Stingl J, Caldas CMolecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat Rev Cancer 7: 791-799

Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Nature Reviews Cancer (Impact Factor: 37.4). 11/2007; 7(10):791-9. DOI: 10.1038/nrc2212
Source: PubMed


Human breast cancers are heterogeneous, both in their pathology and in their molecular profiles. This suggests the hypothesis that breast cancers can initiate in different cell types, either breast epithelial stem cells or their progeny (transit amplifying cells or committed differentiated cells). In this respect, breast cancer could be viewed as being similar to haematological malignancies for which an analogous model has been proposed. Drawing such parallels might help to unravel the molecular nature of the initiating events in breast cancer and might have substantial clinical implications.

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    • "There is mounting evidence suggesting that tumors are driven to grow by a small subfraction of cancer-inducing stem cells with the ability to initiate and maintain tumor growth and plasticity (Al-Hajj et al., 2003; O'Brien et al., 2007; Zhang et al., 2008; Hubbard and Gargett, 2010). Those studies led to investigations into tumor initiation and stemness, and subsequently to the hypothesis that certain tumors may arise from undifferentiated stem cells or that these undifferentiated stem cells undergo spontaneous dedifferentiation to give rise to cancer-inducing cells (Reya et al., 2001; Beachy et al., 2004; Lobo et al., 2007; Stingl and Caldas, 2007). Gene expression analysis has recently been utilized to identify the re-activation of pluripotency-related markers in different human tumors. "
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    ABSTRACT: Though expression of the homeobox transcription factor Nanog is generally restricted to pluripotent cells and early germ cells, many contradictory reports about Nanog’s involvement in tumorigenesis exist. To address this, a modified Tet-On system was utilized to generate Nanog-inducible mice. Following prolonged Nanog expression, phenotypic alterations were found to be restricted to the intestinal tract, leaving other major organs unaffected. Intestinal and colonic epithelium hyperplasia was observed—intestinal villi had doubled in length and hyperplastic epithelium outgrowths were seen after 7 days. Increased proliferation of crypt cells and downregulation of the tumor suppressors Cdx2 and Klf4 was detected. ChIP analysis showed physical interaction of Nanog with the Cdx2 and Klf4 promoters, indicating a regulatory conservation from embryonic development. Despite downregulation of tumor suppressors and increased proliferation, ectopic Nanog expression did not lead to tumor formation. We conclude that unlike other pluripotency-related transcription factors, Nanog cannot be considered an oncogene.
    Full-text · Article · Sep 2014 · Stem Cell Research
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    • "Cancer stem cells have the capacity of self-renewal, and are thought to be responsible for the generation of multiple cell lineages that are characteristic of many tumors [9]–[10]. Cancer stem cells have roles in tumorigenesis and resistance to therapy, so the identification of markers for cancer stem cell may provide important information regarding patient prognosis and response to therapy [11]–[12]. "
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    ABSTRACT: Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and Nanog, in esophageal squamous cell carcinoma (ESCC) tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG), and 5-year overall survival (OS). There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05). However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (p = 0.033). TRG after treatment was significantly associated with expression of ALDH-1 (p = 0.001), Bmi-1 (p = 0.004), and Nanog (p<0.001). Although OS was significantly better in patients with low TRGs (p = 0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi-1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "One of the main biological challenges is heterogeneity of the CTC population. The significance of many molecularly different CTC subpopulations (i.e., cancer stem CTCs and CTCs with epithelial to mesenchymal transition [EMT]) has been clarified in the last decade [3,7,31,33,34], but quantitative and temporal heterogeneity of CTCs remains poorly understood. This, at least partly, can be explained by technical limitations of existing CTC assays that mainly use in vitro testing of blood samples. "
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    ABSTRACT: Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs' diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0-54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.
    Full-text · Article · Mar 2014 · Cancers
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