The Human Prostate Expresses
            <i>Sonic Hedgehog</i>
            During Fetal Development

Barnett, Daniel H.; Huang, Hong; Wu, Xianwei; Laciak, Robert; Shapiro, Ellen; Bushman, Wade

doi:10.1016/s0022-5347(05)64356-x

Cited by 40 publications

(24 citation statements)

References 16 publications

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“…The normal human prostatic ductal morphogenesis, partially regulated by sonic hedgehog (Barnett et al, 2002), occurs in two separate periods, prenatally and pubertally (Cunha et al, 1987;Kellokumpu-Lehtinen et al, 1980;Lowsley, 1912). We identified Ck6a+ cells in the urogenital sinus, in fetal and juvenile prostatic glands, and in the fetal stroma.…”

Section: Discussionmentioning

confidence: 92%

Identification of a stem cell candidate in the normal human prostate gland

Schmelz

Moll

Hesse

et al. 2005

European Journal of Cell Biology

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Stem cells of the human prostate gland have not yet been identified utilizing a structural biomarker. We have discovered a new prostatic epithelial cell phenotype-expressing cytokeratin 6a (Ck6a+ cells). The Ck6a+ cells are present within a specialized niche in the basal cell compartment in fetal, juvenile and adult prostate tissue, and within the stem cell-enriched urogenital sinus. In adult normal prostate tissue, the average abundance of Ck6a+ cells was 4.9%. With proliferative stimuli in the prostate organ culture model, in which the epithelial-stromal interaction was maintained, a remarkable increase of Ck 6a expression was noticed to up to 64.9%. The difference in cytokeratin 6a expression between the normal adult prostate and the prostate organ culture model was statistically significant (p<0.0001). Within the prostate organ culture model the increase of cytokeratin 6a-expressing cells significantly correlated with increased proliferation index (r = 0.7616; p = 0.0467) The Ck6a+ cells were capable of differentiation as indicated by their expression of luminal cell markers such as ZO-1 and prostate specific antigen (PSA). Our data indicate that Ck6a+ cells represent a prostatic epithelial stem cell candidate possessing high potential for proliferation and differentiation. Since the development of benign prostatic hyperplasia and prostate carcinogenesis are disorders of proliferation and differentiation, the Ck6a+ cells may represent a major element in the development of these diseases.

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Section: Discussionmentioning

confidence: 92%

Identification of a stem cell candidate in the normal human prostate gland

Schmelz

Moll

Hesse

et al. 2005

European Journal of Cell Biology

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“…The data suggest activation of the pathway at different levels in primary prostate tumors and cell lines derived from metastatic lesions. These findings, together with the involvement of this pathway in normal prostate development and growth (17)(18)(19)(20)(21)(22), indicate that the normal patterning role of SHH-GLI signaling is deregulated in cancer. This Fold increase in gene expression in tumors versus matched normal tissue determined by real-time RT-PCR analyses as calculated by the ⌬CT method.…”

Section: Discussionmentioning

confidence: 97%

“…This observation allowed us to propose the hypothesis that the SHH-GLI pathway participates in prostate cancer (7). Consistently, Shh signaling has been found to be essential for prostate patterning and development (17)(18)(19)(20)(21)(22), and genetic mapping data has revealed that at least two key components of the SHH-GLI pathway [SMOH and SUPPRESSOR OF FUSED (SUFUH)] are located in chromosomal regions implicated in familial human prostate cancer (23,24). Here we have tested the involvement of SHH-GLI signaling in prostate cancer.…”

mentioning

confidence: 93%

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

Sánchez

Hernández

Stecca

et al. 2004

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

468

486

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Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)-GLI signaling pathway is implicated in prostate cancer. We report expression of SHH-GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1 ؉ ͞PSA ؉ primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH-GLI function and suggest a novel therapeutic approach.S ONIC HEDGEHOG (SHH) signaling has been implicated in different aspects of animal development, acting through several components, including the transmembrane proteins PATCHED1 (PTCH1) and SMOOTHENED (SMOH), to activate the GLI zinc-finger transcription factors (1, 2). In addition, we and others have shown that SHH signaling is implicated in a number of tumors (reviewed in refs. 2 and 3), such as basal cell carcinomas (4-6), medulloblastomas (7,8), gliomas (7), sarcomas (9, 10), tumors of the digestive tract (11), small cell lung cancers (12,) and pancreatic carcinomas (13). To date there is no direct evidence linking SHH signaling to prostate cancer, the most common solid cancer in men (14), although we have found that sporadic prostate tumors express GLI1 (7), a reliable marker of SHH signaling (15,16). This observation allowed us to propose the hypothesis that the SHH-GLI pathway participates in prostate cancer (7). Consistently, Shh signaling has been found to be essential for prostate patterning and development (17)(18)(19)(20)(21)(22), and genetic mapping data has revealed that at least two key components of the SHH-GLI pathway [SMOH and SUPPRESSOR OF FUSED (SUFUH)] are located in chromosomal regions implicated in familial human prostate cancer (23,24). Here we have tested the involvement of SHH-GLI signaling in prostate cancer. MethodsCell Lines and Primary Cultures. The PC3, LNCaP, and DU145 cell lines (25-27) were purchased from American Type Culture Collection and grown as specified. All primary prostate tumors were obtained following approved protocols. Tumors in PBS were chopped with a razor blade and incubated with Papain for 1 h at 37°C, they were then dissociated by passing them through a fire-polished pipette and washed several times in serum containing media. All dissociated primary tumors were plated in polyornithinand laminin-treated p16 plates in DMEM-F12 with 10% FBS at Ϸ30,000 cells per p16 well. Primary cultures were ...

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“…[1][2][3][4] In particular, the SHH protein is expressed in an embryo and participates in regulating cell proliferation, differentiation and tissue patterning of many organs including the prostate gland, pancreas, lung, biliary tract and brain. 1,[4][5][6][7][8][9] The SHH ligand mediates its biological effects through the multi-component receptor complex constituted from a transmembrane protein, PATCHED-1 (PTCH-1). PTCH-1 binds SHH with high affinity and Smoothened (SMO), a second signaling transmembrane G-protein coupled receptor.…”

mentioning

confidence: 99%

Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells

Mimeault

Moore

Moniaux

et al. 2005

Intl Journal of Cancer

118

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Although the blockade of the hedgehog cascade by using cyclopamine has been reported to inhibit the growth of some cancer cell types, few studies on the mechanism by which this drug alone or in combination with other cytotoxic agents induces its cytotoxic effect have been reported. In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells. The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog-(SHH), epidermal growth factor-(EGF) and serum-stimulated androgensensitive LNCaP-C33 and LNCaP-LN3 and androgen-independent LNCaP-C81, DU145 and PC3 cells. The antiproliferative effect of cyclopamine and gefitinib, alone or in combination, was mediated via a blockade of the PC3 cells in the G1 phase of the cell cycle. Importantly, the combined cyclopamine and gefitinib also caused a higher rate of apoptotic death of PC cells compared to single agents. The cytotoxic effect induced by these drugs in PC3 cells appears to be mediated at least, in part, via the mitochondrial pathway through the depolarization of the mitochondrial membrane and the release of cytochrome c and reactive oxygen species into the cytosol. This was also accompanied by the activation of caspase cascades, PARP cleavage and DNA fragmentation. Additionally, the combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone. These findings indicate that the simultaneous blockade of SHH-GLI-1 and EGF-EGFR signaling, which results in the growth arrest and massive rate of apoptotic cell death, represents a promising strategy for a more effective treatment of metastatic PC forms. ' 2005 Wiley-Liss, Inc.

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The Human Prostate Expresses Sonic Hedgehog During Fetal Development

Abstract: expression in the human fetal prostate is contemporaneous with the fetal testosterone surge and with ductal budding of the prostatic urothelium. expression is also present in the female urogenital sinus but in the absence of testosterone it is not associated with ductal budding.

Cited by 40 publications

References 16 publications

Identification of a stem cell candidate in the normal human prostate gland

Identification of a stem cell candidate in the normal human prostate gland

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells

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