Epithelial Ovarian Cancer Histotypes Research Articles

Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium.

Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14-1.57), and similar associations were observed for each histotype. In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114-24. ©2016 AACR.

Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients.

High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10–0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0238-7) contains supplementary material, which is available to authorized users.

Ovarian Cancer: The Fallopian Tube as the Site of Origin and Opportunities for Prevention.

High-grade serous carcinoma (HGSC) is the most common and aggressive histotype of epithelial ovarian cancer (EOC), and it is the predominant histotype associated with hereditary breast and ovarian cancer syndrome (HBOC). Mutations in BRCA1 and BRCA2 are responsible for most of the known causes of HBOC, while mutations in mismatch repair genes and several genes of moderate penetrance are responsible for the remaining known hereditary risk. Women with a history of familial ovarian cancer or with known germline mutations in highly penetrant genes are offered the option of risk-reducing surgery that involves the removal of the ovaries and fallopian tubes (salpingo-oophorectomy). Growing evidence now supports the fallopian tube epithelia as an etiological site for the development of HGSC and consequently, salpingectomy alone is emerging as a prophylactic option. This review discusses the site of origin of EOC, the rationale for risk-reducing salpingectomy in the high-risk population, and opportunities for salpingectomy in the low-risk population.

Abstract B18: Prediagnostic physical inactivity and epithelial ovarian cancer risk and mortality: Evidence from the Ovarian Cancer Association Consortium.

Abstract Despite a growing number of studies evaluating associations between physical activity and epithelial ovarian cancer risk and mortality, the extant evidence is inconclusive, both for epithelial ovarian cancer (EOC) overall, and by individual histotypes. The inconsistency of epidemiological findings may be due to some apparent limitations in the literature. First, individual studies of EOC often have relatively small numbers of case subjects, especially for less common histotypes. Second, physical activity is a complex behavior involving several characteristics that have been measured differently by the various self-report questionnaires utilized among epidemiological studies. Third, many studies in the existing literature have utilized referent groups combining women who report no regular physical activity with women who report some physical activity, which could obscure the relationship between physical activity and EOC risk or mortality, if one exists. Objective: We conducted a pooled analysis of individual-level data from 12 studies from the Ovarian Cancer Association Consortium to investigate the association between recreational physical inactivity and EOC risk and mortality. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women were classified as inactive, our exposure of interest, if they reported participating in recreational physical activities less than once per week, on average, throughout adulthood. To decrease the likelihood of reverse causation as an explanation for observed associations, studies using activity data from the reference date only were excluded in sensitivity analyses. For risk assessment, case data were from 9,024 women aged 18 years and older with a primary diagnosis of borderline or invasive EOC including serous, mucinous, endometrioid or clear cell tumors. Control data were from 13,643 women aged 18 years and older who had at least partially intact ovaries and no histories of ovarian cancer. We employed both meta-analytic and combined individual-data approaches to evaluate the associations between physical inactivity and EOC risk. For mortality outcomes, follow-up data and vital status were available for 6,807 cases. Using a combined dataset, multivariable Cox proportional hazards regression analyses were utilized to generate Hazard Ratios (HRs) and 95% CIs for the association between physical inactivity and all-cause mortality. We also examined risks of EOC-specific mortality and disease progression in a smaller subset of patients with available follow-up data. Results: In risk analyses, we observed a significant positive association between recreational physical inactivity and risk of EOC (OR=1.39, 95% CI: 1.18-1.63, p&amp;lt;0.001). Significant risk elevations ranging between 30% to 55% among inactive women were also observed across the individual EOC histotypes. In survival analyses, there were 3,899 all-cause deaths for analysis. We observed a significant increased multivariable adjusted risk of death among inactive women in comparison to more active women (HR=1.14, 95% CI: 1.06-1.23, p&amp;lt;0.001). We also observed increased risk of EOC-specific mortality, but the association did not achieve statistical significance (HR=1.10, 95% CI: 0.95-1.28, p=0.211). Lastly, we observed a significantly higher risk of disease progression among inactive patients (HR=1.22, 95% CI: 1.09-1.37, p=0.001). Conclusions: These data suggest that recreational physical inactivity in adulthood is associated with an increased risk of EOC. Our data also supports an association between inactivity with risk of disease progression and mortality. These associations were robust to adjustment for relevant confounders and to sensitivity analyses designed to decrease the likelihood of reverse causation as an explanation for observed associations. Given the growing prevalence of inactivity in the U.S. and worldwide, these findings are relevant to public health and cancer prevention and control. Citation Format: Rikki A. Cannioto, Michael LaMonte, Ovarian Cancer Association Consortium (OCAC), Kirsten B. Moysich. Prediagnostic physical inactivity and epithelial ovarian cancer risk and mortality: Evidence from the Ovarian Cancer Association Consortium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B18.

Integrins and haptoglobin: Molecules overexpressed in ovarian cancer

Integrins are adhesion molecules whose expression is upregulated during different cellular processes such as adhesion, growth, proliferation, migration, survival and differentiation, all of which are involved in neoplastic development. Several reports have linked the overexpression of integrins with epithelial ovarian cancer (EOC). Furthermore, fucosylated haptoglobin (Hp) isoforms with antioxidant activity and synthesized primarily in the liver have also been associated with various types of cancer, including ovarian cancer. Here, we determined the level of expression of three integrin heterodimers (α5β1, α6β4, and αVβ3) and fucosyltated Hp in two different settings: cell cultures and biopsies from ovarian cancer patients. On the one hand, integrin heterodimers were analyzed in the ovarian cancer cell line (SKOV-3), two primary cultures (INCan017 and INCan019) and a tumor derived from INCan017 (T-017) by Western blot. Statistical analysis was performed using one-way ANOVA. The SKOV-3 cell line, INCan017 and INCan019 primary cultures, and the T-017 tumor showed increased expression patterns of the α5, αV, β1, β3, and β4 integrin subunits when compared with healthy ovary tissue. We then analyzed the expression pattern of the integrin subunits as well as the fucosylated Hp in biopsies from patients with different histotypes of EOC by immunofluorescence. α5β1 and α6β4 integrins were expressed by 90% of the samples, whereas 80% expressed the αVβ3 integrin. Furthermore, Hp, fucosylated or not, was present at high levels in most biopsies. In fact, there was a statistical correlation between the expression of integrins or Hp and the presence of the disease given that α5β1, α6β4, and αVβ3 integrins, Hp, fucosylated Hp and additional fucosylation state of proteins were highly expressed in biopsies of EOC histotypes when compared with healthy ovarian tissue. However, the statistical analysis showed no association of the presence of integrins, Hp or fucosylation with clinical or pathological characteristics of EOC patients. These results suggest that increased expression of these molecules and of the fucosylation modification are characteristics of the malignant process itself. Therefore, these molecules may be promising therapeutic targets in patients with this type of neoplasia.

DNA methylation changes in epithelial ovarian cancer histotypes

Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There's considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field.

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

During tumor progression, epithelial ovarian cancer (EOC) cells undergo epithelial-to-mesenchymal transition (EMT), which influences metastatic success. Mutation-dependent activation of Wnt/β-catenin signaling has been implicated in gain of mesenchymal phenotype and loss of differentiation in several solid tumors; however, similar mutations are rare in most EOC histotypes. Nevertheless, evidence for activated Wnt/β-catenin signaling in EOC has been reported, and immunohistochemical analysis of human EOC tumors demonstrates nuclear staining in all histotypes. This study addresses the hypothesis that the bioactive lipid lysophosphatidic acid (LPA), prevalent in the EOC microenvironment, functions to regulate EMT in EOC. Our results demonstrate that LPA induces loss of junctional β-catenin, stimulates clustering of β1 integrins, and enhances the conformationally active population of surface β1 integrins. Furthermore, LPA treatment initiates nuclear translocation of β-catenin and transcriptional activation of Wnt/β-catenin target genes resulting in gain of mesenchymal marker expression. Together these data suggest that LPA initiates EMT in ovarian tumors through β1-integrin-dependent activation of Wnt/β-catenin signaling, providing a novel mechanism for mutation-independent activation of this pathway in EOC progression.

Abstract 1470: Ovarian cancer PDXs preserve preexisting genetic oligoclonality

Abstract Advanced Epithelial Ovarian Cancer (EOC) is the leading cause of female cancer casualties and its prognosis remains grim, with about 30% of 5-year overall survival. Classically EOCs have been stratified according to 5 histotypes, tumor grading and disease stages. However, worst prognosis is associated to high grade EOCs, which mostly comprise serous ovarian carcinomas (SOC). A large majority of the patients relapse by 18 to 24 months after end of chemotherapy (CT) and eventually develop resistant disease. Research aiming at proposing more effective therapies relies on a limited set of cancer cell lines established several decades ago and whose representativeness of the actual disease has been put in doubt (Domcke et al., 2013; Nature Comm). This strongly calls for the production of novel EOC models to support experimental and preclinical work. In the last decade patient derived xenografts (PDX) have gained considerable interest, because they faithfully reproduce the characteristics of the tumor of origin. We, here, report the establishment of a collection of 35 ovarian cancer PDXs resulting from the original graft of 77 ovarian tumor samples onto immuno-compromised mice. Interestingly, established PDXs covered the diversity of EOC histotypes. We characterized a subset of 14 EOC PDXs at the genetic (array-CGH and transcriptome) and histological levels. This revealed that PDXs perfectly reproduce the original genetic and morphological features of the ovarian tumors they stemmed from. It was of note that PDXs conserved the principal characteristics of the original CNC profiles over several passages. However, a detailed comparison revealed fluctuation of CNC patterns in a fraction of chromosomal regions between the original tumor and the PDXs, that could be attributed to the oligoclonal nature of the original tumor. The analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDX globally maintained an oligoclonal structure. Despite fluctuations in the relative prevalence of some mutations according to the sample, we did not observe any overgrowth of a particular subclone present in the original tumor. This suggests that xenotransplantation of ovarian tumors and growth as PDX is not associated to a drastic change in selective pressure. We believe these findings are of interest to determine the impact of different therapy regimen on the clonality of EOC. Citation Format: Pierre-Emmanuel Colombo, Stanislas du Manoir, Beatrice Orsetti, Rui Bras-Goncalves, Alan MacKay, Maryou Lambros, Tuan T. Nguyen, Florence Boissiere, Didier Pourquier, Jorge Reis-Filho, Charles G. Theillet. Ovarian cancer PDXs preserve preexisting genetic oligoclonality. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1470. doi:10.1158/1538-7445.AM2015-1470

Ovarian carcinoma patient derived xenografts reproduce their tumor of origin and preserve an oligoclonal structure.

Advanced Epithelial Ovarian Cancer (EOC) patients frequently relapse by 24 months and develop resistant disease. Research on EOC therapies relies on cancer cell lines established decades ago making Patient Derived Xenografts (PDX) attractive models, because they are faithful representations of the original tumor. We established 35 ovarian cancer PDXs resulting from the original graft of 77 EOC samples onto immuno-compromised mice. PDXs covered the diversity of EOC histotypes and graft take was correlated with early patient death. Fourteen PDXs were characterized at the genetic and histological levels. PDXs reproduced phenotypic features of the ovarian tumors of origin and conserved the principal characteristics of the original copy number change (CNC) profiles over several passages. However, CNC fluctuations in specific subregions comparing the original tumor and the PDXs indicated the oligoclonal nature of the original tumors. Detailed analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDXs globally maintained an oligoclonal structure. No overgrowth of a particular subclone present in the original tumor was observed in the PDXs. This suggested that xenotransplantation of ovarian tumors and growth as PDX preserved at least in part the clonal diversity of the original tumor. We believe our data reinforce the potential of PDX as exquisite tools in pre-clinical assays.

Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms.

BackgroundMucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations.MethodsUsing the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously.ResultsWe detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event.ConclusionsOverall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1421-8) contains supplementary material, which is available to authorized users.

Functional characterization of epithelial ovarian cancer histotypes by drug target based protein signaling activation mapping: implications for personalized cancer therapy.

Epithelial ovarian carcinoma (EOC) is a deadly disease, with a 5-year survival of 30%. The aim of the study was to perform broad-scale protein signaling activation mapping to evaluate if EOC can be redefined based on activated protein signaling network architecture rather than histology. Tumor cells were isolated using laser capture microdissection (LCM) from 72 EOCs. Tumors were classified as serous (n = 38), endometrioid (n = 13), mixed (n = 8), clear cell (CCC; n = 7), and others (n = 6). LCM tumor cells were lysed and subjected to reverse-phase protein microarray to measure the expression/activation level of 117 protein drug targets. Unsupervised hierarchical clustering analysis was utilized to explore the overall signaling network. ANOVA was used to detect significant differences among the groups (p < 0.05). Regardless of histology, unsupervised analysis revealed five pathway-driven clusters. When the EOC histotypes were compared by ANOVA, only CCC showed a distinct signaling network, with activation of EGFR, Syk, HER2/ErbB2, and SHP2 (p = 0.0007, p = 0.0021, p < 0.0001, and p = 0.0410, respectively). The histological classification of EOC fails to adequately describe the underpinning protein signaling network. Nevertheless, CCC presents unique signaling characteristics compared to the other histotypes. EOC may need to be characterized by functional signaling activation mapping rather than pure histology.

BRCA and Early Events in the Development of Serous Ovarian Cancer.

Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk of developing epithelial ovarian cancer (EOC), and epidemiological factors related to parity, ovulation, and hormone regulation have a dramatic effect on the risk in both BRCA mutation carriers and non-carriers. The most common and most aggressive histotype of EOC, high-grade serous carcinoma (HGSC), is also the histotype associated with germline BRCA mutations. In recent years, evidence has emerged indicating that the likely tissue of origin of HGSC is the fallopian tube. We have reviewed, what is known about the fallopian tube in BRCA mutation carriers at both the transcriptional and translational aspect of their biology. We propose that changes of the transcriptome in BRCA heterozygotes reflect an altered response to the ovulatory stresses from the microenvironment, which may include the post-ovulation inflammatory response and altered reproductive hormone physiology.

MiRNA Landscape in Stage I Epithelial Ovarian Cancer Defines the Histotype Specificities

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic diseases, with survival rate virtually unchanged for the past 30 years. EOC comprises different histotypes with molecular and clinical heterogeneity, but up till now the present gold standard platinum-based treatment has been conducted without any patient stratification. The aim of the present study is to generate microRNA (miRNA) profiles characteristic of each stage I EOC histotype, to identify subtype-specific biomarkers to improve our understanding underlying the tumor mechanisms. A collection of 257 snap-frozen stage I EOC tumor biopsies was gathered together from three tumor tissue collections and stratified into independent training (n = 183) and validation sets (n = 74). Microarray and quantitative real-time PCR (qRT-PCR) were used to generate and validate the histotype-specific markers. A novel dedicated resampling inferential strategy was developed and applied to identify the highest reproducible results. mRNA and miRNA profiles were integrated to identify novel regulatory circuits. Robust miRNA markers for clear cell and mucinous histotypes were found. Specifically, the clear cell histotype is characterized by a five-fold (log scale) higher expression of miR-30a and miR-30a*, whereas mucinous histotype has five-fold (log scale) higher levels of miR-192/194. Furthermore, a mucinous-specific regulatory loop involving miR-192/194 cluster and a differential regulation of E2F3 in clear cell histotype were identified. Our findings showed that stage I EOC histotypes have their own characteristic miRNA expression and specific regulatory circuits.

Abstract 799: Global genomic analysis identified PRKCI as a potential therapeutic target gene for human clear cell ovarian cancer.

Abstract Clear cell ovarian cancer (CCOC), a rare epithelial ovarian cancer histotype, is more resistant to standard chemotherapy and has a worse prognosis than serous and endometrioid histotypes. We attempted to identify genes that are responsible for the aggressive behavior of CCOC and could be potential therapeutic targets using genomic and expression profilings. To identify gene amplification, genome-wide DNA copy number alterations were measured in 13 CCOC cell lines using high-resolution oligonucleotide array CGH (Agilent 105k Human Genome CGH Microarray). GISTIC analysis identified 16 amplified regions containing 391 genes. After comparison to our database of differentially expressed genes between human CCOC specimens and normal ovarian surface epithelium specimen (Affymetrix U133 Plus 2.0 microarrays), 45 of the amplified genes showed mRNA overexpression in CCOC specimens. Among the 45 genes, protein kinase C iota (PRKCI) was amplified in 9/13 CCOC cell lines and was overexpressed (6.7 fold) in CCOC specimens. Analysis using PathwayStudio software identified PRKCI mediated pathways for cell migration and invasion. Knock-down of PRKCI by transfection with PRKCI specific siRNAs suppressed cell migration and invasion in KOC-7c and OVISE cells. On the other hand, ectopic expression of PRKCI by transfection with PRKCI expressing vector enhanced cell migration and invasion in ES2 and TOV21G cells. The results from the present study therefore suggested that PRKCI may promote metastasis and serve as a potential target gene for treatment of human clear cell ovarian cancer. Citation Format: Tsun Yee Tsang, Gayatry Mohapatra, Hiroaki Itamochi, Samuel C. Mok, Michael J. Birrer. Global genomic analysis identified PRKCI as a potential therapeutic target gene for human clear cell ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 799. doi:10.1158/1538-7445.AM2013-799

Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

Secretory Leukocyte Protease Inhibitor: Immunohistochemical Evidence Supporting a Fallopian Tube Origin for Serous Papillary Carcinoma

Serous papillary carcinoma (SPC) represents the most common histological type of ovarian carcinoma, which is the fifth leading cause of cancer-related death in women in the United States. 1 The tissue of origin for SPC remains controversial. It is believed by many authors that the cancer arises from the surface epithelia of the ovary or the cells that line ovarian inclusion cysts. 2-3 In this theory, the ovarian surface epithelium (OSE), usually flattened with no distinct features, undergoes Mullerian metaplasia and through possible undefined molecular events, acquires serous papillary morphology during malignant transformation. A contrasting opinion is that SPC may arise from the fallopian tube (FT), this supposition based on the morphologic resemblance of SPC to the fimbriated end of the FT. A recent report 4 investigating the patterns of gene expression among different histotypes of epithelial ovarian cancer showed strong correlation of expression profile of serous papillary carcinoma with that of the fallopian tube. [N A J Med Sci. 2009;2(2):42-43.]

Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer

To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC). We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E2 (PGE2), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB4), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachidonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvic disease. (a) Eicosanoid products were detected in tumor, MP, and BP specimens. PGE2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001). Combined levels of PGE2, 12-HETE, 5-HETE, and LTB4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of MP, BP, and tumor showed that a number of eicosanoid and arachidonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors. Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachidonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC.

Patterns of Gene Expression in Different Histotypes of Epithelial Ovarian Cancer Correlate with Those in Normal Fallopian Tube, Endometrium, and Colon

Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.

817 Optimized schedule of gemcitabine (G), paclitaxel (T) and cisplatin (P) in the treatment of stage IIIB/IV non-small cell lung cancer (NSCLC): results of a phase II study

The cell of origin of the different histotypes of epithelial ovarian cancer (EOC) has been debated for some time. The dogma for nearly 50 years has been that EOCs develop from the ovarian surface epithelium (OSE), a single layer of mesoepithelial cells with multipotent properties. More recently, evidence suggests that the most common EOC histotype, serous, might develop predominantly from mutated secretory cells at the fimbriated end of the fallopian tube, but another extra-ovarian source has also been proposed, as well as nonovarian sources for endometrioid, mucinous, and clear cell types. This chapter will describe the evidence supporting both the OSE and these extraovarian sources as sites of origin for EOC.