Papers by Andrew S Goldstein
Endocrine-related cancer, 2015
Research in the area of stem/progenitor cells has led to the identification of multiple stem-like... more Research in the area of stem/progenitor cells has led to the identification of multiple stem-like cell populations implicated in prostate homeostasis and cancer initiation. Given that there are multiple cells that can regenerate prostatic tissue and give rise to prostate cancer, our focus should shift to defining the signaling mechanisms that drive differentiation and progenitor self-renewal. In this article, we will review the literature, present the evidence and raise important unanswered questions that will help guide the field forward in dissecting critical mechanisms regulating stem-cell differentiation and tumor initiation.
Journal of Biological Chemistry, 2012
SV40 small t-antigen (ST) collaborates with SV40 large T-antigen (LT) and activated rasv12 to pro... more SV40 small t-antigen (ST) collaborates with SV40 large T-antigen (LT) and activated rasv12 to promote transformation in a variety of immortalized human cells. A number of oncogenes or the disruption of the general serine-threonine phosphatase protein phosphatase 2A (PP2A) can replace ST in this paradigm. However, the relationship between these oncogenes and PP2A activity is not clear. To address this, we queried the connectivity of these molecules in silico. We found that p27 was connected to each of those oncogenes that could substitute for ST. We further determined that p27 loss can substitute for the expression of ST during transformation of both rodent and human cells. Conversely, knock-in cells expressing the degradation-resistant S10A and T187A mutants of p27 were resistant to the transforming activities of ST. This suggests that p27 is an important target of the tumor-suppressive effects of PP2A and likely an important target of the multitude of cellular oncoproteins that emulate the transforming function of ST.
Proceedings of the National Academy of Sciences, 2016
Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-sp... more Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.
Cold Spring Harbor protocols, 2015
Animal models of cancer provide fundamental insight into the cellular and molecular mechanisms of... more Animal models of cancer provide fundamental insight into the cellular and molecular mechanisms of human cancer development. As an alternative to genetically engineered mouse models, increasing evidence shows that tissue recombination and transplantation models represent an efficient approach to faithfully recapitulate solid epithelial cancer in mice. Cancer can be rapidly initiated through lentiviral delivery of defined genetic alterations into target cells that are grown in a physiological milieu with an appropriate epithelial-stromal interaction. Through genetic manipulation of distinct subpopulations of epithelial cells and mesenchymal cells, this powerful system can readily test both cell-autonomous roles of genetic events in the epithelial compartment and the paracrine effects of the microenvironment. Here we review the recent advances in mouse models of several epithelial cancers achieved using orthotopic transplantation and tissue recombination strategies, with an emphasis on...
Cold Spring Harbor Protocols, 2015
Cleared mammary fat pad (MFP) transplantation has been a standard technique for studies of mammar... more Cleared mammary fat pad (MFP) transplantation has been a standard technique for studies of mammary development and cancer for several decades. The mammary gland is comprised of several fundamental components: The epithelial compartment contains basal/myoepithelial cells and luminal cells, and the stromal compartment (called the MFP) contains adipocytes, smooth muscle cells, fibroblasts, and immune cells. In 3- to 4-wk-old female mice, the mammary epithelium is concentrated very close to the nipple and has not yet grown beyond the mammary lymph node to penetrate the bulk of the MFP. This developmental feature provides an anatomical fixed point, and enables one to cut away the portion of the MFP from the nipple to the lymph node, leaving behind the majority of the MFP free of epithelium. The "cleared" MFP can serve as a supportive native microenvironment fully sufficient for the organogenesis of injected donor epithelium. Normal mammary epithelial donor cells will produce histologically and functionally normal mammary ductal epithelium several weeks posttransplant, with the exception that the ducts will not be connected to the nipple. The assay described here provides a powerful platform for assessing the developmental and tumorigenic potential of engineered cells of interest.
Cancer Cell Microenvironment, Mar 5, 2014
Our recent study provides evidence that a common cell of origin can produce alternative variants ... more Our recent study provides evidence that a common cell of origin can produce alternative variants of human epithelial cancer. Our findings also reveal that the cell of origin that initiates cancer is not continuously required to maintain and propagate the disease. Importantly, the cells responsible for initiating human prostate cancer can have a distinct cellular phenotype from the cells needed to maintain it.
Cold Spring Harbor Protocols, 2015
Tissue recombination models are useful for studying cancer initiation, progression, and metastasi... more Tissue recombination models are useful for studying cancer initiation, progression, and metastasis. They also provide an in vivo environment in which to investigate the functional role of stem cells in tissue repair. In this protocol, we describe in detail the dissociated prostate regeneration assay. Dissociated adult murine prostate cells are combined with embryonic urogenital sinus mesenchymal cells and implanted under the renal capsule. Morphological tissue structures with appropriate epithelial-stroma interactions are reconstituted in the grafts.
Cold Spring Harbor Protocols, 2015
An appropriate microenvironment provided by the mesenchyme is important for establishing tissue r... more An appropriate microenvironment provided by the mesenchyme is important for establishing tissue recombination models for epithelial cancer. Urogenital sinus mesenchymal (UGSM) cells derived from embryonic rodent show potent inductive effects for prostate regeneration. Genetic manipulation of these mesenchymal cells allows us to define the contribution of the tumor microenvironment to prostate cancer development. This protocol describes preparation and propagation of murine UGSM cells in culture.
Cancer cell & microenvironment
The cells that initiate and propagate cancer are important therapeutic targets. However, the prog... more The cells that initiate and propagate cancer are important therapeutic targets. However, the progression from cells of origin to tumor-propagating cells is poorly defined for most human cancers. Mouse models indicate that both basal and luminal cells can initiate prostate cancer, while studies with human prostate tissue have demonstrated a role for basal cells in transformation. Our recent study provides evidence that a common cell of origin can produce alternative variants of human epithelial cancer. Our findings also reveal that the cell of origin that initiates cancer is not continuously required to maintain and propagate the disease. Importantly, the cells responsible for initiating human prostate cancer can have a distinct cellular phenotype from the cells needed to maintain it.
Proceedings of the National Academy of Sciences of the United States of America, Jan 17, 2013
Nature Protocols, 2011
Epithelial cell transformation has been demonstrated in numerous animal models for the study of s... more Epithelial cell transformation has been demonstrated in numerous animal models for the study of solid tumor biology. However, little evidence exists for human epithelial cell transformation without prior immortalization via genetic influences such as SV40 T-antigen, limiting our knowledge of the events that can transform naĂ¯ve human epithelium. Here we describe a system developed in our lab to directly transform freshly-isolated primary human prostate epithelial cells without prior culture or immortalization. Prostate tissue is obtained from patients, and benign tissue is separated from cancer. Benign and cancer tissue are mechanically and enzymatically dissociated to single cells overnight, and immune cells and epithelial subsets are isolated based on differential expression of surface antigens. Epithelial progenitor cells are transduced with lentiviruses expressing oncogenes and combined with inductive stroma for in vivo studies. 8-16 weeks after transplantion into immune-deficient mice, the development of lesions histologically classified as benign prostate, prostatic intraepithelial neoplasia (PIN) and adenocarcinoma can be evaluated.
STEM CELLS, 2013
Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometri... more Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometrium expand to accommodate a growing fetus during pregnancy. In the absence of an embryo the endometrium, composed of epithelium and stroma, undergoes numerous hormonally regulated cycles of breakdown and regeneration. The hormonally mediated regenerative capacity of the endometrium suggests that signals that govern the growth of endometrial progenitors must be regulated by estrogen and progesterone. Here, we report an antigenic profile for isolation of mouse endometrial epithelial progenitors. These cells are EpCAM 1 CD44 1 ITGA6 hi Thy1 2 PECAM1 2 PTPRC 2 Ter119 2 , comprise a minor subpopulation of total endometrial epithelia and possess a gene expression profile that is unique and different from other cells of the endometrium. The epithelial progenitors of the endome-trium could regenerate in vivo, undergo multilineage differentiation and proliferate. We show that the number of endometrial epithelial progenitors is regulated by reproductive hormones. Coadministration of estrogen and progesterone dramatically expanded the endometrial epithelial progenitor cell pool. This effect was not observed when estrogen or progesterone was administered alone. Despite the remarkable sensitivity to hormonal signals, endometrial epithelial progenitors do not express estrogen or progesterone receptors. Therefore, their hormonal regulation must be mediated through paracrine signals resulting from binding of steroid hormones to the progenitor cell niche. Discovery of signaling defects in endometrial epithelial progenitors or their niche can lead to development of better therapies in diseases of the endometrium. STEM CELLS 2013;31:808-822
Science Translational Medicine, 2011
Identifying the dominant genetic alterations that drive tumorigenesis is essential for developing... more Identifying the dominant genetic alterations that drive tumorigenesis is essential for developing targeted cancer therapies. Recent work has demonstrated that prostate tumors can be stratified by dominant genetic alterations, such as chromosomal rearrangements involving ETS (Erythroblastosis virus E26 transformation-specific) family transcription factors or overexpression of SPINK1, a gene that encodes a secreted serine protease inhibitor. In this issue of Science Translational Medicine, Ateeq et al. provide evidence to support a rationale for targeting the SPINK1 protein in the SPINK1 + /ETS − subset of prostate tumors and also describe a potential interaction of SPINK1 with epidermal growth factor receptor that could be an additional target for therapeutic intervention.
Science China Life Sciences, 2013
Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and... more Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.
Science, 2010
Prostate cancer induced in primary human prostate basal cells recapitulates disease initiation an... more Prostate cancer induced in primary human prostate basal cells recapitulates disease initiation and progression in immunodeficient mice.
Proceedings of the National Academy of Sciences, 2010
Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in... more Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.
Proceedings of the National Academy of Sciences, 2014
Proceedings of the National Academy of Sciences, 2009
Chromosomal rearrangements involving erythroblast transformation specific (ETS) family transcript... more Chromosomal rearrangements involving erythroblast transformation specific (ETS) family transcription factors were recently defined as the most common genetic alterations in human prostate cancer. Despite their prevalence, it is unclear what quantitative role they play in either initiation or progression of the disease. Using a lentiviral transduction and dissociated cell prostate regeneration approach, we find that acutely increased expression of ETS proteins in adult murine prostate epithelial cells is sufficient to induce the formation of epithelial hyperplasia and focal prostatic intraepithelial neoplasia (PIN) lesions, but not progression to carcinoma. However, combined expression of ERG with additional genetic alternations associated with human prostate cancer can lead to aggressive disease. Although ERG overexpression does not cooperate with loss of the tumor suppressor p53, it does collaborate with alterations in PI3K signaling, such as Pten knockdown or AKT up-regulation, to produce a well-differentiated adenocarcinoma. Most striking is our finding that overexpression of androgen receptor (AR) does not give rise to any hyperplastic lesions, but when combined with high levels of ERG, it promotes the development of a more poorly differentiated, invasive adenocarcinoma. These findings suggest that in human prostate cancer, the most potent function of ETS gene fusions may be to synergize with alternative genetic events and provide different pathways for carcinoma production and invasive behavior. Our results provide direct evidence for selective cooperating events in ERG-induced prostate tumorigenesis and offer a rational basis for combined therapeutic interventions against multiple oncogenic pathways in prostate cancer.
Proceedings of the National Academy of Sciences, 2008
The epithelium of the adult prostate contains 3 distinct cell types: basal, luminal, and neuroend... more The epithelium of the adult prostate contains 3 distinct cell types: basal, luminal, and neuroendocrine. Tissue-regenerative activity has been identified predominantly from the basal cells, isolated by expression of CD49f and stem cell antigen-1 (Sca-1). An important question for the field is whether all basal cells have stem cell characteristics. Prostate-specific microarray databases were interrogated to find candidate surface antigens that could subfractionate the basal cell population. Tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1/GA733-1) was identified because it was enriched after castration, in prostate sphere cells and in the basal fraction. In the murine prostate, Trop2 shows progenitor characteristics such as localization to the region of the gland proximal to the urethra and enrichment for sphere-forming and colony-forming cells. Trop2 subfractionates the basal cells into 2 populations, both of which express characteristic basal cell markers by quantitative PCR. However, only the basal cells expressing high levels of Trop2 were able to efficiently form spheres in vitro. In the human prostate, where Sca-1 is not expressed, sphere-forming progenitor cells were also isolated based on high expression of Trop2 and CD49f. Trop2-expressing murine basal cells could regenerate prostatic tubules in vivo, whereas the remaining basal cells had minimal activity. Evidence was found for basal, luminal, and neuroendocrine cells in prostatic tubules regenerated from Trop2 hi basal cells. In summary, functionally distinct populations of cells exist within the prostate basal compartment and an epithelial progenitor can give rise to neuroendocrine cells in vivo.
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Papers by Andrew S Goldstein