Aldehyde Dehydrogenase 1-Positive Cancer Stem Cells Mediate Metastasis and Poor Clinical Outcome in Inflammatory Breast Cancer

Department of Molecular Oncology, Institut Paoli-Calmettes/UMR891 Institut National de la Sante et de la Recherche Medicale, Université de la Méditerranée, Marseille Cancer Research Center, Marseille, France.
Clinical Cancer Research (Impact Factor: 8.72). 12/2009; 16(1):45-55. DOI: 10.1158/1078-0432.CCR-09-1630
Source: PubMed


To examine the role of cancer stem cells (CSC) in mediating metastasis in inflammatory breast cancer (IBC) and the association of these cells with patient outcome in this aggressive type of breast cancer.
CSCs were isolated from SUM149 and MARY-X, an IBC cell line and primary xenograft, by virtue of increased aldehyde dehydrogenase (ALDH) activity as assessed by the ALDEFLUOR assay. Invasion and metastasis of CSC populations were assessed by in vitro and mouse xenograft assays. Expression of ALDH1 was determined on a retrospective series of 109 IBC patients and this was correlated with histoclinical data. All statistical tests were two sided. Log-rank tests using Kaplan-Meier analysis were used to determine the correlation of ALDH1 expression with development of metastasis and patient outcome.
Both in vitro and xenograft assays showed that invasion and metastasis in IBC are mediated by a cellular component that displays ALDH activity. Furthermore, expression of ALDH1 in IBC was an independent predictive factor for early metastasis and decreased survival in this patient population.
These results suggest that the metastatic, aggressive behavior of IBC may be mediated by a CSC component that displays ALDH enzymatic activity. ALDH1 expression represents the first independent prognostic marker to predict metastasis and poor patient outcome in IBC. The results illustrate how stem cell research can translate into clinical practice in the IBC field.

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Available from: Gabriela Dontu
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    • "More recently, it has been shown to play a role in breast cancer pathways like Notch, Sonic Hedgehog Shh, Hedgehog or Wnt. Those signaling pathways are involved in the regulation and differentiation of stem/progenitor cells and are often mis-regulated during carcinogenesis [16] [30] [32]. On the other hand, BRCA1 and p53 play an important role in the DNA Damage Response and in the genomic stability. "
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    • "While more than 50,000 unsorted cells were required to generate tumors [8]. Subsequent studies found that the aldehyde dehydrogenase (ALDH) activity could also be used to enrich for breast CSCs and normal mammary stem cells [9], [10]. The convenient isolation of CSCs has allowed the investigation of the molecular mechanisms involved in their origin, self-renewal, differentiation into cancer cells, resistance to radiation therapy and chemotherapy, and invasiveness and metastatic ability [11]. "
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    • "The high ALDH activity described for CSCs suggested also this enzyme as a probe to isolate these cells. Aldefluor, an ALDH1 substrate, initially used for the isolation of hematopoietic stem cells by FACS (Storms et al., 1999; Cheung et al., 2007) and for CSCs separation in tumor tissue and cancer cell lines (Moreb, 2008; Jiang et al., 2009), has been successfully used for ALDH1 activity detection of CSCs in lung (Jiang et al., 2009), prostate (Li et al., 2010), breast (Charafe-Jauffret et al., 2010), colon (Huang et al., 2009a), and bladder (Su et al., 2010). Aldefluor contains the ALDH1 substrate BODIPY-aminoacetaldehyde (BAAA), that is converted into the fluorescent metabolite BODIPY-aminoacetate (BAA) by ALDH1 (Storms et al., 1999). "
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