The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild‐type and androgen‐insensitive (Tfm) Mice

Cunha, Gerald R.; Lung, Ben

doi:10.1002/jez.1402050203

Cited by 279 publications

(210 citation statements)

References 25 publications

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“…The essence of these assays is that cells are put back into their natural environment already containing the appropriate structure and supportive stroma. Because the prostate cannot easily be cleared of epithelial cells, Cunha and Lung (1978) developed a prostate tissue fragment recombination assay that has been used to study prostate development and epithelial-mesenchymal interactions. In this procedure, fragments of rodent urogenital sinus mesenchyme (UGSM) are combined with adult prostate epithelial fragments and implanted under the kidney capsule of an immunodeficient mouse to generate prostatic tubules.…”

Section: In Vivo Regeneration Assaymentioning

confidence: 99%

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

Lukacs¹,

Lawson²,

Long-zuo³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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Prostate cancer is a leading cause of cancer-related death in adult men. It can regress dramatically upon antihormonal therapy, but it often recurs in a more aggressive, androgen-independent form. Defining the prostate tissue stem cells (PrSCs) and their involvement in cancer initiation and maintenance may lead to better therapeutics. Using a tissue-regeneration model in which dissociated prostate epithelial cells mixed with inductive mesenchyme give rise to prostatic tubules, we have identified a small population of prostate cells that contains multiple stem cell characteristics. In this system, prostate cancer can be initiated by autocrine or paracrine growth factor signaling and intracellular overexpression of genes often found mutated in human prostate cancer. Using an in vitro prostate sphere assay, we further defined the PrSC population and demonstrated their selfrenewal and multilineage differentiation capabilities. Microarray analyses of the stem-and non-stem-cell populations have assisted us in finding and evaluating additional markers that can better define the PrSC population and further delineate the different cell types of the prostate, including those that serve as the target cell for tumor initiation.

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Section: In Vivo Regeneration Assaymentioning

confidence: 99%

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

Lukacs¹,

Lawson²,

Long-zuo³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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“…The tissue recombination procedure developed by Cunha and Lung (16) uses fragments dissected from rat or mouse urogenital sinus mesenchyme (UGSM) in combination with adult epithelial tissue to regenerate prostate-like tissues. We developed a dissociated cell system to facilitate the study of unique prostate cell subpopulations to demonstrate that a subpopulation of murine prostate cells possesses stem-like capacity for de novo tubule regeneration (17).…”

mentioning

confidence: 99%

The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis

Lawson

Witte

2005

Proc. Natl. Acad. Sci. U.S.A.

405

402

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The prostate contains classes of epithelial cells with variable differentiation status that may serve as targets for tumor initiation (8-10). Androgen cycling experiments suggest that stem cell activity is present in the prostate (11). These cells are thought to reside in the basal layer of the prostate because these cells are androgen-independent and preferentially retained in castrated rodents. Stem cells in the basal layer give rise to transit-amplifying epithelial cells (TACs) that differentiate to produce terminally differentiated secretory luminal cells (12).The most common form of human prostate cancer expresses luminal cell-specific markers (cytokeratins 8 and 18 and prostate-specific antigen) but low levels of the basal cell marker (p63), suggesting that the disease originates in terminally differentiated luminal cells (12,13). Some studies suggest that the disease is derived from high-grade prostatic intraepithelial neoplasia (PIN), which is believed to arise from intermediate epithelial cells (14). Other studies demonstrate that the majority of androgen-independent tumors express genes such as bcl-2 that are characteristic of the basal͞stem cell compartment in normal prostate tissue (8). Prostate cancers may arise from stem cells that undergo aberrant proliferation and differentiation to produce a heterogeneous population of cells expressing luminal-, basal-, and intermediate cell-specific genes (14, 15).The tissue recombination procedure developed by Cunha and Lung (16) uses fragments dissected from rat or mouse urogenital sinus mesenchyme (UGSM) in combination with adult epithelial tissue to regenerate prostate-like tissues. We developed a dissociated cell system to facilitate the study of unique prostate cell subpopulations to demonstrate that a subpopulation of murine prostate cells possesses stem-like capacity for de novo tubule regeneration (17). We find that Sca-1 (stem cell antigen-1), a glycosylphosphatidylinositol-linked cell surface protein known to enrich for somatic stem cells in other tissues (18,19), can be used to enrich for prostate-regenerating cells (PRCs). Sca-1 ϩ cell fractions contain an increased percentage of cells with immature cell properties, including replication quiescence, androgen independence, and multilineage differentiation potential. Perturbations of the PTEN͞AKT signaling axis in these cells result in the initiation of prostate tumorigenesis, and cancer progression is associated with a concomitant increase in Sca-1 ϩ cells. These studies suggest that Sca-1-enriched PRCs possess multiple stem͞progenitor cell properties and can serve as targets for the initiation of prostate tumorigenesis. Materials and Methods Infection of Dissociated Prostate Cells with Lentivirus and ProstateRegeneration. ␤-Actin GFP transgenic mice were purchased from The Jackson Laboratory [C57BL͞6-TgN(ACTbEGFP)1Osb]. Dissociated prostate cells were prepared from 6-to 10-week-old C57BL͞6 and ␤-actin GFP transgenic mice as described in ref.

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“…Previous in vitro studies using long-term passaged cancer cell lines have demonstrated that PTEN and AKT are, respectively, negative and positive modulators of AR transcriptional activity (12-15). Some papers have reported that AKT negatively regulates AR protein levels and transcriptional activity at the posttranscriptional (16) and posttranslational (17, 18) levels.We have modified and improved a prostate cell regeneration assay in which dissociated adult murine prostate epithelial cells are combined with embryonic urogenital sinus mesenchymal (UGSM) cells and engrafted under the kidney capsule of immunodeficient host CB.17 SCID/SCID mice to regenerate murine prostate tissue (19,20). The Sca-1 surface antigen can enrich for prostatic stem cell activity, and a single stem͞progenitor cell is capable of regenerating a whole tubule containing both basal and luminal cells in such regeneration experiments (21,22).…”

mentioning

confidence: 99%

“…We have modified and improved a prostate cell regeneration assay in which dissociated adult murine prostate epithelial cells are combined with embryonic urogenital sinus mesenchymal (UGSM) cells and engrafted under the kidney capsule of immunodeficient host CB.17 SCID/SCID mice to regenerate murine prostate tissue (19,20). The Sca-1 surface antigen can enrich for prostatic stem cell activity, and a single stem͞progenitor cell is capable of regenerating a whole tubule containing both basal and luminal cells in such regeneration experiments (21,22).…”

mentioning

confidence: 99%

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Teitell²,

Lawson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

149

141

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Classic work by Huggins and Hodges demonstrated that human prostate cancer regresses dramatically during antihormonal therapy but recurs frequently with androgen independence. Perturbations in the androgen receptor (AR) and PTEN-AKT signaling axes are significantly correlated with the progression of prostate cancer. Genetic alterations of the AR cause receptor hypersensitivity, promiscuity, and androgen-independent receptor transactivation. Prostate cancers maintain an elevated AKT activity through the loss of PTEN function or the establishment of autocrine signaling by growth factors and cytokines. We used an in vivo prostate regeneration system to investigate the biological potency of the potential crosstalk between these two signal transduction pathways. We demonstrate a direct synergy between AKT and AR signaling that is sufficient to initiate and progress naïve adult murine prostatic epithelium to frank carcinoma and override the effect of androgen ablation. Both genotropic and nongenotropic signals mediated by AR are essential for this synergistic effect. However, phosphorylation of AR by AKT at Ser-213 and Ser-791 is not critical for this synergy. These results suggest that more efficient therapeutics for advanced prostate cancer may need to target simultaneously AR signaling and AKT or the growth factor receptor tyrosine kinases that activate AKT.prostate regeneration ͉ tissue structure F undamental changes take place in androgen receptor (AR) signaling during prostate cancer progression (1, 2). AR signaling mediates cell differentiation and growth inhibition in the normal adult human and murine prostate (3-6). For example, AR can induce the expression of the luminal cell differentiation marker prostate-specific antigen (PSA) and the cell-cycle inhibitor p21. Transgenic mice harboring a prostatespecific AR transgene develop normal prostate tissues or show mild hyperplasia after a long latency period (7,8). However, cell autonomous androgen signals stimulate the proliferation of human or rodent AR-positive cancer cells (9). AR signaling also plays a critical role in the transition of prostate cancer from the androgen-dependent to -independent stage. Increased transcriptional level of AR mRNA has been demonstrated as the most common molecular determinant of resistance to antiandrogen therapy in a xenograft castration model (1).Loss of function of PTEN and activation of AKT are significantly correlated with the progression of prostate cancer (10). In vivo studies showed that murine prostatic intraepithelial neoplasia (mPIN) develops in transgenic mice expressing activated AKT1 specifically in the prostate (11). Previous in vitro studies using long-term passaged cancer cell lines have demonstrated that PTEN and AKT are, respectively, negative and positive modulators of AR transcriptional activity (12-15). Some papers have reported that AKT negatively regulates AR protein levels and transcriptional activity at the posttranscriptional (16) and posttranslational (17, 18) levels.We have modified and improved a p...

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The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild‐type and androgen‐insensitive (Tfm) Mice

Cited by 279 publications

References 25 publications

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

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