Article

Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy

Brigham and Women's Hospital, United States of America
PLoS ONE (Impact Factor: 3.53). 02/2008; 3(6):e2428. DOI: 10.1371/journal.pone.0002428
Source: PubMed Central

ABSTRACT 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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    • "This subset of stem cells could be insensitive to chemical or radiation therapy. ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide – a classical chemotherapeutic agent (Dylla et al, 2008). ALDH1 is now widely accepted as a CRC-CSC marker (Arcaroli et al, 2012; Shenoy et al, 2012). "
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    ABSTRACT: Background: About one in five patients with locally advanced rectal cancer (RC) suffers recurrence or distant metastasis after neoadjuvant therapy. We investigated how cancer stem cell markers change after neoadjuvant therapy and how these markers relate to recurrence. Methods: Pretreatment biopsies and postoperative specimens were taken from 64 patients with locally advanced rectal adenocarcinoma who received preoperative radiochemotherapy (RCT) between sampling. Samples were tested immunohistochemically for CD44, LGR5, ALDH1 and CD166; scores were dichotomised as high or low. The median follow-up period was 36 months. Results: High expression of CD44, LGR5, ALDH and CD166 was found in 38%, 5%, 48% and 10%, respectively, before RCT and 86%, 33%, 71% and 52%, respectively, after RCT. CD44 (P=0.001), LGR5 (P=0.049) and CD166 (P=0.003) were significantly upregulated after RCT. Whereas no recurrence was seen during the follow-up in the low ALDH group, 40% of the high ALDH group suffered recurrence. In multivariate COX analysis, postoperative ALDH1 independently predicted poor prognosis in patients with RC who received RCT (P=0.0095). Conclusion: Preoperative RCT upregulates expression of stem cell markers in patients with RC. High post-treatment ALDH1 expression predicts poor prognosis for these patients after neoadjuvant therapy.
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    • "Aside from such a suppressive role, studies in vitro demonstrated that ALDH activity or ALDH1A1 protein expression was strong in stem cell fractions in a variety of malignancies including lung cancer [8] [9] [10] [11] [12] [13] [24] [25] [26], and suggested that ALDH1A1 could participate in the maintenance of cancer stem cells. Also, silencing experiments in vitro showed that a forced reduction of ALDH1A1 attenuated growth and migration in some lung cancer cell lines, suggesting an oncogenic role [26]. "
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    • "For instance, CD44 over expression in breast cancer patients after chemotherapy (X. Li et al., 2008), CD133 over expression in human glioblastoma after radiation (Bao et al., 2006), and ALDH1 over expression and increased enzyme activity in human colorectal xenograft tumors after chemotherapy (Dylla et al., 2008) have been reported. Other forms of stress such as hypoxia and products of metabolism, including lactate and ketones, have also recently been shown to induce stemness in tumor tissues (Kim et al., 2009; Martinez-Outschoorn et al., 2011). "
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