Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy

Brigham and Women's Hospital, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(6):e2428. DOI: 10.1371/journal.pone.0002428
Source: PubMed Central


Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.
Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent.
CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy.

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    • "Current standard of care in many cancers focuses on targeting the highly proliferative phenotype of cancer cells with genotoxic drugs such as platinums, anthracyclines, and pyrimidine analogs, among others. However, these therapies are limited by the near inevitability of acquired resistance and metastatic relapse [Rebucci and Michiels, 2013], often of a more aggressive phenotype and poor patient outcome [Dylla et al., 2008; Li et al., 2008; Loges et al., 2009; Milone et al., 2013]. By utilizing therapeutics which do not rely solely on targeting rapid proliferation, that is, genotoxic therapies, but instead which target other intrinsic properties of malignant cells, it may be possible to avoid development of MDR and subsequent relapse. "
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    • "However, taken into consideration that 5-FU also stimulated enrichment of CSC marker positive cells in high density tumor microenvironment co-cultures, these results might be regarded as a defense reaction/response of the tumor cell culture and the tumor microenvironment. In fact, it has been reported that in contrast to the differentiated population of tumor cells, cancer stem cells are characterized by increased resistance to cytotoxic chemotherapeutic agents [62], enhanced ability to form colonospheres [6], [13], [63] and induce remission, providing basis for why cancer cells cannot be completely destroyed by conventional chemotherapeutic agents [57], [64]. Indeed, we could further show that combinational treatment of curcumin and 5-FU dramatically suppressed tumor promoting factors, activation of NF-κB signaling pathway and enrichment of CSCs in high density tumor microenvironment co-cultures. "
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