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.
Highlights
In the majority of cancer cases, mortality is caused by metastasis or recurrence, with only 10% being caused by the primary tumor [1]
slow-cycling tumor cell (SCC) enriched by cell cycle inducer combined chemotherapy are more resistant to Dendritic cells (DC)-CIKmediated cytotoxic killing in vitro
SCCs enriched by cell cycle inducer combined chemotherapy are more resistant to DC-Cytokine induced killer (CIK) adoptive immunotherapy in vivo
Summary
In the majority of cancer cases, mortality is caused by metastasis or recurrence, with only 10% being caused by the primary tumor [1]. Based on the concept of cancer stem cells (CSCs), claims are made that the ability of a tumor to grow and propagate may depend on small subsets of cells exhibiting increased self renewal and tumor initiating potential [2,3,4]. Surface antigens such as CD24, CD44, CD133 or ALDH activity are used as CSC markers gradually. The ability to isolate and better characterize these slow-cycling cancer cells will be a key component of future therapies that better target CSCs [9]
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