Therapeutic potential of targeting sphingosine kinase 1 in prostate cancer

Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipid sphingosine into the antiapoptotic lipid sphingosine-1-phosphate, which activates the signal transduction pathways that lead to cell proliferation, migration, activation of the inflammatory response and impairment of apoptosis. Compelling evidence suggests that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization and metastatic spread. High levels of SK1 expression or activity have been associated with poor prognosis in several cancers, including those of the prostate. Recent studies using prostate cancer cell and mouse models demonstrate a significant potential for SK1-targeting therapies to synergize with the effects of docetaxel chemotherapy and radiotherapy. However, until recently the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. With the recent discovery that clinically approved drug fingolimod has SK1-inhibiting properties, SK1 has gained significant attention from both clinicians and the pharmaceutical industry and it is hoped that trials of newly developed SK1 inhibitors might follow soon.     

老年人移行区前列腺癌的临床病理学特征

目的:分析大切片病理所观察的移行区前列腺癌癌灶大小、分布及其肿瘤分级、分期的特征。方法:回顾性分析,入选2017年7月至2020年3月行前列腺癌根治术且术后前列腺标本制作病理大切片患者129例。记录病理学病灶位置、最大径线、国际泌尿外科病理学会分级分组(ISUP);影像学病灶最大径线、前列腺影像报告和数据系统(PI-R...     

Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol

The proliferation and differentiation of normal prostate epithelial cells depends upon the action of androgens produced by the testis. Prostate cancers retain the ability to respond to androgens in the initial stages of cancer development, but progressively become independent of exogenous androgens in advanced stages of the disease while maintaining the expression of functional androgen receptor (AR). In the present study, we have determined the potential of prostate cancer cells to synthesize androgens from cholesterol which may be involved in intracrine regulation of AR in advanced stages of the disease. Established androgen-independent prostate cancer cell lines, PC3 and DU145 cells, expressed mRNA and proteins for scavenger receptor type B1 (SRB1), steroidogenic acute regulatory (StAR) protein, cytochrome P450 cholesterol side chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and other enzymes involved in androgen biosynthesis. Expression of all these proteins and enzymes was significantly higher in the androgen-independent derivative of LNCaP prostate cancer cells (C81) than in the androgen-dependent cell line (C33). In serum-free cultures, the androgen-independent C81 cells secreted approximately 5-fold higher testosterone than C33 cells as determined in the conditioned media by immunoassays. These cells could also directly convert radioactive cholesterol into testosterone which was identified by thin layer chromatography. These results for the first time show that prostate cancer cells in advanced stages of the disease could synthesize androgens from cholesterol and hence are not dependent upon testicular and/or adrenal androgens.     

Genetic variants associated with predisposition to prostate cancer and potential clinical implications

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.     

Activins and activin antagonists in the prostate and prostate cancer

Activins are members of the TGF-β super-family. There are 4 mammalian activin subunits (β(A), β(B), β(C) and β(E)) that combine to form functional proteins. The role of activin A (β(A)β(A)) is well characterized and known to be a potent growth and differentiation factor. Two of the activin subunits (β(C) and β(E)) were discovered more recently and little is known about their biological functions. In this review the evidence that activin-β(C) is a significant regulator of activin A bioactivity is presented and discussed. It is concluded that activin-β(C), like other antagonists of activin A, is an important growth regulator in prostate health and disease.     

Proteoglycans in prostate cancer

The complexity and diversity of proteoglycan structure means that they have a range of functions that regulate cell behavior. Through multiple interactions of their core proteins and glycosaminoglycans with extracellular matrix proteins, growth factors and chemokines, proteoglycans affect cell signaling, motility, adhesion, growth and apoptosis. Progressive changes in proteoglycans occur in the tumor microenvironment, but neither the source nor consequences of those changes are well understood. Proteoglycans studied in prostate cancer include versican--a hyalectan regulator of cell adhesion and migration-and the small leucine-rich proteoglycans decorin, biglycan and lumican, which have roles in cell signaling and tissue organization. Studies support an inhibitory role in prostate cancer for decorin and lumican. Conversely, the basement membrane proteoglycan perlecan might be a tumor promoter through upregulation of sonic hedgehog signaling. Loss of the growth-inhibitory cell-surface proteoglycans syndecan-1 and betaglycan in early prostate cancer might facilitate progression, but syndecan-1 effects are pleiotropic and its renewed expression in advanced tumors might adversely affect outcome. Importantly, cellular changes and enzymatic activity in the developing tumor can alter proteoglycan composition and structure to modify their function. Emerging studies suggest that cancers, including those of the prostate, use these changes to promote their own survival, growth, and spread.     

Coagulopathy in prostate cancer

Patients with metastatic hormone-refractory prostate carcinoma may have dramatic and life-threatening coagulation complications from their disease. We report here the case of a man with relapsing disseminated intravascular coagulation, and review the different coagulation disorders that may occur during prostatic carcinoma evolution. We focus mainly on disseminated intravascular coagulation (DIC), the most frequent coagulation complication. Other coagulopathies associated with prostate cancer are thrombocytopenic thrombotic purpura, thrombosis, Trousseau's syndrome and acquired factor VIII inhibitor development.     

经直肠超声前列腺癌声像特征及前列腺内腺PSA密度在前列腺癌诊断中的作用

目的通过经直肠超声分析前列腺癌声像特征并测量前列腺内腺、外腺与总体积，参考PSA探讨前列腺内腺PSA密度(IPSAD)在前列腺癌与前列腺增生鉴别诊断中的意义。方法回顾分析经直肠超声前列腺癌声像特征及经超声引导下6点活检病理诊断的49例前列腺癌、96例前列腺增生的临床资料。结果(1)前列腺癌声像特征以低回声为主，晚期可见被膜浸润及不规则。(2)前列腺内腺体积增生与癌有显著性差别。(3)PSA、PSA密度(PSAD)、IPSAD在增生与前列腺癌中的比较，均有显著性差异。(4)IPSAD在前列腺癌诊断的特异度为75．5％，敏感度为93．3％，优于PSAD。结论前列腺癌声像特征及IPSAD是鉴别前列腺癌与增生的重要指标。     

Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor

A possible role of the PDZ domain-containing protein 2 (PDZD2) in prostate tumorigenesis has been suggested. Besides, PDZD2 is posttranslationally cleaved by a caspase-dependent mechanism to form a secreted PDZ domain-containing protein 2 (sPDZD2) with unknown functions in humans. In this study, we demonstrate the endogenous expression of PDZD2 and secretion of sPDZD2 in cancerous DU145, PC-3, 22Rv1, LNCaP, and immortalized RWPE-1 prostate epithelial cells. Inhibition of endogenous sPDZD2 production and secretion by DU145, PC-3, 22Rv1, and RWPE-1 cells via the caspase-3 inhibitor Z-DEVD-FMK resulted in increased cell proliferation, which was abrogated by treatment with exogenous recombinant sPDZD2. Whereas sPDZD2-induced antiproliferation in DU145, PC-3, and 22Rv1 cells, it induced apoptosis in LNCaP cells. The data suggest that endogenous sPDZD2, produced by caspase-3-mediated cleavage from PDZD2, may function as a novel autocrine growth suppressor for human prostate cancer cells. The antiproliferative effect of sPDZD2 was apparently mediated through slowing the entry of DU145, PC-3, and 22Rv1 cells into the S phase of the cell cycle. In DU145 cells, this can be attributed to stimulated p53 and p21(CIP1/WAF1) expression by sPDZD2. On the other hand, the apoptotic effect of sPDZD2 on LNCaP cells was apparently mediated via p53-independent Bad stimulation. Together our results indicate the presence of p53-dependent and p53-independent PDZD2/sPDZD2 autocrine growth suppressive signaling pathways in human prostate cancer cells and suggest a novel therapeutic approach of harnessing the latent tumor-suppressive potential of an endogenous autocrine signaling protein like sPDZD2 to inhibit prostate cancer growth.