:99–107. 2017. View Article : Google Scholar : PubMed/NCBI
8	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:6466–6474. 2011. View Article : Google Scholar
9	Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
10	Kitadai Y: Angiogenesis and lymphangiogenesis of gastric cancer. J Oncol. 2010:4687252010. View Article : Google Scholar : PubMed/NCBI
11	Yamamoto S, Yasui W, Kitadai Y, Yokozaki H, Haruma K, Kajiyama G and Tahara E: Expression of vascular endothelial growth factor in human gastric carcinomas. Pathol Int. 48:499–506. 1998. View Article : Google Scholar : PubMed/NCBI
12	Bădescu A, Georgescu CV, Vere CC, Crăiţoiu S and Grigore D: Correlations between Her2 oncoprotein, VEGF expression, MVD and clinicopathological parameters in gastric cancer. Rom J Morphol Embryol. 53:997–1005. 2012.PubMed/NCBI
13	Tenderenda M, Rutkowski P, Jesionek-Kupnicka D and Kubiak R: Expression of CD34 in gastric cancer and its correlation with histology, stage, proliferation activity, p53 expression and apoptotic index. Pathol Oncol Res. 7:129–134. 2001. View Article : Google Scholar : PubMed/NCBI
14	Zhu XR, Wang YW, Xue WJ, Wang R, Wang L, Zhu ML and Zheng L: The VEGFR-2 protein and the VEGFR-2 rs1870377 A>T genetic polymorphism are prognostic factors for gastric cancer. Cancer Biol Ther. 20:497–504. 2019. View Article : Google Scholar : PubMed/NCBI
15	Lin C, Zhang Z, Xu Y, Wang R, Chen S, Gao J, Wang D, Huang Q, Tu X and Wang L: High tumor vascular endothelial growth factor expression is associated with poorer clinical outcomes in resected T3 gastric adenocarcinoma. Am J Clin Pathol. 146:278–288. 2016. View Article : Google Scholar : PubMed/NCBI
16	Li T, Yu J, Luo X, Ren W, Zhang Y and Cao B: VEGFR-2 as a novel predictor of survival in gastric cancer: A systematic review and meta-analysis. Pathol Res Pract. 214:560–564. 2018. View Article : Google Scholar : PubMed/NCBI
17	Polkowski W, van Sandick JW, Offerhaus GJ, ten Kate FJ, Mulder J, Obertop H and van Lanschot JJ: Prognostic value of Laurén classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol. 6:290–297. 1999. View Article : Google Scholar : PubMed/NCBI
18	Berlth F, Bollschweiler E, Drebber U, Hoelscher AH and Moenig S: Pathohistological classification systems in gastric cancer: Diagnostic relevance and prognostic value. World J Gastroenterol. 20:5679–5684. 2014. View Article : Google Scholar : PubMed/NCBI
19	Chen YC, Fang WL, Wang RF, Liu CA, Yang MH, Lo SS, Wu CW, Li AF, Shyr YM and Huang KH: Clinicopathological variation of Lauren classification in gastric cancer. Pathol Oncol Res. 22:197–202. 2016. View Article : Google Scholar : PubMed/NCBI
20	Stiekema J, Cats A, Kuijpers A, van Coevorden F, Boot H, Jansen EP, Verheij M, Balague Ponz O, Hauptmann M and van Sandick JW: Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach? Eur J Surg Oncol. 39:686–693. 2013. View Article : Google Scholar : PubMed/NCBI
21	Qiu M, Zhou Y, Zhang X, Wang Z, Wang F, Shao J, Lu J, Jin Y, Wei X, Zhang D, et al: Lauren classification combined with HER2 status is a better prognostic factor in Chinese gastric cancer patients. BMC Cancer. 14:8232014. View Article : Google Scholar : PubMed/NCBI
22	Yamashita K, Sakuramoto S, Katada N, Futawatari N, Moriya H, Hirai K, Kikuchi S and Watanabe M: Diffuse type advanced gastric cancer showing dismal prognosis is characterized by deeper invasion and emerging peritoneal cancer cell: The latest comparative study to intestinal advanced gastric cancer. Hepatogastroenterology. 56:276–281. 2009.PubMed/NCBI
23	Yu CC, Levison DA, Dunn JA, Ward LC, Demonakou M, Allum WH and Hallisey MT: Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer. Br J Cancer. 71:1106–1110. 1995. View Article : Google Scholar : PubMed/NCBI
24	Rajabi M and Mousa SA: The role of angiogenesis in cancer treatment. Biomedicines. 5(pii): E342017. View Article : Google Scholar : PubMed/NCBI
25	Cleary JM, Horick NK, McCleary NJ, Abrams TA, Yurgelun MB, Azzoli CG, Rubinson DA, Brooks GA, Chan JA, Blaszkowsky LS, et al: FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial. Cancer. Mar 26–2019.(Epub ahead of print). doi: 10.1002/cncr.32029. View Article : Google Scholar : PubMed/NCBI
26	Kim ST, Lee J, Lee SJ, Park SH, Jung SH, Park YS, Lim HY, Kang WK and Park JO: Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer. Oncotarget. 7:24088–24096. 2016.PubMed/NCBI
27	Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, et al: Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 20:420–435. 2019. View Article : Google Scholar : PubMed/NCBI
28	Fontanella C, Ongaro E, Bolzonello S, Guardascione M, Fasola G and Aprile G: Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med. 2:1232014.PubMed/NCBI
29	Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 383:31–39. 2014. View Article : Google Scholar : PubMed/NCBI
30	Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 15:1224–1235. 2014. View Article : Google Scholar : PubMed/NCBI
31	Aoyama T and Yoshikawa T: Targeted therapy: Apatinib-new third-line option for refractory gastric or GEJ cancer. Nat Rev Clin Oncol. 13:268–270. 2016. View Article : Google Scholar : PubMed/NCBI
32	Li J, Qin SK, Xu JM, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, et al: Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 34:1448–1454. 2016. View Article : Google Scholar : PubMed/NCBI
33	Roviello G, Petrioli R, Marano L, Polom K, Marrelli D, Perrella A and Roviello F: Angiogenesis inhibitors in gastric and gastroesophageal junction cancer. Gastric Cancer. 19:31–41. 2016. View Article : Google Scholar : PubMed/NCBI
34	Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 29:3968–3976. 2011. View Article : Google Scholar : PubMed/NCBI
35	Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD and Ellis LM: Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 2:1679–1684. 1996.PubMed/NCBI
36	Chen CN, Hsieh FJ, Cheng YM, Cheng WF, Su YN, Chang KJ and Lee PH: The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett. 213:73–82. 2004. View Article : Google Scholar : PubMed/NCBI
37	Wang L, Yang M, Shan L, Qi L, Chai C, Zhou Q, Yao K, Wu H and Sun W: The role of SPARC protein expression in the progress of gastric cancer. Pathol Oncol Res. 18:697–702. 2012. View Article : Google Scholar : PubMed/NCBI
38	Wang X, Cao W, Mo M, Wang W, Wu H and Wang J: VEGF and cortactin expression are independent predictors of tumor recurrence following curative resection of gastric cancer. J Surg Oncol. 102:325–330. 2010. View Article : Google Scholar : PubMed/NCBI
39	Lastraioli E, Boni L, Romoli MR, Crescioli S, Taddei A, Beghelli S, Tomezzoli A, Vindigni C, Saragoni L, Messerini L, et al: VEGF-A clinical significance in gastric cancers: Immunohistochemical analysis of a wide Italian cohort. Eur J Surg Oncol. 40:1291–1298. 2014. View Article : Google Scholar : PubMed/NCBI
40	Chen L, Shi Y, Yuan J, Han Y, Qin R, Wu Q, Jia B, Wei B, Wei L, Dai G and Jiao S: HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy. PLoS One. 9:e906782014. View Article : Google Scholar : PubMed/NCBI