Overexpression of follicle-stimulating hormone receptor facilitates the development of ovarian epithelial cancer

We previously showed that the expressing level of FSH receptor (FSHR) increased from ovarian epithelial inclusions (OEIs) to benign ovarian epithelial tumors (OETs) and to borderline OETs, whereas FSHR levels decreased with an increase in carcinoma grade. The aim of this study was to investigate the role of FSHR in OET development. MCV152 cells with FSHR overexpression showed an increased cellular proliferation and invasive capacity, which was associated with reduced levels of prohibitin and RII-β expression and increased levels of HER-2/neu, c-Myc, and EGFR expression. Overexpression of FSHR may be associated with an elevated level of OET cell proliferation via an enhanced activity of potential oncogenic pathways. Therefore, the findings in this study suggest that overexpression of FSHR may play a role in OET development.     

GnRH及其受体表达与卵巢癌细胞增殖和分化的相关性研究

目的探讨卵巢癌中促性腺激素释放激素(GnRH)及其受体(GnRHR)表达与细胞增殖调节因子之间的相互调节作用。方法应用免疫组织化学SABC技术方法,对49例卵巢癌和15例卵巢良性肿瘤组织中增殖细胞核抗原(proliferationcellsnuclearantigens,PNCA)、GnRH及其受体的表达进行相关性研究。结果GnRH及其受体均定位于卵巢癌细胞的胞膜和胞浆,GnRH表达阳性卵巢癌的PCNA标记指数为(26.1±15.2)%,显著低于GnRH阴性卵巢癌的PCNA标记指数(45.2±28.7)%(P<0.05)。GnRHR阳性卵巢癌的PCNA标记指数为(21.1±14.2)%,亦明显低于GnRHR阴性卵巢癌(38.6±29.1)%的PCNA标记指数(P<0.01)。结论GnRH可能参与卵巢癌细胞的增殖和分化的调节。     

激素受体与卵巢癌预后、发病机制及治疗的研究进展

卵巢癌作为恶性程度最高的妇科肿瘤,在肿瘤靶向治疗方面已取得了一定进展。激素疗法在乳腺癌治疗中的成功应用,使激素受体成为靶向治疗的首要研究方向。卵巢癌不同病理类型对激素的敏感性不同是激素疗法对卵巢癌治疗效果不同的根本原因。本文对卵巢癌激素受体的表达及其表达对预后的影响、发病机制的研究及临床治疗做综述。     

Interleukin-1 receptor antagonist gene polymorphism is associated with increased risk of epithelial ovarian cancer.

BACKGROUND: Different studies indicate that immunological components play a key role in the development of cancer. Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis and in other solid tumors. Therefore, we investigated the possible influence of the polymorphism of the IL-1 receptor antagonist (IL-1 RA) genes on the development of ovarian cancer. PATIENTS AND METHODS: In a prospective study we analyzed the polymorphism of the IL-1 RA gene in 108 women with ovarian cancer compared with 112 patients with benign gynecological diseases. Genomic DNA fragments were amplified by PCR. RESULTS: The distribution of genotype frequencies was significantly different between the study and control group with respect to allele 1/2 heterozygotes (32.4% versus 15.2%; P = 0.004). Patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk of ovarian cancer with a calculated odds ratio of 2.7 (95% confidence interval 1.4-5.2). There were no differences between IL-1 RA 1/2 polymorphism and all other alleles in tumor stage (International Federation of Gynecology and Obstetrics), histological type, grading, postoperative tumor volume, volume of ascites, recurrence status or age. CONCLUSIONS: The allele 2 polymorphism of the IL-1 RA gene seems to play a role in the occurrence of ovarian cancer and should be investigated for screening and risk evaluation.     

Soluble isoforms but not the transmembrane form of coxsackie-adenovirus receptor are of clinical relevance in epithelial ovarian cancer

The coxsackie-adenovirus receptor (hCAR) has been extensively studied in context of adenoviral-based gene therapy for cancer. However, there is strong evidence that besides its decisive role in coxsackie and adenovirus cell-entry, hCAR is a component of epithelial tight junctions and involved in cell-cell adhesions in normal and cancer cells. Furthermore, this adhesion molecule behaves like a cell surface receptor endowed with tumor suppressive properties via signal transduction. Moreover, 3 truncated soluble isoforms of hCAR were recently identified. We investigated the quantitative expression of all known CAR isoforms in a training set of 140 ovarian cancer samples and 21 controls by RT-PCR. The expression levels of the various isoforms were compared with clinicopathologic parameters and their prognostic significance was assessed. Expression levels of all CAR isoforms were elevated in ovarian carcinomas as compared with those of non-malignant controls. mRNA-expression correlated with protein levels. Moreover, expression of the soluble isoforms CAR 3/7 and CAR 4/7 but not that of hCAR was significantly increased in advanced ovarian cancer as revealed by a highly significant correlation with FIGO stage and residual disease > 2 cm in diameter after debulking surgery. High expression of CAR 3/7 and 4/7 was shown to be of independent prognostic relevance for progression-free (CAR 4/7) and overall survival (CAR 3/7 and CAR 4/7). In conclusion, soluble CAR isoforms 3/7 and 4/7 may play a pivotal role in ovarian cancer biology, possibly by counteracting migration- and growth-inhibitory properties of the membranous hCAR and thus favoring cancer cell dissemination throughout the peritoneal cavity.     

Polymorphisms in the growth hormone receptor: a case-control study in breast cancer

The human growth hormone receptor (GHR) mediates the effects of growth hormone (GH1), starting a signalling cascade that is involved in the regulation of proliferation, differentiation and apoptosis. Recently, an isoform of the GHR gene lacking exon 3 (GHRd3) was associated with accelerated responsiveness to growth hormone. In this study, we investigated the association of the GHRd3 polymorphism with breast cancer risk and performed a haplotype analysis with 3 additional single nucleotide polymorphisms (SNPs) (Gly186Gly, Cys440Phe and Ile544Leu) in the GHR coding region in a Polish cohort. We did not observe any effect of the 4 polymorphisms on breast cancer risk. Neither did the 3 most common haplotypes influence breast cancer risk. However, a rare haplotype (dGGC), containing the GHRd3 allele, was associated with a decreased breast cancer risk (OR 0.30, 95% CI 0.11-0.80).     

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.     

Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer

Background:

The sigma-2 receptor has been validated as a biomarker for proliferating tumours. Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria into the cytosol, leading to apoptosis. In this study, we investigated a sigma-2 ligand as a tumour-targeting drug delivery agent for treating ovarian cancer.

Methods:

A sigma-2 ligand, SW 43, was conjugated with a Smac mimetic compound (SMC), SW IV-52s, to form SW III-123. The delivery function of the sigma-2 moiety and cell killing mechanisms of SW III-123 were examined in human ovarian cancer cell lines.

Results:

SW III-123 internalisation into ovarian cancer cells was mediated by sigma-2 receptors. SW III-123, but not SW IV-52s or SW 43, exhibited potent cytotoxicity in human ovarian cancer cell lines SKOV-3, CaOV-3 and BG-1 after 24-h treatment, suggesting that the sigma-2 ligand successfully delivered SMC into ovarian cancer cells. SW III-123 induced rapid degradation of inhibitor of apoptosis proteins (cIAP1 and cIAP2), accumulation of NF-κB-inducing kinase (NIK) and phosphorylation of NF-κB p65, suggesting that SW III-123 activated both canonical and noncanonical NF-κB pathways in SKOV-3 cells. SW III-123 cleaved caspase-8, -9 and -3. Tumour necrosis factor alpha (TNFα) antibody markedly blocked SW III-123-induced cell death and caspase-3 activity in SKOV-3 cells, indicating that SW III-123 activated both intrinsic and extrinsic apoptotic pathways and induced TNFα-dependent cell death in SKOV-3 cells.

Conclusion:

Sigma-2 ligands are a promising tumour-targeting drug delivery agent. Sigma-2-conjugated SMC exemplifies a novel class of therapeutic drugs for treating ovarian cancer.     

Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells

Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late‐stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at‐risk women as they preferentially target low‐grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (L_d). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in L_d (% fold‐increase > 50%, p‐value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with micro‐RNA expression data.     

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study

Background:

Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25–70 years at recruitment from 1992 to 2000.

Methods:

Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre.

Results:

After a mean follow-up of 3.6 years (±3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR=0.80, 95% CI=0.62–1.03) and a significant survival benefit in long-term MHT users (⩾5 years use vs never use, HR=0.70, 95% CI=0.50–0.99, P_trend=0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk.

Conclusions:

Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.     

Splenectomy and surgical cytoreduction in epithelial ovarian cancer: a review

HANPRASERTPONG J. & FUJIWARA K. (2011) European Journal of Cancer Care 20 , 287–293
Splenectomy and surgical cytoreduction in epithelial ovarian cancer: a review Surgical cytoreduction and platinum/taxane combination chemotherapy are the mainstay for the treatment of epithelial ovarian cancer patients. In order to minimise the tumour mass before chemotherapy, cytoreductive surgery is usually performed first. Currently, a splenectomy is included as part of surgical cytoreduction in epithelial ovarian cancer, but it is rarely performed. A splenectomy is also performed as part of secondary cytoreduction surgery. Although there are many reports on surgical techniques, safety and associated clinical outcomes of a splenectomy as a standard adjunct of ovarian cytoreductive surgery, most evidence is from case(s) reports, with only a few studies. Thus, we conducted a review of the literature on this unusual procedure in the context of primary and secondary cytoreduction of epithelial ovarian cancer to assess the published evidence for its efficacy and safety.     

卵巢上皮癌淋巴结转移化疗的临床疗效分析

背景与目的：卵巢上皮癌属化疗中度敏感肿瘤,随着肿瘤细胞减灭术及铂类联合化疗的应用,其疗效有明显改善,但其淋巴结转移病灶对化疗的敏感性尚存异议。本研究通过回顾性分析临床资料,以评价卵巢上皮癌患者淋巴结转移对化疗的敏感性及其预后,方法：对1986年6月－2001年2月收治的50例卵巢上皮癌淋巴结转移患者进行回顾性分析,其中Ⅲ-Ⅳ期32例,治疗后复发18例,50例均有可评价疗交的淋巴结转移灶,其中38例有可评价的盆腔,腹腔肿瘤。46例接受术前化疗1－3疗程,肿瘤细胞减灭术、术后化疗。化疗疗效评价按实体瘤疗效评价标准。化疗包括术前、术后或复发患者的化疗,其中45例接受含铂类联合化疗,包括CP（环磷酰胺＋顺铂）,CAP（环磷酰胺＋顺铂＋阿霉素或表阿霉素）,TC（紫杉醇＋卡铂）,TP（紫杉醇＋顺铂）,吉西他滨＋卡铂及IEP（顺铂＋异环磷酰胺＋足叶乙甙）方案,1例用美法仑,1例用CF（环磷酰胺和5－氟尿嘧啶）方案,3例用IFO＋VP－16（异环磷酰胺＋足叶乙甙）,结果：全组淋巴结转移灶和肿瘤的有效率分别为68．0％、71．1％,Ⅲ-Ⅳ期初治患者淋巴结转移和盆腹腔肿瘤有效率分别为78．1％,76．6％,而复发组两者有效率均为50．0％,结论：卵巢上皮癌的淋巴结转移,无论Ⅲ-Ⅳ期还是复发患者,其对化疗敏感性与盆腹腔肿瘤相近,Ⅲ-Ⅳ期患者预后与减瘤术是否彻底,以及化疗的疗程数多少有明显的相关性。     

Maintenance therapy in epithelial ovarian cancer: from chemotherapy to targeted agents

Over the past years, although no increase in the cure rate for advanced epithelial ovarian cancer patients has been achieved, a slow prolongation in patients survival has been observed, thanks to the introduction of effective second line or salvage therapies. Attempts to disease chronicization seem therefore of value in this setting. A major effort has been pursued to establish the role of maintenance therapies for epithelial ovarian cancer patients. Although chemotherapy does not seem to have an effective role, promising results are coming from trials investigating maintenance targeted treatments, especially with antiangiogenic agents or PARP inhibitors for selected patients. The aim of this article is to review current evidences on maintenance therapy for epithelial ovarian cancer and put the results in perspective.     

CDC20 is a novel biomarker for improved clinical predictions in epithelial ovarian cancer

Epithelial ovarian cancer (EOC), a common tumor of the female reproductive system, ranks first in fatalities among gynecological malignancies. Most patients find tumors at late stage and have extremely poor prognoses, which necessitates improvements in early detection. This study applied bioinformatic methods to identify potential biomarkers of EOC. First, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on differentially expressed genes (DEGs) and hub genes, and a protein-protein interaction (PPI) network was constructed. The network of hub genes was analyzed using GeneMANIA, and an analysis of biological processes was constructed with BINGO. Lastly, hub genes were analyzed for EOC-related oncology using the Oncomine and TCGA databases, and the cBioPortal online platform. Overall, cell division cycle 20 (CDC20) was identified as a key gene in EOC. Short hairpin RNA (shRNA) was used to silence CDC20 to explore its effects on EOC cell proliferation, apoptosis and SRY-related HMG-box 2 (SOX2) expression. DEGs were enriched in pathways related to cell cycle signaling, cancer, progesterone-mediated oocyte maturation, Wnt signaling and P53 signaling. Analysis revealed high expression of CDC20 in EOC tissues and a correlation with histology and tumor grade. CDC20 levels are highest in serous adenocarcinoma, when compared to ovarian clear cell carcinoma, ovarian endometrioid carcinoma and mucinous adenocarcinoma. High CDC20 expression within the tumor is associated with poor EOC prognosis. After silencing CDC20, EOC cell proliferation and migration decreased, apoptosis increased, and SOX2 expression decreased. In conclusion, CDC20 is likely a key biomarker of EOC and may act as an upstream regulator of SOX2 to mediate the SOX2 signaling in the progression of EOC. Future application of CDC20 analysis to early detection may improve prognosis, and it has the potential to be a therapeutic target.     

Anti‐Müllerian hormone and risk of ovarian cancer in nine cohorts

Animal and experimental data suggest that anti‐Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case‐control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme‐linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable‐adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable‐adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59–1.67) (P_trend: 0.91). The association did not differ by age at blood draw or oral contraceptive use (all P_{heterogeneity}: ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all P_{heterogeneity}: ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.     

Comprehensive approach to advanced primary and recurrent ovarian cancer: a personal experience

Despite improvements in chemotherapy agents and schedules and new drug combinations, epithelial ovarian cancer remains a leading cause of gynecologic cancer death in Western countries. It is usually diagnosed at late stages of the disease, which makes complete surgical resection technically more difficult. The targeted comprehensive approach described in this review includes cytoreductive surgery and perioperative intraperitoneal chemotherapy. The goal of this aggressive therapy is to remove all the macroscopic disease with the use of peritonectomy procedures and visceral resections, and also to eradicate microscopic disease using heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Patients that received a complete cytoreduction followed by perioperative intraperitoneal chemotherapy had an improved survival, with reasonable morbidity and mortality, as compared with those who received incomplete cytoreduction.     

287例盆腔及腹主动脉旁淋巴结清扫术与卵巢上皮性癌生存预后的临床分析

Objective: To evaluate the relationship between the pelvic and para-aortic lymphadenectomy and the prognosis of epithelial ovarian cancer. Methods: 287 patients suffering from primary epithelial ovarian cancer from 1995 to 2005 were analyzed retrospectively. Results: The 3-, 5-, 10-year survival with systematic lymphadenectomy (SL) were slightly higher than those without SL, but there were no statistically significance (P ＞ 0.05). The 3-, 5-, 10-year survival of clinical stages without SL were lower than those with SL, but there were no significant difference either (P ＞ 0.05). The 3-,5-, and 10-year survival rates with SL were higher than those without SL with no statistically differences (P ＞ 0.05) among the subgroups such as absent, ≤ 2 cm and ＞ 2 cm residual tumor. The survival rates of the groups without residual tumor and the group with ≤ 2cm residual tumor were significantly higher than that of ＞ 2 cm (P ＜ 0.005). On multivariate analysis, patient staging (P = 0.01)and size of residual disease after primary cytoreductive surgery (P ＜ 0.001 and = 0.002, respectively) retained prognostic significance. SL was not proved to be an independent prognostic factor (P = 0.69). Conclusion: Systematic pelvic and paraaortic lymphadenectomy can not improve and prolong the survival time significantly.