前列腺癌肿瘤标志物应用的研究进展

前列腺癌是男性常见的泌尿系统恶性肿瘤.在美国,前列腺癌的发病率居男性恶性肿瘤首位,病死率居第2位[1].我国前列腺癌发病率虽低于美国,但近年来有明显增长趋势.自1979年发现前列腺特异性抗原(prostate specific antigen,PSA)以来,血清PSA检测已成为前列腺癌诊断、分期、疗效及判断预后的重要肿瘤标志物之一.同时,自PSA检测广泛应用于临床以来,早期、无症状和可治愈阶段的前列腺癌检出率得到明显提高[2].尽管PSA具有器官特异性,但并不具有癌症特异性.相关资料表明,急性尿潴留、前列腺炎、前列腺按摩、经尿道器械检查等均可在一定程度上导致PSA值增高,并且介于前列腺癌和良性疾病之间的患者,血清PSA水平有所重叠,从而导致许多不必要的前列腺穿刺活检.     

前列腺癌肿瘤体积与游离PSA百分率的关系

目的探讨游离PSA百分率与前列腺癌肿瘤体积及其前列腺体积的关系.方法前瞻性分析50例经直肠穿刺活检确诊为前列腺癌的患者.抽血检测游离PSA百分率和经直肠B超测量前列腺癌的肿瘤体积(取各患者肿瘤体积总数).并予Gleason评分及病理分级.结果游离PSA百分率与前列腺癌肿瘤体积成反比(P=0.015),与Gleason评分成反比(P=0.013),与前列腺体积成正比(P=0.035).结论游离PSA百分率可以预测前列腺癌的生物学特性,以决定是否可行前列腺癌根治术.     

类器官在癌症基础研究和临床转化中的应用

类器官是成体干细胞或多能干细胞体外三维培养形成具有特定结构的组织类似物,与对应的器官具有高度相似的组织特性和生理功能。肿瘤类器官能够很好地保留癌症患者体内肿瘤的组织学和突变特征,在构建肿瘤类器官样本库、重建肿瘤微环境、研究肿瘤的发生发展机制以及制定个性化治疗方案和药物筛选等方面发挥了重要的作用,但目前仍存在着一些因素限制了肿瘤类器官的进一步发展。综述类器官技术在肿瘤基础研究和临床转化中的应用及面临的挑战,并对未来肿瘤类器官的发展方向予以展望。     

tPSA与fPSA／tPSA在前列腺癌早期诊断中的应用

前列腺癌是一种常见的男性生殖系统肿瘤，早期多无症状或症状不明显，不易早期诊断。前列腺特异性抗原（Total Prostote Specific Antigen，tPSA）在临床上已广泛用于前列腺癌与良性前列腺疾病的鉴别诊断，同时也是前列腺癌患者术后随访的重要标志，但对前列腺癌的筛选诊断来说，其特异性仍不高。而结合fPSA／tPSA比用tPSA更为可靠。本院对90例前列腺疾病患者的tPSA，fPSA／tPSA的测定结果进行分析，现将结果报告如下。     

临床前肿瘤模型的建立和应用进展

癌症一直是威胁人类生命安全的重大疾病之一，传统的治疗方式无法保证药物针对肿瘤细胞的高效杀伤和治疗后的良好预后，主要原因是人们对肿瘤及其微环境的了解还不够充分。近年来随着人们对肿瘤研究的不断深入，肿瘤的发生机制和肿瘤对人体免疫系统的影响成为当下研究的热点，研究肿瘤细胞的相关机制需要既能够代表人体免疫系统，又能还原患者肿瘤微环境的临床前肿瘤模型。近年来随着各种临床前肿瘤模型的发展，包括以患者肿瘤组织来源的异种移植模型(PDX)为代表的体内模型和以类器官芯片为代表的体外模型，在肿瘤的临床前研究中充当不同的角色并且发挥了各自重要的作用。临床前肿瘤模型作为一种便捷有效的工具，在探索肿瘤与免疫系统相互作用、临床前抗肿瘤药物的评价、发现免疫治疗的生物标志物等方面发挥着不可替代的作用。     

类器官研究进展及应用

类器官是一种新型体外研究模型,由干细胞或肿瘤细胞在三维培养条件下自我组装而成。它能够高度模拟原位组织的生理结构和功能,经长期传代保持遗传信息的稳定,因此类器官在构建疾病模型、药物筛选及个体化医疗等方面具有广阔前景。目前,食道、胃、肠、肝、胰、前列腺和乳腺等结构的类器官和相应的肿瘤类器官均已面世,开拓了体外培养的新平台。本文将对类器官的类型及其在生物医学领域的应用做一综述。     

前列腺特异性抗原在前列腺癌诊断中的临床意义

对经病理证实的57例前列腺增生和19例前列腺癌患者作PSA双抗体放射免疫测定，并对其临床资料进行分析。结果显示：前列腺癌组的ISA平均水平（56．89±23．93ug/L）明显超过前列腺增生组（7．99±2．26ug/L（P＜0．01），前列腺癌阳性检出率为78．9%（15／19），对临床筛选前列腺癌具有重要意义；但由于PSA值测定时影响因素较多，前列腺增生38．6％（22／57）与早期前列腺癌有重叠现象，在分析结果时宜综合判断；此外，PSA水平对前列腺癌的临床分期也是重要参考指标。     

前列腺癌诊断新进展

前列腺癌是老年男性的多发肿瘤,近年来,我国前列腺癌的发病率有上升趋势。世界各地的发病率相差悬殊,如美国已居男性肿瘤的首位,超过了肺癌。我国由于老龄人数增加,加之B超,CT等检查手段的多样化以及前列腺穿刺病理活检技术的开展,前列腺癌的病例在逐年增多,国内统计前列腺良性肥大的活检标本中合并癌者占4.9%,故应引起各级医疗单位的重视。1 当今前列腺癌的临床病理分期研讨情况 分期与预后关系密切,当前国内外临床应用主要有4种分期方案,包括ABCD方案,TNM方案,美国NIH的OSCC方案及超声分期(VA)方案,其中以前2种应用较多。1.1 ABCD方案(亦称Jewett-Whitmore-Prout方案)     

前列腺特异性抗原在前列腺癌诊断中的运用

前列腺癌早期很少引起症状,当前列腺癌引起症状时表明肿瘤局部或远处出现转移。自 1979年从前列腺组织内分离和提纯前列腺特异性抗原(PSA)以来,PSA在诊断前列腺癌(PCa)中发挥了巨大作用,目前已被广泛应用于前列腺癌的筛选诊断和随访。1 PSAPSA是一种丝氨酸蛋白水解酶, 在男性前列腺上皮及尿道周围腺体产生。PSA基因密码位于 19号染色体上,其DNA序列也完全清楚。PSA在精液中呈高浓度, 其功能与性生殖能力有关,在正常情况下人血清中PSA的浓度较低,除小部分外,大部分以复合物形式存在。血清中结合型PSA的清除主要是通过肝脏,血清…     

Hedgehog信号途径与前列腺癌

目前前列腺癌(prostate cancer,PCa)已成为欧美国家危害男性健康的最常见肿瘤,在我国随着人民生活水平的提高、生活方式的改变和人口的老龄化,近年来发病率呈上升趋势.大量的研究表明,Hedgehog(HH)信号通路对于动物的正常胚胎发育和器官形成具有重要作用.近年来发现HH调节异常导致多种癌症的发生和发展,已成为肿瘤研究热点.现就HH信号途径组成及其与前列腺发育、前列腺癌关系进行综述.     

Orthotopic Metastatic Mouse Models for Anticancer Drug Discovery and Evaluation: a Bridge to the Clinic

Currently used rodent tumor models, including transgenictumor models, or subcutaneously-growing human tumors inimmunodeficient mice, do not sufficiently represent clinicalcancer, especially with regard to metastasis and drugsensitivity. In order to obtain clinically accurate models, wehave developed the technique of surgical orthotopic implantation(SOI) to transplant histologically-intact fragments of humancancer, including tumors taken directly from the patient, to thecorresponding organ of immunodeficient rodents. It has beendemonstrated in 70 publications describing 10 tumor types thatSOI allows the growth and metastatic potential of thetransplanted tumors to be expressed and reflects clinical cancer.Unique clinically-accurate and relevant SOI models of humancancer for antitumor and antimetastatic drug discovery include:spontaneous SOI bone metastatic models of prostate cancer, breastcancer and lung cancer; spontaneous SOI liver and lymph nodeultra-metastatic model of colon cancer, metastatic models ofpancreatic, stomach, ovarian, bladder and kidney cancer.Comparison of the SOI models with transgenic mouse models ofcancer indicate that the SOI models have more features ofclinical metastatic cancer. Cancer cell lines have been stablytransfected with the jellyfish Aequorea victoriagreenfluorescent protein (GFP) in order to track metastases in freshtissue at ultra-high resolution and externally image metastasesin the SOI models. Effective drugs can be discovered andevaluated in the SOI models utilizing human tumor cell lines andpatient tumors. These unique SOI models have been used forinnovative drug discovery and mechanism studies and serve as abridge linking pre-clinical and clinical research and drugdevelopment.     

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro prostate cell models

Prostate cancer is the most commonly diagnosed malignancy in the United States, as well as in the Western world, and the second leading cause of male cancer death in the United States. Despite its high incidence, the molecular and genetic events involved in prostate cancer progression remain poorly understood. A hurdle in understanding the molecular genetic changes in prostate cancer has been the difficulty in establishing premalignant lesions and primary prostate tumors as in vitro cell cultures. Primary epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. In order to examine these early stages, we and others have developed in vitro models of prostate epithelial cell immortalization. Because prostate cancer is a multistep, progressive disease with a typical onset later in life and with an usually high number of latent cases that do not develop into clinically manifest cancer, the steps in the progression to malignancy are of particular interest. To understand the many factors that are suspected to contribute to the development of this malignancy, there is a need for an in vitro multistep human prostate epithelial culture system. These models have been extremely important in identifying genetic and molecular changes involved in prostate cancer progression. Recently, novel human cell culture models for the study of prostate cancer have been developed. Successful establishment of primary prostate cancer cell lines from patients' familial and sporadic prostate cancer has been accomplished using telomerase, the gene that prevents cellular senescence. The novel models will be useful for identification and characterization of prostate cancer genes and will provide the new means for testing for chemoprevention and chemotherapeutic agents.     

Colorectal cancer models for novel drug discovery

Introduction: Despite increased screening rates and advances in targeted therapy, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality. CRC models that recapitulate key features of human disease are essential to the development of novel and effective therapeutics. Classic methods of modeling CRC such as human cell lines and xenograft mice, while useful for many applications, carry significant limitations. Recently developed in vitro and in vivo models overcome some of these deficiencies and thus can be utilized to better model CRC for mechanistic and translational research.

Areas covered: The authors review established models of in vitro cell culture and describe advances in organoid culture for studying normal and malignant intestine. They also discuss key features of classic xenograft models and describe other approaches for in vivo CRC research, including patient-derived xenograft, carcinogen-induced, orthotopic transplantation and transgenic mouse models. We also describe mouse models of metastatic CRC.

Expert opinion: No single model is optimal for drug discovery in CRC. Genetically engineered models overcome many limitations of xenograft models. Three-dimensional organoids can be efficiently derived from both normal and malignant tissue for large-scale in vitro and in vivo (transplantation) studies and are thus a significant advance in CRC drug discovery.     

Identification of SPP1 as an extracellular matrix signature for metastatic castration-resistant prostate cancer

OBJECTIVE Resistance to androgen deprivation therapy(ADT) is the main challenge for advanced fatal prostate cancer(PCa), which can gradually develop into metastatic castration-resistant prostate cancer(m CRPC). However, the pathologic mechanisms of m CRPC are still far from clear. Given the high incidence and mortality related to m CRPC, understanding the causes and pathogenesis of this condition as well as identifying potential biomarkers are of great importance.METHODS In the research reported here, we integrated several gene expression profiles from hormone sensitive prostate cancer(HSPC) and m CRPC datasets to identify differentially expressed genes(DEGs), key biological pathways, and cellular components. K-nearest neighbor,logistic regression, naive Bayes, and random forest classifiers models were established to identify key regulated genes. Furthermore, organoid models were employed to validate the results in vitro. RESULTS We found that extracellular matrix(ECM) genes were significantly enriched, and further filtered them using Pearson correlation analysis and stepwise regression to find ECM signatures to differentiate between the HSPC and m CRPC phenotypes. Six ECM signatures were input into K-nearest neighbor, logistic regression, naive Bayes, and random forest classifiers models. Random forest algorithm with the six-gene prognostic signature showed best performance, which had high sensitivity and specificity for HSPC and m CRPC classification. Among the six ECM genes, SPP1 was identified as the key hub signature for PCa metastasis and drug resistance development; we found that both protein and m RNA expression levels of SPP1 were remarkably up-regulated in m CRPC compared with HSPC in organoid models and could regulate the androgen receptor signaling pathway. CONCLUSION Therefore, SPP1 is a potential novel biomarker and therapeutic target for m CRPC. Further understanding of the role of SPP1 in m CRPC development may help to explore effectively therapeutic approaches for the prevention and intervention of drug resistance and metastasis.     

Screening of 14C-polyamines in the AT3B-1 rat prostate tumor model: the search for a new PET prostate imaging agent

BACKGROUND: We have previously reported the polyamine uptake kinetics in various prostate and non-prostate cancer cell lines, concluding that the prostate cancer cell lines took up and accumulated polyamines at higher levels than non-prostate cell lines, with a view to their use as PET agents. The objective of the present study was to assess their in vivo accumulation in a rat prostate tumor model. MATERIALS AND METHODS: A comparative biodistribution study of the polyamines was conducted in AT3B-1 prostate tumors in male Copenhagen rats to determine which of the polyamines show preferential accumulation in the tumor. Tissue samples were collected one hour post administration of the polyamines (i.v.), and the radioactivity of the samples was measured by first combusting the tissue samples in a biological oxidizer and then assaying the trapped 14CO2 in a liquid scintillation counter. RESULTS: Putrescine exhibited the highest tumor accumulation followed by ornithine (4.1% and 1.8% of injected dose/g of the tumor respectively). The tumor-to-blood ratio was highest with putrescine followed by spermidine (18.7 and 12.9 respectively) and the order of tumor-to-normal prostate accumulation ratio was putrescine>ornithine>spermine>spermidine. CONCLUSION: The results indicated preferential accumulation of putrescine and ornithine in the prostate tumor.     

3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells

Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis.     

3D organoids derived from the small intestine: An emerging tool for drug transport research

Small intestine in vitro models play a crucial role in drug transport research. Although conventional 2D cell culture models, such as Caco-2 monolayer, possess many advantages, they should be interpreted with caution because they have relatively poor physiologically reproducible phenotypes and functions. With the development of 3D culture technology, pluripotent stem cells (PSCs) and adult somatic stem cells (ASCs) show remarkable self-organization characteristics, which leads to the development of intestinal organoids. Based on previous studies, this paper reviews the application of intestinal 3D organoids in drug transport mediated by P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2). The advantages and limitations of this model are also discussed. Although there are still many challenges, intestinal 3D organoid model has the potential to be an excellent tool for drug transport research.     

The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells

We previously identified the induction of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters: the prototypic PKC-activating drug TPA (12-O-tetradecanoylphorbol-13-acetate), and the novel compound PEP008 (20-O-acetyl-ingenol-3-angelate) in cell lines derived from melanoma, breast cancer and colon cancer. The diterpene esters induced permanent growth arrest with characteristics of senescence in a subset of cell lines in all three solid tumor models at 100–1000 ng/ml. Use of the PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling identified pivotal genes involved in DNA synthesis and cell cycle control down-regulated by treatment in all three sensitive tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21^WAF1/CIP1 and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Additionally, the type II tumor suppressor HRASLS3, which has a role in mitogen-activated protein kinase (MAPK) pathway suppression, was constitutively elevated in cell lines resistant to the senescence effects compared to their sensitive counterparts. Together, these results demonstrate that both TPA and the novel PKC-activating drug PEP008 induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types, and by a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a subset of breast cancer, colon cancer and melanoma tumors.     

核糖体蛋白L6 在前列腺癌中的表达及临床意义

摘要:目的 探讨核糖体蛋白 L6 （RPL6） 在前列腺癌组织中的表达及临床意义。方法 应用实时荧光定量 PCR （RT-qPCR） 和 Western blot 检测 RPL6 在前列腺癌组织 （80 例） 及癌旁组织 （62 例） 中的表达水平, 分析 RPL6 mRNA 表达水平与前列腺癌患者的临床病理特征及预后之间的关系。结果 RPL6 在前列腺癌组织中的表达水平明显高于癌旁组织(P < 0.05); 血清前列腺特异性抗原 （PSA） 值高、 Gleason 评分高、 临床分期晚、 有淋巴结转移患者的 RPL6 mRNA 表达水平增高 （均 P < 0.05）, 而不同年龄、 精囊侵袭、 血管侵犯及手术切缘阳性情况患者的 RPL6 mRNA 表达水平无明显差异(均 P > 0.05)。 RPL6 mRNA 高表达前列腺癌患者的术后无生化复发生存率较低 （χ2 =4.530,P= 0.033）。结论 RPL6 表达水平增高与前列腺癌的发生发展及不良预后相关; 或可用其作为初步判断前列腺癌患者预后的肿瘤标志物。