Jian-Xian Lin1,2, Changhwan Yoon2, Ping Li1, Qian Yu3, Sheng-Liang Qiu3, Chao-Hui Zheng1, Sam S Yoon4, Chang-Ming Huang5. 1. Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian Province, China. 2. Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-1209, New York, NY, 10065, USA. 3. Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. 4. Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-1209, New York, NY, 10065, USA. yoons@mskcc.org. 5. Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian Province, China. hcmlr2002@163.com.
Abstract
PURPOSE: We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. METHODS: CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. RESULTS: Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p < 0.05). Both factors were also significant on multivariate analysis when the cohorts were combined (p ≤ 0.003). On subgroup analysis, the 5-year OS of patients with both high CD44 and high p-MEK was 39.5-41.6% compared with 55.4-66.4% for patients with low CD44. High CD44 expression was associated with more advanced TNM stage in the FMUUH cohort and larger tumor size and undifferentiated histology in the MSKCC cohort. High p-MEK was associated with undifferentiated histology in the FMUUH cohort and larger tumor size in the MSKCC cohort. CONCLUSIONS: Increased CD44 and p-MEK expression are predictive of worse OS in GA patients. Thus, targeting the RTK-RAS pathway may benefit patients with CD44-positive, RAS-activated GA by inhibiting metastasis and reversing chemotherapy resistance.
PURPOSE: We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. METHODS: CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. RESULTS: Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p < 0.05). Both factors were also significant on multivariate analysis when the cohorts were combined (p ≤ 0.003). On subgroup analysis, the 5-year OS of patients with both high CD44 and high p-MEK was 39.5-41.6% compared with 55.4-66.4% for patients with low CD44. High CD44 expression was associated with more advanced TNM stage in the FMUUH cohort and larger tumor size and undifferentiated histology in the MSKCC cohort. High p-MEK was associated with undifferentiated histology in the FMUUH cohort and larger tumor size in the MSKCC cohort. CONCLUSIONS: Increased CD44 and p-MEK expression are predictive of worse OS in GA patients. Thus, targeting the RTK-RAS pathway may benefit patients with CD44-positive, RAS-activated GA by inhibiting metastasis and reversing chemotherapy resistance.
Authors: H Oka; Y Chatani; R Hoshino; O Ogawa; Y Kakehi; T Terachi; Y Okada; M Kawaichi; M Kohno; O Yoshida Journal: Cancer Res Date: 1995-09-15 Impact factor: 12.701