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.

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Available from: Sasha Lazetic
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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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    ABSTRACT: Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Preview · Article · Jan 2015 · Journal of Cellular Biochemistry
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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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    ABSTRACT: Objective Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Methods Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Results Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment. Conclusion Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Strategies to modulate EMT by blocking the translocation of active β-catenin to the nucleus might play a role in the down-regulation of CSCs. In addition to 5-FU, there are many drug resistance processes caused by CSCs enrichment such as those involved in resistance to cisplatin [42] and cyclophosphamide [43]. This study provides us with a new approach to reverse drug resistant for the treatment of patients with HCC. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the few cancers in which a continuous increase in incidence has been observed over several years. Drug resistance is a major problem in the treatment of HCC. In the present study, we used salinomycin (Sal) and 5-fluorouracil (5-FU) combination therapy on HCC cell lines Huh7, LM3 and SMMC-7721 and nude mice subcutaneously tumor model to study whether Sal could increase the sensitivity of hepatoma cells to the traditional chemotherapeutic agent such as 5-FU. The combination of Sal and 5-FU resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. Sal reversed the 5-FU-induced increase in CD133(+) EPCAM(+) cells, epithelial-mesenchymal transition and activation of the Wnt/β-catenin signaling pathway. The combination of Sal and 5-FU may provide us with a new approach to reverse drug resistant for the treatment of patients with HCC.
    Full-text · Article · May 2014 · PLoS ONE
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