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Cancer stem cells and cells of origin in MMTV-Her2/neu-induced mammary tumorigenesis

Oncogene volume 32, pages 1339–1340 (2013)Cite this article

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The main purpose of our study was to find new biomarkers to identify and enrich the tumor-initiating cells (TIC) or cancer stem cells (CSCs) in MMTV-Her2/neu-induced mammary tumors. The cancer stem cell hypothesis is an evolving concept of oncogenesis that the definition of a cancer stem cell does not necessarily imply its origin from a stem, progenitor or differentiated cell.1 Two previous studies attempted to address the same issue using the MMTV-Her2/neu transgenic mice model.2, 3 In order to be consistent with these previous studies,2 we used the term ‘tumor-initiating cell’ instead of ‘cancer stem cell’ to represent the subpopulation of tumor cells that can self-renew, propagate the tumor and differentiate into many types of cells found in a tumor. Liu et al.2 first reported that TICs can be functionally isolated from MMTV-Her2/neu tumors but no specific markers have been identified to enrich them. It was also found that the majority of tumor cells shown in their study were CD24+. When the CD24+ cells were stratified into two subpopulations, Sca1+/CD24+ and Scal1−/CD24+, using the Sca1 marker for analysis, both fractions contained similar levels of TICs and exhibited equal tumorigenicity.2 In another study, CD61 has been reported as a biomarker for identification of the TIC subset arising in MMTV-wnt-1 tumors and 50% of p53−/−-derived tumors, but not in MMTV-Her2/neu tumors.3 They concluded that MMTV-Her2/neu tumors are composed of a homogeneous cell population and no distinct CSC population can be identified. In our study, we screened many potential biomarkers and found that a combination of two mammary stem/progenitor markers (CD49fhiCD61hi) can be utilized to identify and sort out TICs from primary tumors and their derivative cell lines. The sorted CD49fhiCD61hi subpopulation displayed typical characteristics of TICs, such as the increased tumorsphere formation ability and enhanced tumorigenicity both in vitro and in vivo. Furthermore, we found that the integrin-β3-TGFβ pathway is critical for maintenance of this population within a tumor. To our knowledge, we for the first time found that a combination of CD49f and CD61 can be utilized to successfully isolate and enrich TICs from MMTV-Her2/neu mammary tumors.4

During identification of TIC markers for HER2 mammary tumors, we systematically analyzed normal, pre-malignant and malignant mammary epithelial cells using a panel of stem cell markers. Although identification of the origin of tumor cells is not the main focus in our paper, these studies indeed gave us some clues about the originating cells of MMTV-Her2/neu tumors.4 In light of our finding and other published results, we posited that TICs in the MMTV-Her2/neu tumors are potentially derived from luminal progenitors. This hypothesis is supported by the following evidence. First, CD61 which we used to identify TICs is a putative luminal progenitor marker.5, 6, 7 Recently, Weinberg and colleagues have also shown that CD49flowCD61+ cells are enriched in luminal progenitor activity.7 Second, the CD24highCD49fmed/low Ma-CFC progenitor population was anomalously expanded in preneoplastic MMTV-Her2/neu mammary glands relative to age-matched, normal counterparts.4, 8 Third, the detected, expanded cell population also displayed ESAhigh, a feature similar to human mammary luminal progenitor cells.6 Last, gene expression profiles of MMTV-Her2/neu tumor cells are most concordant with the luminal progenitor gene signature.9

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  1. Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA

    P-K Lo & H Chen

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Lo, PK., Chen, H. Cancer stem cells and cells of origin in MMTV-Her2/neu-induced mammary tumorigenesis. Oncogene 32, 1339–1340 (2013). https://doi.org/10.1038/onc.2012.456

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