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: 29.54). 11/2007; 7(10):791-9. DOI: 10.1038/nrc2212
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: John Stingl, Feb 10, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Stem Cell Research 09/2014; 13(2). DOI:10.1016/j.scr.2014.08.001 · 3.91 Impact Factor
  • Source
    • "Of note, tumor cells with stem cell properties can develop from non-stem-like cells suggesting that stemness rather comprises a transitional functional phenotype than a continuous cell-specifi c feature and can be adjusted in critical situations such as environmental stress or nutrient changes (Gupta et al. 2011). It is believed that such cell-state dynamics in tumors are of particular signifi cance in tumorpathology and determine the aggressive nature of tumors, their tumor-seeding capacity and drug resistance (Stingl and Caldas 2007, Gupta et al. 2011). Due to their relative resistance to radiation and cytotoxic treatment cancer stem cells (CSC) may contribute to treatment failure and relapse (Creighton et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To review the results from previous studies aiming at the molecular characterization of circulating tumor cells (CTC), to specifically address the role of epithelial-mesenchymal-transition (EMT) and stemness features of CTC in their contribution to tumor progression and to summarize potential interference of CTC with the efficacy of radiotherapy. Conclusions: Detection of CTC has been reported for most epithelial tumors and has been associated with an increased risk of local and regional recurrence as well as the development of distant metastases. Given a causal relationship between the presence of CTC and tumor progression at the primary or distant sites, several distinct features have to be postulated for these cells: first, a change from an epithelial to a mesenchymal cell-like phenotype which should alleviate the disconnection of individual tumor cells from tight cell-to-cell junctions within the epithelial cell layer and endow single tumor cells with the capacity to migrate into blood vessels; secondly, the presence of stem-cell properties which contribute to the re-establishment of bulk tumor tissue at the primary or metastatic site upon tumor recurrence or distant progression, respectively. Indeed, EMT and stem-cell features were frequently observed in CTC and the phenotype of CTC was established as a stronger predictor of outcome than sole enumeration of CTC in a defined volume of blood. The exploitation of CTC above their use as prognostic marker is still a subject of many ongoing investigations as are the identification of suitable therapeutic targets for this small cell subpopulation.
    International Journal of Radiation Biology 01/2014; 90(8). DOI:10.3109/09553002.2014.886798 · 1.84 Impact Factor
  • Source
    • "In the present analysis, we assume a lower limit of Td > 30 days. 4) Fraction of stem cells: Based on [37], breast tumor stem cells are a minority population with a frequency of 5% at best. Here, we assume that the frequency of cancer stem cells among living tumor cell population does not exceed the above value (< 5%). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper outlines the major components and function of the Technologically Integrated Oncosimulator developed primarily within the ACGT (Advancing Clinico Genomic Trials on Cancer) project. The Oncosimulator is defined as an information technology system simulating in vivo tumor response to therapeutic modalities within the clinical trial context. Chemotherapy in the neoadjuvant setting, according to two real clinical trials concerning nephroblastoma and breast cancer, has been considered. The spatiotemporal simulation module embedded in the Oncosimulator is based on the multiscale, predominantly top-down, discrete entity - discrete event cancer simulation technique developed by the In Silico Oncology Group, National Technical University of Athens. The technology modules include multiscale data handling, image processing, invocation of code execution via a spreadsheet-inspired environment portal, execution of the code on the grid and visualization of the predictions. A refining scenario for the eventual coupling of the Oncosimulator with immunological models is also presented. Parameter values have been adapted to multiscale clinical trial data in a consistent way, thus supporting the predictive potential of the Oncosimulator. Indicative results demonstrating various aspects of the clinical adaptation and validation process are presented. Completion of these processes is expected to pave the way for the clinical translation of the system.
    10/2013; DOI:10.1109/JBHI.2013.2284276
Show more