Effect of c-Met and CD44v6 Expression in Resistance to Chemotherapy in Esophageal Squamous Cell Carcinoma
c-Met relies on CD44v6 for its activation and signaling in several cancer cell lines. However, the correlation of c-Met and CD44v6 expression and its biological significance in esophageal squamous cell carcinoma (ESCC) remains unknown.
Expression of c-Met and CD44v6 was examined by immunohistochemistry (IHC) in 147 ESCC specimens. We analyzed the impact of c-Met and CD44v6 expression on clinicopathological parameters, including chemoresistance or prognosis in ESCC.
High expression of c-Met and CD44v6 in cancerous lesions was identified in 49.7% and 50.3% of all patients, respectively. The c-Met-high group comprised more advanced pT and pM stages than the c-Met-low group. In addition, more patients in the c-Met-high group received neoadjuvant chemotherapy (NACT) than the c-Met-low group (64.4% vs. 43.2%, P = 0.010). On the other hand, the CD44v6-high group was associated with more advanced pT/pN stages and a poorer clinical response to NACT (response rate 53.5% vs. 77.8%, P = 0.025) than the CD44v6-low group. Double-positive immunostaining of c-Met and CD44v6 was identified in 28.6% of all cases, and multivariate analysis of overall survival (OS) identified them (hazard ratio 1.79, 95% confidence interval 1.03–3.04, P = 0.038) as independent prognostic factors in addition to pN and pM stage.
c-Met/CD44v6 were associated with tumor progression or chemoresistance. Double-positive expression of c-Met and CD44v6 negatively impacted patient prognosis in ESCC, implying that c-Met and CD44v6 are candidates for targeted therapy in ESCC.
TH, TM, MY, MM, and YD: conception, design of the study; TH, TM, MY, KT, and YD: surgery and acquisition of clinical data; TH: immunohistochemical staining; TH, TM, and NM: evaluation of immunohistochemical staining; TH, TM, YM, TT, YK, and KN: analysis of data; TH: drafting the article; TM: critical revision of the article; MM and YD: final approval of the article.
- 2.Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19(1):68–74.CrossRefGoogle Scholar
- 8.Kim JH, Kim BJ, Kim HS. Clinicopathological impacts of high c-Met expression in head and neck squamous cell carcinoma: a meta-analysis and review. Oncotarget. 2017;8(68):113120–8.Google Scholar
- 10.Li C, Wu JJ, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141(6):2218–27 e2215.Google Scholar
- 17.Pant S, Patel M, Kurkjian C, et al. A Phase II Study of the c-Met inhibitor tivantinib in combination with FOLFOX for the treatment of patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal junction, or stomach. Cancer Invest. 2017;35(7):463–72.CrossRefGoogle Scholar
- 22.Matzke-Ogi A, Jannasch K, Shatirishvili M, et al. Inhibition of tumor growth and metastasis in pancreatic cancer models by interference with CD44v6 signaling. Gastroenterology. 2016;150(2):513–25 e510.Google Scholar
- 26.Zhang T, Li H, Zhang Y, Wang P, Bian H, Chen ZN. Expression of proteins associated with epithelial-mesenchymal transition in esophageal squamous cell carcinoma. Oncol Lett. 2018;15(3):3042–8.Google Scholar
- 27.Yang H, Liu J, Yu H, et al. Expression and association of CD44v6 with prognosis in T2-3N0M0 esophageal squamous cell carcinoma. J Thorac Dis. 2014;6(2):91–8.Google Scholar
- 28.Ren JL, Wu HF, Wang WJ, et al. C-Met as a potential novel prognostic marker in squamous cell carcinoma and adenocarcinoma of esophagus: evidence from a meta-analysis. Panminerva Med. 2017;59(1):97–106.Google Scholar
- 30.Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumors. 7th edn. 2010, Oxford.Google Scholar
- 37.Diseases JSfE. Guidelines for the clinical and pathologic studies on carcinoma of the esophagus. 11th edn. 2015, Tokyo, Japan.Google Scholar
- 46.Zheng B, Ni CH, Chen H, et al. New evidence guiding extent of lymphadenectomy for esophagogastric junction tumor: Application of Ber-Ep4 Joint with CD44v6 staining on the detection of lower mediastinal lymph node micrometastasis and survival analysis. Medicine (Baltimore). 2017;96(14):e6533.CrossRefGoogle Scholar