Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1

Metastasis-suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. BRMS1 (breast cancer metastasis suppressor) has recently been identified as a metastasis-suppressor gene for human breast cancer and melanoma. Expression of BRMS1 messenger RNA (mRNA) in multitissue including normal prostate, ovarian, testis, and colon has been detected by northern blot analysis. We hypothesize that the role of BRMS1 in tumor progression may not be limited to breast cancer and melanoma. We previously found that BRMS1 mRNA levels in primary ovarian epithelial carcinomas were significantly lower than that in normal ovarian and benign tumors (P < 0.05), and statistical analysis of BRMS1 mRNA levels revealed that BRMS1 mRNA levels were significantly higher in early tumor stages (I, II) compared with advanced tumor stages (III, IV) in which lymph node or distant metastases were present (P < 0.01). Our data showed that reduced BRMS1 mRNA seems to influence ovarian carcinoma metastatic ability. Therefore, we transfected BRMS1 plasmid into highly malignant ovarian carcinoma cell line, HO-8910PM, and examined cell biologic behaviors including proliferation, adhesion, invasion, and metastasis in vitro and in vivo. BRMS1 expression did not alter the proliferation of HO-8910PM cells in vitro and primary tumor formation in vivo. But, BRMS1 expression significantly suppressed the cell adhesion to extracellular matrix components and in vitro cell invasion in BRMS1-transfected HO-8910PM cells compared to parental HO-8910PM and vector-only transfectants (HO-8910PM-vect). Furthermore, motility of BRMS1 transfectants was inhibited. lung colony formation of intravenously injected BRMS1 transfectants in nude mice was significantly reduced. Also, BRMS1 transfectants form significantly less metastatic to organs of peritoneal cavity in orthotopically implanted ovarian tumor nude models. We further discovered that BRMS1 expression did downregulate expression of an actin-bundling protein associated with cell motility -fascin, which perhaps is the mechanism underlying BRMS1 suppression of metastasis. These data suggested that in addition to its already described role in breast cancer and melanoma, BRMS1 functions as a metastasis-suppressor gene in ovarian carcinoma by modifying several metastatic-associated phenotypes, offering a new target for therapeutic intervention.     

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.     

Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period

Abstract.   Jaaback KS, Ludeman L, Clayton NL, Hirschowitz L. Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period. Int J Gynecol Cancer 2006; 16(Suppl. 1): 123–128.
The relative incidence of primary peritoneal carcinoma (PPCa) and advanced (FIGO stage III or IV) ovarian serous carcinoma (AOSCa) was assessed over 5 years at a UK cancer center, and the sociodemographic, clinical, and survival data were compared. There were 23 women with PPCa and 55 with AOSCa. The ratio of PPCa:AOSCa was higher than previously reported. No statistical difference was found between the two groups with regard to age (mean 64.43 vs 64.07 years, P = 0.9), parity (1.6 vs 1.8, P = 1.0), personal/family history of another malignancy (although five patients with AOSCa but none with PPCa had personal histories of breast cancer), or serum CA125, CA19.9, and carcinoembryonic antigen (CEA) levels. Similar numbers in both groups had malignant ascites, although 5.8% of patients with AOSCa but none with PPCa had negative cytology. Tumor grade, stage, treatment, and survival were similar (median 586 vs 641 days, P = 0.66). This analysis of the largest published UK series of patients with PPCa does not support previous reports that patients with PPCa are older than those with AOSCa and have a worse prognosis; it suggests that both groups have similar sociodemographic characteristics, clinical profiles, and survival.     

Arsenic trioxide exposure to ovarian carcinoma cells leads to decreased level of topoisomerase II and cytotoxicity

The objective of this study was to investigate the effect of arsenic trioxide (As(2)O(3)) on topoisomerase II levels using western blotting method on MDAH 2774 ovarian carcinoma cell culture. Experimental designs were established to determine the cytotoxic effects of As(2)O(3) on MDAH 2774 cells and the IC50 (fatal dose for the 50% of cells) value. Cytotoxicity experiments were carried out using various concentrations of As(2)O(3). The 2,3-bis[2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) and trypan blue dye-exclusion tests were used to evaluate cytotoxicity. Topoisomerase II expressions were investigated using western blotting method with various concentrations of As(2)O(3). Densitometric analysis of topoisomerase 2 bands was carried out using Quantity One 1-D analysis software (Bio-Rad USA, Life Science Research, Hercules, CA). IC50 value of As(2)O(3) was found to be 5 x 10(-6) M for MDAH 2774 cells. When the bands were evaluated, it was observed that there was a decrease in topoisomerase II levels in MDAH 2774 cells with increasing concentrations of As(2)O(3). It was also observed by the densitometric analysis that topoisomerase II expression ratios of MDAH 2774 cells were decreased by approximately 50% at this concentration. Topoisomerase II levels were significantly decreased with the increasing concentrations of As(2)O(3). Inhibition of topoisomerase II enzyme was one of the antiproliferative influence mechanisms of As(2)O(3).     

胆固醇酯转运蛋白基因多态性在多囊卵巢综合征中的初步研究

目的:探讨胆固醇酯转运蛋白(CETP)在PCOS患者中的基因多态性和血脂、性激素的关系,以进一步认识PCOS脂代谢的特点。方法:应用PCR酶切方法检测108例PCOS患者及60例对照组的CETPTaqIB位点基因多态性。结果:CETPTaqIB基因频率及基因型分布在两组间分布差异无显著性。结论:CETPTaqIB基因多态性影响PCOS患者的HDLC水平,该基因在PCOS患者分布与正常人群分布无差异性。     

卵巢癌中蛋白激酶C的表达及其临床意义

目的　探讨上皮性卵巢癌组织蛋白激酶C (proteinkinaseC ,PKC)的表达和化疗耐药的关系 ,以及与P -糖蛋白 (P -gp)的相关性。方法　用免疫组化S -P法检测 35例卵巢上皮性肿瘤组织、 2 0例卵巢良性肿瘤组织和 2 0例正常卵巢组织中PKC和P -gp的表达 ,并进行相关临床因素分析。结果　①PKC、P -gp在卵巢恶性肿瘤中的表达明显高于在良性及正常组织中的表达 ;并且PKC和P -gp的表达有相关性 (P <0 0 5 ) ;②卵巢癌PKC的表达与临床病理因素无直接关系 ;③恶性肿瘤中 ,初治和复发的PKC表达阳性率分别为 34 8%和 75 % ;④化疗对PKC表达阳性和阴性卵巢癌患者的有效率分别为 2 3 5 %、 6 6 7% (P <0 0 5 ) ;⑤PKC表达阴性患者的预后优于阳性者 (P =0 0 39)。结论　PKC表达与卵巢癌组织化疗耐药明显相关 ,可能在P -gp介导的卵巢癌多药耐药中起重要作用。     

Laparoscopic splenectomy for isolated parenchymal splenic metastasis of ovarian cancer

Metastatic carcinoma of the spleen occurs in a setting of widespread malignant disease. Solitary parenchymal splenic metastasis of ovarian carcinoma is rare. We report a case of a 59-year-old woman who presented with an elevated serum CA125 level due to a solitary splenic metastasis after a long disease-free period. She was treated with laparoscopic splenectomy followed by chemotherapy. The literature contains 16 cases of solitary parenchymal splenic metastasis of ovarian carcinoma. Our case is the third case that was treated with laparoscopic splenectomy. We review the literature, and we focus on the laparoscopic approach in managing these cases.     

孕激素联合化疗治疗卵巢上皮性癌

目的 分析孕激素联合以铂类为主的常规化疗对卵巢上皮性癌1～4期患者的临床疗效。方法 以已行瘤体减灭术的卵巢上皮性癌患者1～4期为研究对象，分为单纯化疗组、己酸孕酮组和普维拉组。随访、统计各组各期患者的生存率及复发率、血清激素水平、骨密度变化以及化疗副反应。结果 孕激素联合以铂类为主的化疗对早期卵巢上皮性癌的预后无明显影响，但对晚期(3期)卵巢上皮性癌的术后近期以及远期(2～5年)生存率及复发率均有改善趋势。单纯化疗组、己酸孕酮组、普维拉组3期患者术后3年生存率分别为34．8％、66．2％、73．9％，复发率分别为72．2％、47．3％、40．6％；单纯化疗组、己酸孕酮组术后5年生存率分别为17．4％、48．4％，复发率分别为81．5％、62．4％。孕激素的使用不影响患者血清激素水平，也不增加化疗的毒、副作用。联合孕激素治疗的患者术后骨密度下降较一般绝经后妇女慢。结论 孕激素联合以铂类为主的常规化疗可改善晚期卵巢上皮性癌的预后，并且不增加化疗的毒副作用，可改善患者的骨量丢失。     

卵巢低反应患者大剂量超排卵的助孕结局

在辅助生殖助孕中通常采用控制性卵巢刺激(controlled ovarian hyperstimulation, COS),以获得适当数量的卵子用于体外受精,既希望获得理想的辅助生殖助孕成功率,又能降低卵巢过度刺激并发症.COS中约有9%~24%[1,2]的卵巢低反应发生率.卵巢低反应者获得有效卵子数少、可移植胚胎数少或无胚胎移植、取消治疗周期率高,累计成功率更低等,导致较差的治疗结局,是辅助生殖助孕中面临的棘手问题.针对卵巢低反应者,大多数辅助生殖中心仍会采用增加促性腺激素(Gn)的起始和(或)总用量以期获得提高助孕结局的目的.而大剂量Gn是否为改善低反应患者助孕结局的有效策略却仍存在争议.