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Abstract

Colorectal cancer is the third most common visceral malignancy and remains one of the leading causes of cancer-related deaths due to late diagnosis and therapy resistance. Even many years after initially successful treatment, the disease recurs in many patients and frequently spreads to distant organs. It is currently hypothesized that relapse may at least partially, be caused by a small population of dormant- or slowly cycling tumor cells. Presumably these cells are more resistant to the effects of DNA-damaging agents such as chemotherapy and irradiation than cycling cells. Such dormant cells have already been identified in the stem cell compartments of many tissues of the body, for instance in the skin, the hematopoietic system and the intestine. In parallel, it has been proposed that tumors arise from cancer stem cells, which might share common features with normal tissue stem cells, such as the ability to remain dormant. However, there is so far very little experimental evidence for the existence of dormant- or slow-cycling cells in cancer. In order to study the occurrence of dormancy in colorectal cancer, primary tumor models were used. Primary colorectal cancer cell lines were labeled with a tetracycline-inducible H2B-GFP reporter that enables the detection and in vivo isolation of label-retaining cells. Slowly cycling cells were identified in vitro and in vivo. Cell cycle analyses demonstrated a correlation between label-retention and cell cycle activation, suggesting the presence of quiescent tumor cells. The properties and hierarchical relation of label-retaining and non-label retaining cells were compared. Sorting into fast-, medium- and slowly cycling cell populations and subsequent tracing demonstrated that the initial phenotypes were preserved over several days in vitro. However, all three populations were capable of generating label-retaining cells as well as fast cycling cells, suggesting a dynamic switch between the different proliferative phenotypes. Furthermore, slowly cycling cells showed an enhanced resistance to standard chemotherapy. These findings suggest that label-retaining cells exist within at least some colorectal tumors and that they can switch from a dormant to an active proliferative state, suggesting a possible role in tumor-recurrence after therapy.