Inhibition of Epithelial Ductal Branching in the Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells

Wang, Bu-Er; Shou, Jianyong; Ross, Sarajane; Koeppen, Hartmut; Sauvage, Frédéric J. de; Gao, Wei‐Qiang

doi:10.1074/jbc.m300968200

Cited by 86 publications

(86 citation statements)

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“…Consistent with previous reports from our group and others on the role of Shh signaling in prostate branching (12)(13)(14)(15)37), both Ptc-lacZ reporter mice crossed to Klf6 f/f Nkx3.1 Cre/ϩ mice and in situ hybridization data in the present study indicate that impaired lateral branching in the Klf6-deficient prostate correlate with an up-regulation and loss of spatial localization of Shh, Ptc, and Gli1. Further support for the involvement of focal Hh signaling in prostate epithelial branching comes from a study by Bushman and co-workers (15), showing a close association between prostate ductal bud formation and localized expression of Shh at the growing tips of elongating prostate ducts.…”

Section: Discussionsupporting

confidence: 82%

“…Our group and others have previously shown that the activated Shh pathway could inhibit prostatic ductal branching (12)(13)(14)(15)37). The lack of branching in the Klf6…”

Section: Characterization Of Gene Expression In Abnormal Prostatementioning

confidence: 99%

“…A number of growth factors/pathways have been implicated in regulating prostatic epithelial proliferation and differentiation, including hedgehog (Hh), 4 bone morphogenic proteins (BMPs), fibroblastic growth factors (FGFs), and Notch and Wnt pathways (12)(13)(14)(15)(16)(17)(18)(19). For example, work done in our laboratory and others showed that sonic hedgehog (Shh) produced in the prostatic epithelium is a negative regulator of prostatic branching morphogenesis, mediated indirectly by periepithelial mesenchymal cells (12)(13)(14)(15). In addition, while mesenchymal FGF10 stimulates prostatic epithelial growth (16), BMP4 is a mesenchymal factor that inhibits prostatic ductal budding and branching morphogenesis (17).…”

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confidence: 99%

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Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Leow¹,

Wang²,

Ross

et al. 2009

Journal of Biological Chemistry

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Krüppel-like factor 6 (Klf6) belongs to a family of zinc finger transcription factors known to play a role in development and tumor suppression. Although Klf6 is highly mutated in prostate cancer, its function in prostate development is unknown. We have generated a prostate-specific Klf6-deficient mouse model and report here a novel role for Klf6 in the regulation of prostate branching morphogenesis. Importantly, our study reveals a novel relationship between Klf6 and the Shh pathway. Klf6-deficiency leads to elevated levels of hedgehog pathway components (Shh, Ptc, and Gli) and loss of their localized expression, which in turn causes impaired lateral branching.

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Section: Discussionsupporting

confidence: 82%

“…Our group and others have previously shown that the activated Shh pathway could inhibit prostatic ductal branching (12)(13)(14)(15)37). The lack of branching in the Klf6…”

Section: Characterization Of Gene Expression In Abnormal Prostatementioning

confidence: 99%

mentioning

confidence: 99%

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Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Leow¹,

Wang²,

Ross

et al. 2009

Journal of Biological Chemistry

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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: 99%

“…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.…”

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confidence: 88%

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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Sonic hedgehog signaling plays an essential role during embryonic salivary gland epithelial branching morphogenesis

Jaskoll¹,

Leo²,

Witcher³

et al. 2004

Developmental Dynamics

105

102

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Gene targeting studies indicate that sonic hedgehog (Shh) signaling plays an essential role during craniofacial development. Because numerous mandibular derivatives (e.g., teeth, tongue, Meckel's cartilage) are absent in Shh null mice and the embryonic submandibular salivary gland (SMG) develops from the mandibular arch, we postulated that Shh signaling is important for embryonic SMG development. To address this question, we first determined the spatiotemporal distribution of Shh; two transmembrane proteins, patched 1 (Ptc) and Smoothened (Smo), which act as a negative or a positive regulator of the Shh signal, respectively; and the Gli 3 transcription factor, which is downstream of the Shh signal. The epithelial localization of Shh, Ptc, Smo, and Gli 3 suggests that Shh signaling may act within the epithelium in a juxtacrine manner. The SMG phenotype in our embryonic day (E) 18.5 Shh null mice can be characterized as "paedomorphic," that is, it fails to progress to ontogenic stages beyond the Early Pseudoglandular (ϳE14). In a complementary set of experiments, we used organ culture to evaluate the effect of enhanced or abrogated Shh signaling on embryonic SMG development in vitro. Paired E13 (Late Initial Bud stage) or E14 (Pseudoglandular stage) SMGs were cultured in the presence or absence of exogenous Shh peptide supplementation; Shh-supplemented explants exhibit a significant stage-dependent increase in branching morphogenesis compared with control explants. Furthermore, by using cyclopamine, a steroidal alkaloid that specifically disrupts the Shh pathway, to abrogate endogenous Shh signaling in vitro, we found a significant decrease in branching in cyclopamine-treated explants compared with controls, as well as a significant decrease in epithelial cell proliferation. Our results indicate that Shh signaling plays an essential role during embryonic SMG branching morphogenesis. Exogenous FGF8 peptide supplementation in vitro rescues the abnormal SMG phenotype seen in cyclopamine-treated explants, demonstrating that overexpression of a parallel, but related, downstream signaling pathway can compensate for diminished Shh signaling and restore embryonic SMG branching morphogenesis.

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Inhibition of Epithelial Ductal Branching in the Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells

Cited by 86 publications

References 77 publications

Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

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

Sonic hedgehog signaling plays an essential role during embryonic salivary gland epithelial branching morphogenesis

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