Hedgehog signaling in the prostate

PURPOSE: Recent discoveries highlight the importance of the hedgehog signaling pathway in prostate growth regulation. We reviewed the role of hedgehog signaling in prostate development, adult prostate homeostasis and prostate cancer. MATERIALS AND METHODS: A comprehensive review of all relevant literature was done. RESULTS: Epithelial expression of hedgehog ligand during prostate development exerts autocrine and paracrine signaling activities that regulate growth and differentiation. Hedgehog signaling also occurs in the adult human prostate but to our knowledge the influence on epithelial proliferation and/or differentiation is unknown. Robust hedgehog signaling occurs frequently in prostate cancer, and autocrine and paracrine signaling have been shown to accelerate the growth of xenograft tumors. Autocrine signaling has been implicated in stimulating stem/progenitor cells and increased hedgehog pathway activity may be a characteristic of advanced, androgen independent cancer. The plant alkaloid cyclopamine is a specific chemical inhibitor of hedgehog signaling that produced sustained regression of established xenograft tumors. CONCLUSIONS: Hedgehog signaling has an important role in prostate development and it appears to be a characteristic feature of prostate cancer. It stimulates tumor growth and may exert a specific role in the proliferation of tumor stem cells. The development of hedgehog inhibitors based on the action of cyclopamine holds promise for novel treatments to slow or arrest tumor growth.     

Expression of focal adhesion kinase in normal and pathologic human prostate tissues

BACKGROUND: Focal adhesion kinase (FAK) regulates multiple cellular processes including growth, differentiation, adhesion, motility, and apoptosis. In tumor cells, including prostate adenocarcinoma, FAK overexpression has been linked to cancer progression. METHODS: By using immunohistochemistry, FAK expression was investigated in human prostate specimens. RESULTS: FAK was expressed predominantly in the basal layer of normal prostate epithelium but not in secretory epithelium. FAK was expressed at similar levels in all stages of prostate tumorigenesis, including preinvasive carcinoma and metastatic disease. Elevated FAK expression was observed at the earliest stages of transformation and expression continued during cancer progression. CONCLUSION: Given the established role for FAK in the regulation of integrin signaling, we suggest that the sustained elevated levels of FAK expression during prostate tumor cell progression is consistent with a role for FAK in the development and maintenance of prostate carcinoma.     

Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells

The involvement of hedgehog signaling in the initiation of osteoblastic differentiation in the bone collar during endochondral bone formation has been well established. The stages at which hedgehog acts during osteoblast differentiation as well as its molecular mechanism of action are less well understood. To address these questions, we have made use of the preosteoblastic cell line KS483. First, a systematic survey of mRNA expression of osteoblastic differentiation showed expression of Ihh and signaling intermediates at all stages. Interestingly, expression of Ihh, Gli1 and Ptc1 peaked during the maturation phase. Addition of recombinant human sonic hedgehog (rShh) potently increased osteoblastic differentiation of KS483 cells dose-dependently as assayed by a modest increase in alkaline phosphatase (ALP) activity, a strong increase in matrix mineralization, and increased mRNA expression of established osteoblast marker genes. These effects were blocked by the hedgehog antagonist cyclopamine, which by itself was ineffective. Addition of rShh during early stages was sufficient, while addition to mature osteoblasts had no effect. Furthermore, hedgehog signaling could be completely blocked by the BMP antagonists, soluble truncated BMPR-IA and noggin. In contrast, the BMP-induced differentiation of KS483 cells could only be partly inhibited by high doses of cyclopamine. These data demonstrate that Hh-induced osteoblastic differentiation requires functional BMP signaling. In KS483 cells, Hh and BMP synergistically induced alkaline phosphatase activity only when suboptimal concentrations of BMP were used. This synergy did not occur at the level of immediate early BMP response, but at the level of Hh response as determined by transient transfection studies using either a BMP reporter or a Gli reporter construct. In addition, rShh inhibited adipogenesis of KS483 cells cultured under adipogenic culture conditions, suggesting that Hh is involved in directing differentiation of KS483 cells toward osteoblasts at the expense of adipogenesis. Using in situ hybridization, we demonstrated, for the first time, Ihh mRNA expression in vivo in osteoblasts and lining cells in the humerus of developing human skeleton. Our in vitro and in vivo data indicate a stimulatory role for osteoblast-expressed Ihh in bone formation in a positive feedback loop. It may recruit progenitor cells in the osteoblastic lineage at the expense of adipocytes and it may stimulate maturation of early osteoblasts.     

sonic hedgehog信号通路蛋白在人胚胎前列腺发育不同阶段的表达及意义

目的:探明son ic hedgehog信号通路中几个关键的效应蛋白son ic hedgehog(SHH)、Patched1(PTC1)、Smoothened(SMO)及GLI1在人胚胎前列腺组织中的定位表达及变化。方法:应用免疫组织化学方法研究SHH、PTC1、SMO及GLI1在不同胎龄(10~39周)人胚胎前列腺组织中的表达变化情况。结果:随胎龄增大,SHH、PTC1、SMO及GLI1在前列腺组织中的表达水平呈由弱变强,由强渐弱,又由弱转强的双峰变化趋势。SHH和SMO仅表达在胚胎前列腺上皮细胞中;而PTC1和GLI1主要表达在上皮细胞外,也可表达在腺体周围的间质中。结论:SHH信号通路参与了人胚胎前列腺发育的调控过程,可能对于腺体发育初期的诱导发生,以及后期的增殖、分化都具有重要的调控作用。     

Stem cells in prostate and prostate cancer development

Most cancers comprise a heterogenous population of cells with marked differences in their potential to proliferate as well as the ability to reconstitute the tumor upon transplantation. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Cell signaling pathways shared by stem cells and cancer cells lend further evidence for a possible link between these 2 populations of cells. Study of the differentiation pathways of normal and abnormal prostate growth has led to the development of a stem cell model for prostate cancer. The basal layer of the normal prostate is believed to be populated by prostate epithelial stem cells and a population of transit-amplifying cells intermediate in differentiation to the stem and fully differentiated cells. There is recent evidence suggesting that prostate cancer occurs from malignant transformation of stem/progenitor cells, thereby resisting apoptosis and spawning proliferation. This new model for prostate cancer will have significant ramifications for the way this disease is studied and treated. Furthermore, through targeting the prostate cancer stem cell and its dysregulated self-renewal, therapies for treatment of prostate cancer are likely to improve.     

Secreted frizzled-related protein 4 inhibits proliferation and metastatic potential in prostate cancer

BACKGROUND: Secreted frizzled-related proteins (sFRP4) inhibits Wnt signaling and thus cellular proliferation in androgen-independent prostate cancer cells in vitro. However, increased expression of membranous sFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease. Here, we investigated the phenotype of sFRP4 overexpression in an androgen-dependent prostate cancer model. METHODS: An sFRP4-overexpressing androgen-dependent (LNCaP) prostate cancer model was established to assess changes in cellular proliferation, the expression, and subcellular localization of adhesion molecules and cellular invasiveness, and compared with the findings in sFRP4-overexpressing androgen-independent cells (PC3). RESULTS: sFRP4 overexpression in both cell line models resulted in a morphologic change to a more epithelioid cell type with increased localization of beta-catenin and cadherins (E-cadherin in LNCaP, N-cadherin in PC3) to the cell membrane. Functionally, sFRP4 overexpression was associated with a decreased rate of proliferation (P = 0.0005), decreased anchorage-independent growth (P < 0.001), and decreased invasiveness in PC3 cells (P < 0.0001). Furthermore, increased membranous sFRP4 expression was associated with increased membranous beta-catenin expression (P = 0.02) in a cohort of 224 localized human androgen-dependent prostate cancers. CONCLUSIONS: These data suggest that sFRP4 is an inhibitor of prostate cancer growth and invasion in vitro independent of androgen receptor (AR) signaling with correlative evidence in human androgen-dependent disease suggesting similar changes in the clinical setting. Consequently, potential therapeutic strategies to modulate Wnt signaling by sFRP4 will be relevant to both localized androgen-dependent prostate cancer and advanced metastatic disease.     

Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression

BACKGROUND: Interleukin-6 (IL-6) has been implicated in the modulation of growth and differentiation in many cancers, and is associated with poor prognosis in renal cell carcinoma, ovarian cancer, lymphoma, melanoma, and prostate cancer. The effects of IL-6 on the growth of LNCaP human prostate cancer cells are puzzling with some groups showing growth stimulation, while others showing growth inhibition. In this study, we investigated the discrepancy of the effects of IL-6 on prostate cancer cells. METHODS: Series of lower and higher passages of LNCaP cell sublines were generated by a long-term exposure of LNCaP cells in IL-6-containing culture media. The characteristics of these cell sublines were analyzed and the potential roles of neuroendocrine (NE) differentiation and androgen receptor (AR) activation were examined. RESULTS: We demonstrated that while short-term treatment of IL-6 inhibits LNCaP cell growth by a paracrine mechanism associated with NE differentiation, long-term treatment of IL-6 promotes LNCaP cell growth by an autocrine mechanism accompanied by an activation of AR signaling. In the lower passages (less than 28 passages) of LNCaP cells treated with IL-6, the cell growth was severely retarded which is associated with NE-like morphology and increased expression of NE markers such as neuronspecific enolase (NSE) and chromgranin A (ChgA), and loss of AR expression. However, in the higher passages (higher than 42 passages) of LNCaP cells treated with IL-6, cells started to express endogenous IL-6. At the same time, NE characteristics were disappeared, AR signaling was activated and cells growth was accelerated. Knocking down the AR activation of the higher passages of LNCaP cells abolished autocrine IL-6-induced growth stimulation. CONCLUSIONS: These studies suggest that acquisition of endogenous IL-6 production after prolong exposure of prostate cancer cells to IL-6 may contribute to an autocrine cell growth stimulation. Furthermore, the transition of IL-6 from a paracrine growth inhibitor to an autocrine growth stimulator suggests that IL-6 plays an important role during prostate cancer progression, possibly androgen-independent progression.     

前列腺神经内分泌细胞与前列腺疾病的关系

前列腺神经内分泌细胞(NECs)是一种非常独特的细胞,它不仅具有神经细胞的特性,同时还具有内分泌细胞和上皮细胞的特性。前列腺组织中存在的少量NECs能分泌神经内分泌肽,参与组成神经内分泌调节系统,通过内分泌、旁分泌、自分泌等多种形式,对前列腺的发育和生长分化及内分泌起着调节作用。在前列腺疾病,如慢性前列腺炎、前列腺增生及前列腺癌的发生、发展及转归中,NECs均起到重要作用。尤其是NECs缺乏雄激素受体,在去势治疗时仍可继续生长,可能通过旁分泌的方式促进肿瘤雄激素非依赖性增值,引起肿瘤复发。本文就近年来对NECs分泌的各种细胞因子及受体进行鉴定、深入研究的进展做一综述。     

Stroma-epithelium crosstalk in prostate cancer

The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-J3, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like growth factor-l, epidermal growth factor, CXC12 and Interleukin-6 play active roles in the progression, androgen-independent conversion and distal metastasis of prostate cancer. Some soluble factors have reciprocal interactions with androgens and the androgen receptor （AR）, and can even activate AR in the absence of the androgen ligand. In this article, we review the complex interactions between cancer cells and the surrounding microenvironment, and discuss the potential therapeutic targets in the stromal compartment of prostate cancer.     

Hedgehog signaling in mouse mammary gland development and neoplasia

Genetic analyses of two hedgehog signal transduction network genes, Patched-1 and Gli2, has demonstrated a critical role for hedgehog signaling in mediating epithelial-stromal tissue interactions during ductal development. Disruption of either gene leads to similar, yet distinct, defects in ductal morphogenesis. Defects are mainly ductal dysplasias that closely resemble some hyperplasias of the human breast. Phenotypic analyses have been coupled with in situ hybridization, transplantation and tissue recombination analyses to formulate a model for tissue compartment-specific control of mouse mammary gland development by hedgehog signaling. In addition, the similarities among hedgehog mutation-induced ductal dysplasias and human breast pathologies suggest a role for altered hedgehog signaling in the development of mammary cancer.     

作用于骨基质的放射性药物在治疗骨转移前列腺癌中的潜在协同作用

遗传学异质性和抗化疗干细胞是制定新的晚期前列腺癌治疗方案过程中面临的两大最严峻的问题．尽管很早以前就有了治疗局限性前列腺癌的方案,但目前,我们对转移性前列腺癌仍束手无策．尽管借助于一些新通过的治疗方案,其治疗结果可能有很大的改善,但很明显还需要制定新的联合疗法．本文主要讨论作用于骨基质的放射性药物与其它骨转移前列腺癌治疗方案的潜在协同作用。放射疗法已被证明与细胞毒性化疗方案有协同作用,最近也有数据显示放射疗法与基于免疫的疗法之间可能有协同作用。将来,可能必须执行联合疗法以盟著提高抗去势型转移型前列腺痛患者的存活率。我们假设作用于骨基质的放射性药物将在这一过程中起重要作用。