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, Oct 13, 2015
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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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    ABSTRACT: Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous “ovarian dysplasia” and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls.Study designMorphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO).ResultsMorphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p < 0.0001, for ovaries and 6.54 vs 1.58, p < 0.0001 for tubes). Increased γH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs.Conclusion The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 10/2014; 183. DOI:10.1016/j.ejogrb.2014.10.003 · 1.70 Impact Factor
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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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    ABSTRACT: Resveratrol, a natural polyphenolic compound, is abundantly found in plant foods and has been extensively studied for its anti-cancer properties. Given the important role of CSCs (Cancer Stem Cells) in breast tumorigenesis and progression, it is worth investigating the effects of resveratrol on CSCs. The article is an attempt to investigate the effects of resveratrol on breast CSCs. Resveratrol significantly inhibits the proliferation of BCSCs (breast cancer stem-like cells) isolated from MCF-7 and SUM159, and decreased the percentage of BCSCs population, consequently reduced the size and number of mammospheres in non-adherent spherical clusters. Accordingly, the injection of resveratrol (100 mg/kg/d) in NOD/SCID (nonobese diabetic/severe combined immunodeficient) mice effectively inhibited the growth of xenograft tumors and reduced BCSC population in tumor cells. After the reimplantation of primary tumor cells into the secondary mice for 30 d, all 6 control inoculations produced tumors, while tumor cells derived from resveratrol-treated mice only caused 1 tumor of 6 inoculations. Further studies by TEM (Transmission electron microscopy) analysis, GFP-LC3-II puncta formation assay and western blot for LC3-II, Beclin1 and Atg 7, showed that resveratrol induces autophagy in BCSCs. Moreover, resveratrol suppresses Wnt/β-catenin signaling pathway in BCSCs; over-expression of β-catenin by transfecting the plasmid markedly reduced resveratrol-induced cytotoxicity and autophagy in BCSCs. Our findings indicated that resveratrol inhibits BCSCs and induces autophagy via suppressing Wnt/β-catenin signaling pathway.
    PLoS ONE 07/2014; 9(7):e102535. DOI:10.1371/journal.pone.0102535 · 3.23 Impact Factor
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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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    ABSTRACT: CSCs are responsible for the high rate of recurrence and chemoresistance of different types of cancer. The current antineoplastic agents able to inhibit bulk replicating cancer cells and radiation treatment are not efficacious toward CSCs since this subpopulation has several intrinsic mechanisms of resistance. Among these mechanisms, the expression of ATP-Binding Cassette (ABC) transporters family and the activation of different signaling pathways (such as Wnt/β-catenin signaling, Hedgehog, Notch, Akt/PKB) are reported. Therefore, considering ABC transporters expression on CSCs membranes, compounds able to modulate MDR could induce cytotoxicity in these cells disclosing an exciting and alternative strategy for targeting CSCs in tumor therapy. The next challenge in the cure of cancer relapse may be a multimodal strategy, an approach where specific CSCs targeting drugs exert simultaneously the ability to circumvent tumor drug resistance (ABC transporters modulation) and cytotoxic activity toward CSCs and the corresponding differentiated tumor cells. The efficacy of suggested multimodal strategy could be probed by using several scaffolds active toward MDR pumps on CSCs isolated by tumor specimens.
    Frontiers in Pharmacology 07/2014; 5:163. DOI:10.3389/fphar.2014.00163 · 3.80 Impact Factor
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