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Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy

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Dylla, Scott J., Beviglia, Lucia, Park, In-Kyung, Chartier, Cecile, Raval, Janak, Ngan, Lucy, Pickell, Kellie, Aguilar, Jorge, Lazetic, Sasha, Smith-Berdan, Stephanie, Clarke, Michael F., Hoey, Tim, Lewicki, John, Gurney, Austin L.·2008·PLoS ONE
DOI 10.1371/journal.pone.0002428
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Abstract

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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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Metadata

Authors
Dylla, S. J., Beviglia, L., Park, I.-K., Chartier, C., Raval, J., Ngan, L., Pickell, K., Aguilar, J., Lazetic, S., Smith-Berdan, S., Clarke, M. F., Hoey, T., Lewicki, J., & Gurney, A. L.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-06-18
Volume
3
Issue
6
Pages
e2428
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0002428
OpenAlex
W2069831652
Cited by
589
References
1
FWCI
22.18
Type
journal article
Language
en
Update notices
correction (2008-08-21)
Open access
gold
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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CoChat. (2026). Citation check: Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy. https://app.cochat.ai/papers/10.1371/journal.pone.0002428
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Dylla, S. J., Beviglia, L., Park, I.-K., Chartier, C., Raval, J., Ngan, L., Pickell, K., Aguilar, J., Lazetic, S., Smith-Berdan, S., Clarke, M. F., Hoey, T., Lewicki, J., & Gurney, A. L. (2008). Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy. PLoS ONE. https://doi.org/10.1371/journal.pone.0002428

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