The CEA -/lo colorectal cancer cell population harbors cancer stem cells and metastatic cells

// Chang Yan 1, 2, * , Yibing Hu 1, 2, * , Bo Zhang 1, 2 , Lei Mu 1, 2 , Kaiyu Huang 1, 2 , Hui Zhao 2 , Chensen Ma 1, 2 , Xiaolan Li 2 , Deding Tao 2 , Jianping Gong 1, 2 , Jichao Qin 1, 2 1 Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors contributed equally to this work Correspondence to: Jichao Qin, email: jcqin@tjh.tjmu.edu.cn Jianping Gong, email: jpgong@tjh.tjmu.edu.cn Keywords: colorectal cancer, carcinoembryonic antigen, cancer stem cell, metastasis Received: June 14, 2016      Accepted: October 26, 2016      Published: November 02, 2016 ABSTRACT Serum carcinoembryonic antigen (CEA) is the most commonly used tumor marker in a variety of cancers including colorectal cancer (CRC) for tumor diagnosis and monitoring. Recent studies have shown that colonic crypt cells expressing little or no CEA may enrich for stem cells. Numerous studies have clearly shown that there exist CRC patients with normal serum CEA levels during tumor progression or even tumor relapse, although CEA itself is considered to promote metastasis and block cell differentiation. These seemingly contradictory observations prompted us to investigate, herein, the biological properties as well as tumorigenic and metastatic capacity of CRC cells that express high (CEA + ) versus low CEA (CEA -/lo ) levels of CEA. Our findings show that the abundance of CEA -/lo cells correlate with poor differentiation and poor prognosis, and moreover, CEA -/lo cells form more spheres in vitro , generate more tumors and exhibit a higher potential in developing liver and lung metastases than corresponding CEA + cells. Applying RNAi-mediated approach, we found that IGF1R mediated tumorigenic and capacity of CEA -/lo cells but did not mediate those of CEA + cells. Notably, our data demonstrated that CEA molecule was capable of protecting CEA -/lo cells from anoikis, implying that CEA + cells, although themselves possessing less tumorigenic and metastatic capacity, may promote metastasis of CEA -/lo cells via secreting CEA molecule. Our observations suggest that, besides targeting CEA molecule, CEA -/lo cells may represent a critical source of tumor progression and metastasis, and should therefore be the target of future therapies.