Abstract
Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high ALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH+ cells represented a core within the CD44+/CD166+ subpopulation that contained the highest frequency of tumorigenic CSCs in vivo The ALDH+ cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH- cells, a process that was partially reversed by verapamil treatment.Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586-97. ©2016 AACR.
Highlights
Gastric cancer is the fourth most common cancer in frequency and the third leading cause of cancer mortality in the world
We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high aldehyde dehydrogenase (ALDH)
Activity was detected in 1.6% to 15.4% of the cells; and the ALDHþ cells represented a core within the CD44þ/CD166þ subpopulation that contained the highest frequency of tumorigenic cancer stem cells (CSC) in vivo
Summary
Gastric cancer is the fourth most common cancer in frequency and the third leading cause of cancer mortality in the world. Ninety-five percent of gastric cancers are gastric carcinomas, which are divided into two types depending on their localization in the stomach: adenocarcinomas of the cardia whose etiology remains unclear, and noncardia gastric carcinomas for which the main factor is a chronic infection by Helicobacter. The intestinal type is composed of glands having more or less preserved their organization and differentiation state, or having acquired intestinal characteristics; it is subclassified into tubular, mucinous, or papillary carcinoma in the WHO classification of gastric carcinoma [4]. The diffuse type is poorly cohesive, composed of isolated cells (often signet ring cells) producing mucins. These classification systems have little clinical utility, as they cannot orientate patient therapy. With the exception of Her positivity which orientates toward a specific treatment, treatment is still based on surgery combined with conventional chemotherapy and/or radiotherapy, and the 5-year survival rates remain under 30% in most countries [5]
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