Identification of stem-like cells and clinical significance of candidate stem cell markers in gastric cancer

// Xiaowei Zhang 1, 4, * , Ruixi Hua 2, * , Xiaofeng Wang 1, 4 , Mingzhu Huang 1, 4 , Lu Gan 1, 4 , Zhenhua Wu 1, 4 , Jiejun Zhang 1, 4 , Hongqiang Wang 3 , Yufan Cheng 1, 4 , Jin Li 1, 4 , Weijian Guo 1, 4 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China 3 Department of Cancer Chemotherapy Center, Zhoushan Hospital, Zhejiang, China 4 Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Weijian Guo, e-mail: guoweijian1@hotmail.com Keywords: cancer stem cell, gastric cancer, stem cell marker, CD44, CD133 Received: June 07, 2015     Accepted: December 29, 2015     Published: January 12, 2016 ABSTRACT The existence of gastric cancer stem cells (CSCs) has not been definitively proven and specific cell surface markers for identifying gastric CSCs have largely not been identified. Our research aimed to isolate potential gastric CSCs and clarify their clinical significance, while defining markers for GCSC identification and verification. Here, we report that spheroid cells possess stem cell-like properties, and overexpress certain stem cell markers. CD133 or CD44-positive cells also exhibit properties of CSCs. The expression of Oct4, Sox2, Gli1, CD44, CD133, p-AKT, and p-ERK was significantly higher in metastatic lesions compared to that in primary lesions. Elevated expression of some of these proteins was correlated with a more aggressive phenotype and poorer prognosis, including Oct4, Sox2, Gli1, CD44, and p-ERK. Multivariate Cox proportional hazards model analysis showed that only CD44 is an independent factor. Knockdown of CD44 down-regulated the stem cell-like properties, which was accompanied by the down-regulation of p-ERK and Oct4. Oct4 overexpression could reverse the decreased CSCs properties induced by CD44 knockdown. Taken together, our research revealed that spheroid cell culture, and CD133 or CD44-labeled FACS methods can be used to isolate gastric CSCs. Some CSC markers have clinical significance in predicting the prognosis. CD44 is an independent prognostic factor and maintains the properties of CSCs in CD44-p-ERK-Oct4 positive feedback loop.