Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling

Ovarian cancer is the leading cause of gynecological malignancy–related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-β signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.     

miRNA control of apoptotic programs: focus on ovarian cancer

miRNAs are a class of small non-coding RNAs that regulate the stability or translational efficiency of targeted mRNAs. miRNAs are involved in many cellular processes, such as differentiation, proliferation and apoptosis, which are altered in cancer through miRNA expression dysregulation. In this article we will discuss recent findings implicating miRNAs in apoptotic program regulation using ovarian carcinoma as an example. Ovarian cancer is the most lethal gynecological malignancy. Most patients are diagnosed with advanced disease that is conventionally managed with surgical resection followed by platinum-based chemotherapy. Killing of cancer cells by chemotherapeutic agents or by triggering cell-surface death receptors relies on activation of apoptotic programs executed through receptor-mediated extrinsic pathways and mitochondrial-dependent intrinsic pathways. Despite an initial good response to chemotherapy, ovarian cancer patients typically experience disease relapse within 2 years of the initial treatment developing resistance even to structurally different drugs. Thus, also in this pathology, tumor cells are able to evade apoptosis using multiple mechanisms, several of which are dependent on miRNA gene regulation.     

Growth inhibition of ovarian tumor-initiating cells by niclosamide

A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.     

原发性卵巢癌组织中肺耐药相关蛋白的表达及其临床价值

目的研究肺耐药相关蛋白(LRP)在原发性卵巢癌组织中的表达状况,探讨其在卵巢癌化学治疗耐药中的作用机制,以及与临床病理生物学特征间的相关性。方法应用免疫组织化学技术对52例原发性卵巢癌、12例卵巢良性肿瘤和10例正常卵巢组织中肺耐药相关蛋白表达状况进行测定。结果肺耐药相关蛋白(LRP)在卵巢癌组织中阳性表达率均显著高于良性肿瘤和正常组织对照组。LRP阳性表达与卵巢癌组织类型、肿瘤分化程度无关,但与临床病理分期及化疗敏感性相关显著,Ⅲ、Ⅳ期组织中LRP阳性表达率显著高于Ⅰ、Ⅱ期。结论LRP在原发性卵巢癌中存在较稳定的表达。检测LRP对前瞻性预测化疗药物敏感性和判断化疗疗效具有一定的临床指导价值。     

内窥镜在诊治化脓性胆管炎中的应用价值

江苏省苏北医院2004年2月成功引经内镜下逆行胰胆管造影术（ERCP）、十二指肠乳头括约肌切开术（EST）、鼻胆管引流术（ENBD）技术以来，对本院收治的9例化脓性胆管炎（ASC）患者试行内镜诊治，达到理想结果，报道如下。     

Clinically localized ovarian cancer. Progress in management

A decade ago the five-year survival rate in patients with stage I ovarian carcinoma was only 60% to 70%. Significant advances in staging and treatment, however, promise an improvement. Initially, improvement will be seen because some patients with clinically localized ovarian cancer will be discovered to have subclinical or occult metastasis at initial surgical staging and thus will be upstaged and treated appropriately for more advanced disease. More encouraging are results of recent studies on adjuvant therapy, which indicate that in some patients the need for postoperative adjuvant therapy may be obviated. A major advance in diagnosis would be development of a serum test specific for ovarian cancer--a discovery that may be forthcoming.     

Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy

Platinum-based drugs that induce DNA damage are commonly used first-line chemotherapy agents for testicular, bladder, head and neck, lung, esophageal, stomach, and ovarian cancers. The inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents, such as cisplatin. An enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. We hypothesized therefore that the targeted impairment of native cellular MRN function could sensitize tumor cells to cisplatin. To test this, we designed what we believe to be a novel dominant-negative adenoviral vector containing a mutant RAD50 gene that significantly downregulated MRN expression and markedly disrupted MRN function in human squamous cell carcinoma cells. A combination of cisplatin and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer xenografts in nude mice, this combination therapy caused dramatic tumor regression with increased apoptosis. Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.     

Preclinical evaluation of a class of infectivity-enhanced adenoviral vectors in ovarian cancer gene therapy

Ovarian carcinoma cells are often infected inefficiently by adenoviruses (Ad) due to low expression of coxsackie-adenovirus receptors (CAR), hindering the application of adenovirus-mediated gene therapy in ovarian cancer. In this study, we explored a class of infectivity-enhanced Ad vectors, which contain CAR-independent targeting motifs RGD (Ad5.RGD), polylysine (Ad5.pK7), or both (Ad5.RGD.pK7), for their utility in ovarian cancer gene therapy using in vitro and in vivo model systems. We found that these vectors infected established ovarian carcinoma cell lines and primary ovarian cancer cells with significantly enhanced infectivity. Among them, Ad5.RGD.pK7 appeared to be most efficient. Further, we evaluated their gene delivery efficiency using two different ovarian cancer mouse models--subcutaneous and intraperitoneal human ovarian cancer xenografts. All of the modified vectors appeared to be more efficient than the unmodified Ad5 vector in both models, although some of the differences are not statistically significant. Of these, Ad5.RGD.pK7 exhibited the highest efficacy in the subcutaneous tumor model, while Ad5.pK7 worked most efficiently in the intraperitoneal tumor model. These preclinical results suggest that Ad5.RGD.pK7 and Ad5.pK7 may be very useful in ovarian cancer gene therapy.     

Potential for cure in ovarian cancer

There has been steady progress in improving the survival stage by stage for women with ovarian carcinoma. Part of this is the "Will Rogers" phenomenon: the improvement in results among two groups by movement of a subset of patients from one stage to the other stage. For those stage I patients at low risk (stage I-A1, I-B1, well or moderately differentiated) for recurrence, the exceeding of 90% survival rates in these carefully staged patients without postoperative radiation or chemotherapy represents significant progress in comparison to results a decade ago. Moreover, those patients thought to be stage I or II but found to have upper abdominal metastasis by careful surgical staging will now receive the best therapy for stage III ovarian cancer. The combination of the small volume of upper abdominal tumor discovered in these latter patients and the effects of receiving the best therapy for stage III disease should result in improved survival for this subset of patients. The impact of cisplatin-based chemotherapy has already impacted positively on improved survival for women with stage III and IV ovarian carcinoma. With more surgeons now trained in the techniques of debulking surgery in advanced ovarian carcinoma, the recent survival rates for patients receiving cisplatin-based chemotherapy should improve significantly in the next decade.     

磁共振扩散加权成像在卵巢癌中的诊断价值

卵巢癌是致死率最高的妇科恶性肿瘤,早期诊断、准确的术前评估及治疗效果的评价都会使患者受益。近年来,磁共振扩散加权成像在卵巢癌的应用逐渐增多,本文针对其诊断价值的研究现状及发展前景进行阐述。     

卵巢癌组织多药耐药性的临床研究

目的 :研究多个耐药基因P -糖蛋白 (P -gp)、谷胱甘肽S -转移酶 (GST -π)、DNA拓朴异构酶Ⅱ (Topo -Ⅱ )在卵巢癌组织中表达 ,探讨其在卵巢癌化学治疗耐药中的作用及与临床病理学特征间的关系。方法 :应用免疫组织化学技术 (SP法 )对 37例卵巢癌 ,10例卵巢良性肿瘤和 8例正常卵巢组织中P -gp、GST -π、Topo -Ⅱ表达状况进行测定。 结果 :P -gp、GST -π和Topo -Ⅱ在卵巢癌组织中阳性表达均高于良性肿瘤和正常组织对照组 ;GST -π、Topo -Ⅱ在低分化癌中阳性率明显高于中高分化癌 ,但与肿瘤组织类型无关。GST -π与临床分期有关。P -gp表达与卵巢癌组织类型、分化、分期均无关。 3者在卵巢癌组织中存在共同表达。结论 :卵巢癌存在原发性耐药并涉及多个耐药基因的共同表达。联合检测对前瞻性预测化疗药物敏感性和判断化疗疗效具有指导意义     

Current management strategies for ovarian cancer

Epithelial ovarian cancer originates in the layer of cells that covers the surface of the ovaries. The disease spreads readily throughout the peritoneal cavity and to the lymphatics, often before causing symptoms. Of the cancers unique to women, ovarian cancer has the highest mortality rate. Most women are diagnosed as having advanced stage disease, and efforts to develop new screening approaches for ovarian cancer are a high priority. Optimal treatment of ovarian cancer begins with optimal cytoreductive surgery followed by combination chemotherapy. Ovarian cancer, even in advanced stages, is sensitive to a variety of chemotherapeutics. Although improved chemotherapy has increased 5-year survival rates, overall survival gains have been limited because of our inability to eradicate all disease. Technologic advances that allow us to examine the molecular machinery that drives ovarian cancer cells have helped to identify numerous therapeutic targets within these cells. In this review, we provide an overview of ovarian cancer with particular emphasis on recent advances in operative management and systemic therapies.     

近10年妇科恶性肿瘤的临床分析

目的 分析本院近10年妇科恶性肿瘤的病种构成比、发病趋势、诊治情况及预后.方法 对1995～1999年间(前5年组)及2000～2004年间(后5年组)收治的共计1 614例妇科恶性肿瘤患者的临床资料进行回顾性分析.结果 子宫颈癌的发病率在妇科恶性肿瘤中由前5年的第二位上升为后5年的第一位,且35岁以下年轻女性宫颈癌的发生率明显升高,各年份年轻宫颈癌构成比比较,差异有统计学意义(P＜0.01).子宫颈癌、子宫内膜癌早中期诊治的病例数后5年组较前5年组增多,故预后较好,而卵巢癌则无明显改变.结论 本院统计的资料显示,近10年来妇科恶性肿瘤的发病呈上升趋势,以子宫颈癌、外阴癌发病率上升最为显著,子宫颈癌发病有年轻化趋势.随着病因学研究的进展以及多种筛查方法的出现,子宫颈癌、子宫内膜癌得到了较早期的诊断和治疗,生存率提高.卵巢癌因缺乏灵敏特异的肿瘤标志物及操作方便的筛查方法,大部分患者诊治时仍为晚期,预后较差.     

Fallopian tube cancer

Primary carcinoma of the fallopian tube is a rare disease and has traditionally been managed in the same manner as epithelial ovarian cancer. However, unlike ovarian cancer, fallopian tube cancer is not routinely suspected and treatment may be delayed. The clinical presentations of seven cases of fallopian tube cancer emphasize the need for accurate assessment of symptoms to ensure early diagnosis and treatment of this disease.     

血清CA125、CA72-4与人附睾分泌蛋白4检测在卵巢癌早期诊断中的临床价值

目的 探讨血清CA125、CA72-4与人附睾分泌蛋白4(human epididymis protein 4,HE 4)联合检测对卵巢癌早期诊断的价值.方法 分别采用ELISA法和电化学发光法测定111例卵巢癌患者(卵巢癌组)、130例良性卵巢疾病患者(良性卵巢疾病组)、90名健康体检者(正常对照组)血清CA125、CA72-4与HE4,分析3种指标单独和联合检测对卵巢癌早期诊断的价值.结果 卵巢癌组CA125、CA72-4与HE 4水平明显高于良性卵巢疾病组和正常对照组(P均＜0.01);Ⅰ期卵巢癌患者的HE4阳性率高于CA125、CA72-4,阳性率分别是63.5%、55.8%、42.6%,而CA125、CA72-4与HE 4联合检测Ⅰ期卵巢癌阳性率较高为75.8%;CA125对浆液性癌、子宫内膜样癌、低分化腺癌诊断敏感性均较高,CA72-4对黏液性癌、子宫内膜样癌诊断敏感性较高,HE 4对浆液性癌、子宫内膜样癌诊断敏感性较高.结论 CA125可作为卵巢癌诊断的首选肿瘤标志物,联合检测血清CA72-4、HE4可使卵巢癌Ⅰ期诊断敏感性提高.

Abstract：

Objective To explore the clinical values of combined detection of serum CA125, CA72-4 and HE4 levels in the early diagnosis of ovarian cancer. Methods The serum levels of CA125, CA72-4 and HE4 in 111 patients with ovarian cancer, 130 patients with benign ovarian disease and 90 healthy female controls were measured by electrochemical luminescence immunoassay (ECLIA) and enzyme-linked immunosorbent assay (ELISA) methods. The diagnostic values of the three markers were analyzed separately and combinedly in ovarian cancer. Results The serum levels of CA125, CA72-4 and HE4 of ovarian cancer patients were significantly higher than those of benign ovarian disease patients and healthy controls(Ps ＜ 0. 01). The positive expression rate of HE4(63.5%) in patients with stage Ⅰ ovarian cancer was significantly higher than that of CA125(55. 8%) and CA72-4 (42. 6%)(Ps ＜ 0. 05) . The combined detection of the three markers may improve the overall accuracy of the early diagnosis of ovarian cancer to 75.8%. The diagnostic sensitivity of serum CA125 was relatively higher in serous cystadenocarcinoma, endometrioid carcinoma and poorly differentiated adenocarcinoma; the diagnostic sensitivity of serum CA72-4 was relatively higher in mucinous cystadenocarcinoma and endometrioid carcinoma; the diagnostic sensitivity of serum HE4 was relatively higher in serous cystadenocarcinoma and endometrioid carcinoma. Conclusion CA125 can serve as the first choice of tumor maker in the diagnosis of ovarian cancer, and the combined detection of serum levels of CA125, CA72-4 and HE4 may increase the diagnostic sensitivity of stage Ⅰ ovarian cancer.     

卵巢癌基因表达的cDNA微阵列研究

目的应用基因表达谱芯片研究人卵巢癌组织和正常卵巢组织中差异表达的基因,筛选出与卵巢癌发生发展相关的基因,并对这些基因的功能进行初步分析.方法采用cDNA芯片技术从有关癌基因和抑癌基因、细胞周期和细胞凋亡相关、DNA合成、转录和修复以及细胞信号传递等肿瘤相关的2304个基因中,分析研究卵巢癌基因表达谱,即寻找出不同于正常卵巢组织而只在卵巢癌实体瘤中上调或下调的特殊基因.结果与正常卵巢组织比较,卵巢浆液性囊腺癌组织表达有明显差异的基因92个,卵巢粘液性囊腺癌差异表达基因110个,卵巢浆液性囊腺癌和粘液性囊腺癌均呈差异表达的基因65个,卵巢浆液性囊腺癌和粘液性囊腺癌中不同的差异表达基因共有173个.结论与卵巢癌有关的基因涉及多种细胞生物学过程,说明卵巢癌的发生是一个多步骤、多基因调控的过程.基因芯片技术实现了基因分析的快速、高通量、微型化和自动化,它为同时分析几百个基因状况提供了一个有效的方法,所获得的差异基因表达谱为深入研究特异相关基因提供了参考.