Prostate Cancer Cells with Stem Cell Characteristics Reconstitute the Original Human Tumor In vivo

Vanderbilt University, Нашвилл, Michigan, United States
Cancer Research (Impact Factor: 9.28). 06/2007; 67(10):4807-15. DOI: 10.1158/0008-5472.CAN-06-4608
Source: PubMed

ABSTRACT Cancer may arise from a cancer stem/progenitor cell that shares characteristics with its normal counterpart. We report the reconstitution of the original human prostate cancer specimen from epithelial cell lines (termed HPET for human prostate epithelial/hTERT) derived from this sample. These tumors can be described in terms of Gleason score, a classification not applied to any of the transgenic mouse models currently developed to mimic human disease. Immunohistochemical and Western blot analyses indicate that they do not express androgen receptor or p63, similar to that reported for prostate stem cells. These cell lines also express embryonic stem markers (Oct4, Nanog, and Sox2) as well as early progenitor cell markers (CD44 and Nestin) in vitro. Clonally derived HPET cells reconstitute the original human tumor in vivo and differentiate into the three prostate epithelial cell lineages, indicating that they arise from a common stem/progenitor cell. Serial transplantation experiments reconstitute the tumors, suggesting that a fraction of parental or clonally derived HPET cells have self-renewal potential. Thus, this model may enhance our understanding of human tumor development and provide a mechanism for studying cancer stem/progenitor cells in differentiation, tumorigenesis, preclinical testing, and the development of drug resistance.

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    • "In addition, BMI1 activates Akt and hTERT (telomerase reverse transcriptase) via PTEN phosphatase repression [130]. Interestingly, Akt and hTERT are required for PCa CRC self-renewal [62] [131]. The pathways regulated by BMI1 suggest that the maintenance of PCa CRC critically depends on BMI1 integrity. "
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    ABSTRACT: Prostate cancer (PCa) is a very common neoplasm, which is generally treated by chemo-, radio-, and/or hormonal-therapy. After a variable time, PCa becomes resistant to conventional treatment, leading to patient death. Prostate tumor-initiating cells (TICs) and cancer repopulating cells (CRCs) are stem-like populations, driving respectively cancer initiation and progression. Histone modifiers (HMs) control gene expression in normal and cancer cells, thereby orchestrating key physiological and pathological processes. In particular, Polycomb group genes (PcGs) are a set of HMs crucial for lineage-specific gene silencing and stem cell self renewal. PcG products are organized into two main Polycomb Repressive Complexes (PRCs). At specific loci, PRC2 catalyzes histone H3 Lys27 trimethylation, which triggers gene silencing by recruiting PRC1, histone deacetylases and DNA methyl transferases. PRC1 catalyzes addition of the repressive mark histone H2A ubiquitination. Recently, the catalytic component of PRC1 (BMI1) was shown to play critical roles in prostate CRC self-renewal and resistance to chemotherapy, resulting in poorer prognosis. Similarly, pharmacological disruption of PRC2 by a small molecule inhibitor reduced the tumorigenicity and metastatic potential of prostate CRCs. Along with PcGs, some histone lysine demethylases (KDMs) are emerging as critical regulators of TIC/CRC biology. KDMs may be inhibited by specific small molecules, some of which display antitumor activity in PCa cells at micromolar concentrations. Since epigenetic gene regulation is crucial for stem cell biology, exploring the role of HMs in prostate cancer is a promising path that may lead to novel treatments.
    Current pharmaceutical design 07/2013; DOI:10.2174/13816128113199990522 · 3.29 Impact Factor
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    • "It is widely accepted that adult stem cells are involved in normal tissue replenishment throughout life while cancer stem cells support cancer growth (Presnell et al., 2002, Smith et al., 2007). Although the cell(s) of origin for prostate cancer may include luminal, basal, neuroendocrine, progenitor and stem cells (Kasper, 2008, Wang et al., 2009), it is increasingly evident that the resultant prostate cancers contain cancer stem cells that continuously seed and maintain tumor growth (Gu et al., 2007, Kasper, 2008, Kasper, 2009). Even though conventional therapies for prostate cancer eradicate the majority of cells within a tumor, most patients with advanced cancer eventually progress to androgen-independent, metastatic disease that remains essentially incurable by current treatment strategies. "
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    ABSTRACT: Estrogen reprogramming of the prostate gland as a function of developmental exposures (aka developmental estrogenization) results in permanent alterations in structure and gene expression that lead to an increased incidence of prostatic lesions with aging. Endocrine disrupting chemicals (EDCs) with estrogenic activity have been similarly linked to an increased prostate cancer risk. Since it has been suggested that stem cells and cancer stem cells are potential targets of cancer initiation and disease management, it is highly possible that estrogens and EDCs influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this article, we review recent literature highlighting the effects of estrogens and EDCs on prostate cancer risk and discuss recent advances in prostate stem/progenitor cell research. Our laboratory has recently developed a novel prostasphere model using normal human prostate stem/progenitor cells and established that these cells express estrogen receptors (ERs) and are direct targets of estrogen action. Further, using a chimeric in vivo prostate model derived from these normal human prostate progenitor cells, we demonstrated for the first time that estrogens initiate and promote prostatic carcinogenesis in an androgen-supported environment. We herein discuss these findings and highlight new evidence using our in vitro human prostasphere assay for perturbations in human prostate stem cell self-renewal and differentiation by natural steroids as well as EDCs. These findings support the hypothesis that tissue stem cells may be direct EDC targets which may underlie life-long reprogramming as a consequence of developmental and/or transient adult exposures.
    Molecular and Cellular Endocrinology 09/2011; 354(1-2):63-73. DOI:10.1016/j.mce.2011.08.032 · 4.24 Impact Factor
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    • "Different systems have been used to culture PCSCs, including using suspension, low adherence culture on a layer of agar [16] [18], or use of low adherence plates [17] [20]. In general, two types of media are used to culture these stem-like PC cells that contained either fetal bovine serum (FBS) [17] [19], or supplemented with epidermal growth factor (EGF; 10 or 20 ng/ml) and basic fibroblast growth factor (bFGF; 10 or 20 ng/ml) [16] [20]. Although these stem-like PC cells have been demonstrated to have CSC properties, these cells have not been cultured for an extended period of time. "
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    ABSTRACT: While accumulating evidence demonstrates the existence of prostate cancer stem cells (PCSCs), PCSCs have not been isolated and thoroughly characterized. We report here the enrichment and characterization of sphere-propagating cells with stem-like properties from DU145 PC cells in a defined serum-free medium (SFM). Approximately 1.25% of monolayer DU145 cells formed spheres in SFM and 26% of sphere cells formed secondary spheres. Spheres are enriched for cells expressing prostate basal and luminal cytokeratins (34βE12 and CK18) and for cancer stem cell markers, including CD44, CD24, and integrin α2β1. Upon culturing spheres under differentiating media conditions in the presence of 10% serum, cells positive for CD44 and CD24 were substantially reduced. Furthermore, spheres could be generated from the sphere-derived adherent cell cultures and xenograft tumors, demonstrating the stemness of DU145 spheres. We have maintained spheres for more than 30 passages within 1.5years without noticeable loss of their "stemness". Sphere cells possess self-renewal capacity, display significant increases in proliferation potential, and initiate xenograft tumors with enhanced capacity compared to monolayer DU145 cells. While EGF promoted the generation and maintenance of these stem-like cells, bFGF inhibited these events. Sphere cells proliferate slowly with a significant reduction in the activation of the PI3K-AKT pathway compared to monolayer DU145 cells. While knockdown of PTEN enhanced AKT activation, this did not affect the generation of primary spheres and the propagation of secondary spheres. Consistent with this observation, we were able to demonstrate the generation and propagation of spheres without the addition of external growth factors. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
    Biochimica et Biophysica Acta 05/2011; 1813(5):683-94. DOI:10.1016/j.bbamcr.2011.01.018 · 4.66 Impact Factor
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