Article

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

Vanderbilt University, Нашвилл, Michigan, United States
Cancer Research (Impact Factor: 9.33). 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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    • "A number of primary non-malignant and malignant tumor-derived human prostate epithelial cell lines have been developed using a retroviral vector encoding human telomerase reverse transcriptase. These cell lines exhibit the characteristics of stem cells and express embryonic stem (ES) cell markers, such as NANOG, octamer 4 (OCT4) and SRY-box 2 (Sox-2), as well as the early progenitor cell markers, cluster of differentiation 133 (CD133), CD44 and NESTIN (7,8). "
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    ABSTRACT: Cancer stem cells (CSCs) have been identified in a variety of cancer types, including prostate cancer. The aim of the present study was to evaluate the immunohistochemical expression of NANOG, octamer 4 (OCT4), cluster of differentiation 133 (CD133) and NESTIN, which are all CSC markers, and assess their function in prostate carcinogenesis. A total of 114 patients were referred to the Kanazawa Medical University Hospital (Uchinada, Japan) having presented with elevated serum prostate-specific antigen levels and/or abnormal digital rectal examinations, and underwent transrectal ultrasound sonography guided eight core biopsies. The prostate pathological specimens were re-evaluated for selection in this study. When specimens were diagnosed as prostate cancer, immunohistochemical analysis of the four different stem cell markers (NANOG, OCT4, CD133 and NESTIN) and hypoxia-inducible factor (HIF)-1α was performed. Prostate cancer was found in 38 cases (33.3%), while the other patients had benign prostate hyperplasia with prostatitis. All prostate cancers were histopathologically identified as adenocarcinomas of various grades, and cancer cells and intraepithelial neoplasia (high grade) were immunohistochemically shown to express NANOG and OCT4, but not CD133 and NESTIN. The intensity of NANOG expression was much greater than that of OCT4, and the positivity and intensity of the four stem cell markers, including NANOG, were elevated with high Gleason scores. A significant correlation was observed between the NANOG- and HIF-1α-positive regions. The CSC markers, in particular OCT4 and NANOG, were immunohistochemically expressed in prostate cancers. Furthermore, HIF-1α expression may affect NANOG and/or OCT4 expression. The findings of the current study suggested that NANOG expression may be a biomarker for the diagnosis of prostate cancer, and the coexpression of NANOG and HIF-1α may be involved in prostate carcinogenesis.
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    • "Oct4 and Sox2 are overexpressed in some cancer stem cell types [34]. Examples include human oral, prostate and breast carcinoma [34–37] and are sometime selectively elevated in advanced cancer [34,36,38]. The observation that SCC-13 cell derived spheroids are enriched in Oct4 and Sox2 suggest that they share properties with embryonic stem cells and may reflect the fact that they are transformed [34,39]. "
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    • "For ERβ, there was a 4-fold increase in the PCa-E derived stem/progenitor cells but not the benign EPZ cells relative to normal donor PrEC expression. Since the prostaspheres from PCa-E were mixed stem and progenitor cells that are not confirmed as prostate cancer stem-like cells, ERs were also evaluated in two human prostate cancer stem-like cell lines, HPET (Gu et al., 2007) and HuSLC (kindly supplied by Dr. S. Kasper, University of Cincinnati). Each cell line was generated from separate Gleason score 9 tumors, spontaneously immortalized and is capable of fully re-establishing the original tumors in vivo. "
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