Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy

// Feng-Hua Wu 1, 2 , Lei Mu 1 , Xiao-Lan Li 1 , Yi-Bing Hu 1 , Hui Liu 2 , Lin-Tao Han 2 and Jian-Ping Gong 1 1 Cancer Research Institution, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, People’s Republic of China 2 Department of Physiology, Hubei University of Chinese Medcine, Wuhan 430065, People’s Republic of China Correspondence to: Jian-Ping Gong, email: jpgong@tjh.tjmu.edu.cn Keywords: slow-cycling tumor cells, cancer stem cell, DC-CIK, adoptive transfer, tumor dormancy Received: August 04, 2016     Accepted: May 22, 2017     Published: July 26, 2017 ABSTRACT The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo . Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo . Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro . Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.