Spread Of Ovarian Cancer Research Articles

Getting to Know Ovarian Cancer Ascites: Opportunities for Targeted Therapy-Based Translational Research

More than one third of ovarian cancer patients present with ascites at diagnosis, and almost all have ascites at recurrence. The presence of ascites correlates with the peritoneal spread of ovarian cancer and is associated with poor disease prognosis. Malignant ascites acts as a reservoir of a complex mixture of soluble factors and cellular components which provide a pro-inflammatory and tumor-promoting microenvironment for the tumor cells. Subpopulations of these tumor cells exhibit cancer stem-like phenotypes, possess enhanced resistance to therapies and the capacity for distal metastatic spread and recurrent disease. Thus, ascites-derived malignant cells and the ascites microenvironment represent a major source of morbidity and mortality for ovarian cancer patients. This review focuses on recent advances in our understanding of the molecular, cellular, and functional characteristics of the cellular populations within ascites and discusses their contributions to ovarian cancer metastasis, chemoresistance, and recurrence. We highlight in particular recent translational findings which have used primary ascites-derived tumor cells as a tool to understand the pathogenesis of the disease, yielding new insights and targets for therapeutic manipulation.

Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression.

Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the peri-ovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer.

FDG PET/CT in staging of advanced epithelial ovarian cancer: Frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread

ObjectiveEpithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. MethodsThirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. ResultsIn 20/30patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. ConclusionsA significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.

Abstract 3439: Tissue tranglutaminase (TG2) targeting by multifunctional field responsive gold nanoparticles

Abstract Background: Ovarian cancer (OC) spreads by direct exfoliation into the peritoneal cavity, bypassing vascular mechanisms. Our previous studies demonstrated that intraperitoneal (IP) metastasis is critically dependent on TG2, an enzyme that catalyzes protein post-translational modifications and crosslinking. In this study we assessed TG2 expression in OC, measured effects of TG2 overexpression on OC cell proliferation and tumorigenicity, and designed a novel method for cancer-specific TG2 targeting. As in-vivo delivery of siRNAs is inefficient and nonspecific, we engineered folate-coated gold nanorods (GNR) that deliver and release TG2 siRNAs into tumor cells by photothermal activation, and used small animal models to evaluate the efficacy of siRNA delivery. Materials &amp; Methods: Immunohistochemistry (IHC) evaluated TG2 expression in 58 OC specimens. Correlation with histological subtype, grade, and stage was performed by Kruskal-Wallis test. Human full length TG2 and mutants lacking enzymatic activity (C277S), GTPase activity (R580A), or both (TG1-140) were stably expressed in OV90 cells. Cell proliferation was measured by MTT and clonogenic assays. Tumorigenicity and IP metastasis were assessed in orthotopic xenografts. GNRs were synthesized by seed mediated growth, cleansed by treatment with polystyrenesulfonate, then functionalized with a mixture of thiolated siRNA and folate-conjugated PEG for targeted TG2 knockdown in tumor cells overexpressing the folate receptor (FR). Localization of FR-targeted GNRs in orthotopic ovarian tumors and metastatic colonies in the peritoneum was assessed ex vivo by confocal microscopy, two-photon luminescence (TPL), and fluorescence imaging. Results: TG2 expression was noted in 84% of OC specimens, of which 71% had &amp;gt; 2+ expression. TG2 expression levels correlated with histological subtype (p=0.005), and with high grade (p=0.005), but not with surgical stage. Forced expression of TG2 or of one of the three mutants did not affect OV90 cell proliferation in vitro or tumor volume in vivo. Mice injected with TG2-OV90 cells developed milliary peritoneal metastases (8/8) compared to mice implanted with control cells (2/9, p=0.002). TG2 knockdown via siRNA yielded &amp;gt;70% reduction in TG2 expression level in vitro. The uptake of folate-labeled GNRs into SKOV3 cells was confirmed in vitro by confocal microscopy and TPL. FR-targeted GNR delivery in vivo was most notable in peritoneal metastases, primary ovarian tumor, and liver. Little or no uptake was noted in other normal tissues, suggesting that this modality achieves cancer-specific delivery. Conclusions: TG2 is overexpressed in OC and its overexpression increases peritoneal metastasis. GNR uptake and delivery to ovarian tumors is facilitated by FR targeting. Ongoing studies are assessing the effects of GNRs carrying TG2 siRNA on OC metastasis in an orthotopic xenograft model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3439. doi:1538-7445.AM2012-3439

Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination

BackgroundA crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line.MethodsMolecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells.ResultsAfter murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate.ConclusionsThese results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Natural History of Ovarian Cancer Metastasis: An Integrated Approach

Abstract Epithelial Ovarian Carcinoma (EOC) is the sixth most common malignancy in women and the leading cause of death of gynecological cancer in the world. EOC has a predisposition to metastasis to the peritoneal cavity. A late stage peritoneal dissemination results in ascites and high mortality rates with an overall survival of 20 to 30 percent at 5 years after surgery. While many studies in the literature address the issue of distant metastasis, the biology of peritoneal tumor spread in advanced ovarian cancer is not clear. Development of peritoneal carcinomatosis involves well-defined critical steps, including cell shedding and transport, interaction and adhesion to the mesothelial layer, and colonization of and proliferation into the sub-mesothelial microenvironment. It is now appreciated that there must be an initiation of a pre-metastatic niche within the target organ, one that facilitates the survival of tumor cells in a non-receptive organ. We think that a dual approach looking at oncogenomics a...

Retrocrural Lymph Node Metastasis Disclosed by (18)F-FDG PET/CT: A Predictor of Supra-diaphragmatic Spread in Ovarian Cancer.

Retrocrural lymph nodes (RCLNs) communicate with retroperitoneal and posterior mediastinal LNs. It is possible that, when RCLNs are involved, supra-diaphragmatic extension will occur in abdomino-pelvic cancers. The authors investigated performance of (18)F-FDG PET/CT to diagnose RCLN metastasis and whether RCLN metastases were associated with supra-diaphragmatic lymphatic metastases of ovarian cancer. Sixty-seven patients with stage IV ovarian cancer who had undergone (18)F-FDG PET/CT were included in this retrospective study. Diagnostic performance of (18)F-FDG PET/CT for RCLN metastasis was evaluated. Patients were divided into two groups by presence or absence of supra-diaphragmatic LN metastasis. The prevalences of RCLN metastasis between the two groups were compared and the odds ratio was calculated. Sensitivity and specificity of (18)F-FDG PET/CT for RCLN metastasis were 96.3 and 100%, respectively. Of the 67 study subjects, 27 patients had RCLN metastases (40.3%). Fifty patients had supra-diaphragmatic LN metastases. (18)F-FDG PET/CT showed 26 RCLN metastases in patients with supra-diaphragmatic LN metastases (54.5%), and only 1 in patients without supra-diaphragmatic LN metastasis (5.9%), and the difference between two groups was statistically significant (P < 0.05). The odds ratio that patients with RCLN metastasis would have supra-diaphragmatic LN metastasis was 17.3 (95% confidence interval = 2.1 to 140.9, P = 0.008). Performance of (18)F-FDG PET/CT to diagnose RCLN metastasis was excellent. RCLN metastasis revealed by (18)F-FDG PET/CT was strongly associated with supra-diaphragmatic LN spread of ovarian cancer. Thus, RCLN metastasis could be used as a predictor of supra-diaphragmatic lymphatic metastasis of ovarian cancer.

Not Available

Not Available

Metformin Suppresses Ovarian Cancer Growth and Metastasis with Enhancement of Cisplatin Cytotoxicity In Vivo

Ovarian cancer is the most lethal gynecologic cancer in women. Its high mortality rate (68%) reflects the fact that 75% of patients have extensive (>stage III) disease at diagnosis and also the limited efficacy of currently available therapies. Consequently, there is clearly a great need to develop improved upfront and salvage therapies for ovarian cancer. Here, we investigated the efficacy of metformin alone and in combination with cisplatin in vivo. A2780 ovarian cancer cells were injected intraperitoneally in nude mice; A2780-induced tumors in nude mice, when treated with metformin in drinking water, resulted in a significant reduction of tumor growth, accompanied by inhibition of tumor cell proliferation (as assessed by immunohistochemical staining of Ki-67, Cyclin D1) as well as decreased live tumor size and mitotic cell count. Metformin-induced activation of AMPK/mTOR pathway was accompanied by decreased microvessel density and vascular endothelial growth factor expression. More importantly, metformin treatment inhibited the growth of metastatic nodules in the lung and significantly potentiated cisplatin-induced cytotoxicity resulting in approximately 90% reduction in tumor growth compared with treatment by either of the drugs alone. Collectively, our data show for the first time that, in addition to inhibiting tumor cell proliferation, metformin treatment inhibits both angiogenesis and metastatic spread of ovarian cancer. Overall, our study provides a strong rationale for use of metformin in ovarian cancer treatment.

Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

Understanding the problem of inadequately staging early ovarian cancer

Background Early ovarian cancer patients are often incompletely staged during initial surgery. 1–3 This omission can have serious adverse consequences for the prognosis of patients as the completeness of surgical staging has been identified as an independent prognostic parameter for survival. 4,5 The reasons for the problem of inadequate staging of early ovarian cancer are largely unknown. We have analysed the data of a large randomised trial in early ovarian cancer in which detailed information of the surgical staging procedure was monitored. 5 Methods Data of the EORTC Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) Trial were used in which 448 early ovarian cancer patients were randomised between postoperative chemotherapy in one arm and observation following surgery in the other. In this trial strict criteria for surgical staging were advised but optimal, complete staging was performed in only 1/3 of patients. Staging characteristics of the incompletely staged patients were analysed and factors that could explain the failure to perform a complete staging were studied. Results Sampling of para-aortic nodes was omitted in 78% of the incompletely staged patients, while 52% of these patients had no pelvic lymph node dissection. Taking blind biopsies from different peritoneal sites was not performed in more than 1/3 of the incompletely staged group. Omission of the staging steps ranged from 3% (infracolic omentectomy) to 55% (biopsy of the right hemi-diaphragm). A significant difference ( p = 0.04) between the fraction of completely staged patients was found when comparing institutes who entered less than 5 patients (21%) versus those who included more than 20 patients (37%) in the trial. Conclusions Even in a randomised trial in which comprehensive surgical staging was strongly advised in the study protocol the majority of patients (66%) were incompletely staged. Factors relating to a lack of surgical skills attributed most to the number of incompletely staged patients, but insufficient knowledge of the tumour behaviour and routes of spread of ovarian cancer also contributed substantially to this problem. Multicentre trials recruiting patients from many institutes with small volume contribution to the study, run the risk of inadequate adherence to the study protocol.

Abdominal Wall Metastases in Patients With Ovarian Cancer After Laparoscopic Surgery

Laparoscopy is the standard procedure to clarify undefined ovarian masses. However, laparoscopy could induce tumor spread in ovarian cancer (OC). The aim of this study was to assess the incidence, the risk factors, and the complications of abdominal wall metastases (AWM) in patients with OC after laparoscopy. Retrospective study of patients with primary diagnosis of OC who had laparoscopy before cytoreductive surgery and resected port sites in laparotomy between 1999 and 2008 at our institution. Patients with borderline or nonepithelial ovarian tumors were excluded. Of 537 patients with a first diagnosis of OC, 101 had laparoscopy before definitive operation after a median of 31 days. Histological examination at final cytoreductive surgery of the port sites was conducted in 66 patients, whereas 31 patients (47%) showed AWM. Patients experiencing AWM had higher tumor stages and peritoneal carcinomatosis. Ascites with more than 500 mL was a further independent risk factor for AWM (odds ratio: 7.2; 95% confidence interval, 1.5-35.8; P = 0.016). Abdominal wall metastasis did not impact on survival in our cohort; however, affected patients showed significant larger abdominal wall resections (mean [SD]): 41.0 (angled brace 13.1) cm versus 9.1 (angled brace 1.4) cm in comparison with patients without AWM (P = 0.013), and 2 patients developed abdominal wall recurrences. The incidence of AWM in patients experiencing OC was considerably high when laparoscopic surgery was conducted before cytoreductive surgery. Patients experiencing AWM seem to have more surgical burden. However, our series did not show a dramatic impact of AWM on long-term outcome. Patients with highly suspected advanced OC and ascites with more than 500 mL should be referred directly to a gynecologic oncologist who is able to balance risks of laparoscopic staging and direct cytoreductive surgery.

Upper abdominal surgery in advanced and recurrent ovarian cancer: Role of diaphragmatic surgery

Objective Upper abdominal spread of primary and recurrent ovarian cancer is often considered to be a major obstacle to achieve optimal residual disease at the end of surgery. In this study, we investigate the role of diaphragmatic debulking in the natural history of advanced and recurrent epithelial ovarian cancer patients, and the morbidity of this procedure according to clinico-surgical characteristics. Methods Data from 234 consecutive patients with primary and recurrent advanced ovarian cancer, operated at Catholic University of Rome and Campobasso from January 1, 2005 and December 31, 2008, were retrospectively reviewed. Results Eighty-seven patients (37.2%) underwent a diaphragmatic surgery. Median age was 55 years (range 37–76). Diaphragmatic debulking was performed in 50 out of 120 patients at primary surgery (41.7%), in 16 out of 74 at interval debulking surgery (21.6%) and in 21 out of 40 secondary cytoreductions (52.5%). In the whole study population optimal residual disease at the end of surgery was achieved. The most frequent post-operative complication was pleural effusion, observed in 37 patients (42.5%). Presence of a post-operative pleural effusion was correlated liver mobilization (52.3% vs. 16%; p < 0.0027) and large diaphragmatic disease (> 5 cm) removal (54.1% vs. 23.5%; p < 0.034). Conclusions Diaphragmatic surgery represents a crucial step in the debulking of advanced and recurrent ovarian cancer patients. Considering the natural history of advanced epithelial ovarian cancer and the rate of patients needing diaphragmatic debulking during primary cytoreduction, interval debulking surgery and secondary cytoreduction, this procedure should be present in the surgical repertoire of a gynecologic oncologist.

Emerging Roles of Kruppel‐Like Factor 6 and Kruppel‐Like Factor 6 Splice Variant 1 in Ovarian Cancer Progression and Treatment

Epithelial ovarian cancer is one of the most lethal gynecologic cancers and the fifth most frequent cause of female cancer deaths in the United States. Despite dramatic treatment successes in other cancers through the use of molecular agents targeted against genetically defined events driving cancer development and progression, very few insights into epithelial ovarian cancer have been translated from the laboratory to the clinic. If advances are to be made in the early diagnosis, prevention, and treatment of this disease, it will be critical to characterize the common and private (personalized) genetic defects underlying the development and spread of epithelial ovarian cancer. The tumor suppressor Kruppel-like factor 6 and its alternatively spliced, oncogenic isoform, Kruppel-like factor 6 splice variant 1, are members of the Kruppel-like zinc finger transcription factor family of proteins, which have diverse roles in cellular differentiation, development, proliferation, growth-related signal transduction, and apoptosis. Inactivation of Kruppel-like factor 6 and overexpression of Kruppel-like factor 6 splice variant 1 have been associated with the progression of a number of human cancers and even with patient survival. This article summarizes our recent findings demonstrating that a majority of epithelial ovarian cancer tumors have Kruppel-like factor 6 allelic loss and decreased expression coupled with increased expression of Kruppel-like factor 6 splice variant 1. The targeted reduction of Kruppel-like factor 6 in ovarian cancer cell lines results in marked increases in cell proliferation, invasion, tumor growth, angiogenesis, and intraperitoneal dissemination in vivo. In contrast, the inhibition of Kruppel-like factor 6 splice variant 1 decreases cellular proliferation, invasion, angiogenesis, and tumorigenicity; this provides the rationale for its potential therapeutic application. These results and our recent demonstration that the inhibition of Kruppel-like factor 6 splice variant 1 can dramatically prolong survival in a preclinical mouse model of ovarian cancer are reviewed and discussed.

Lymph Node-Positive Stage IIIC Ovarian Cancer: A Separate Entity?

Ovarian cancer spreads via the retroperitoneal lymphatics, and these lymph nodes frequently contain metastasis. A subset of patients whose disease was classified as stage IIIC has retroperitoneal lymph node metastases in the pelvic and/or para-aortic lymph nodes without intraperitoneal carcinomatosis and was upstaged from stage I to IIIB diseases based on these findings. Patients undergoing cytoreductive surgery for advanced-stage ovarian cancer undergo concomitant retroperitoneal lymphadenectomy in an effort to improve their survival. Stratification of patients with stage IIIC ovarian cancer by lymph node status and presence and extent of metastatic disease in the peritoneal cavity has been performed. Studies have determined the impact on disease-free and overall survivals of the resection of retroperitoneal lymph nodes as part of primary and secondary cytoreductive operations. The overall survival of patients with stage IIIC ovarian cancer based on retroperitoneal lymph node metastasis without peritoneal carcinomatosis is 58% to 84% compared with 18% to 36% for those with macroscopic peritoneal carcinomatosis. Although the performance of a pelvic and para-aortic lymphadenectomy in patients with stage IIIC to IV diseases has been reported to prolong survival, an international randomized study did not confirm this finding. Patients who undergo secondary resection of isolated recurrent lymph node metastasis have a better survival than those with more extensive recurrent disease. These data support the stratification of patients with stage IIIC ovarian cancer based on the finding of metastasis to the retroperitoneal lymph nodes without peritoneal carcinomatosis versus those who have peritoneal carcinomatosis. The International Federation of Gynecology and Obstetrics Committee should consider modifying the ovarian cancer staging system by further stratifying stage III disease. Although systematic lymphadenectomy during primary cytoreductive surgery does not appear to improve overall survival, resection of isolated lymph node metastasis and recurrences in lymph nodes may be associated with a survival benefit.

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer.

Spread of Ovarian Cancer

Contemporary Diagnostic Radiology: September 30, 2008 - Volume 31 - Issue 20 - p 6 doi: 10.1097/01.CDR.0000336965.37399.59

Spread of Ovarian Cancer

Spread of Ovarian Cancer

Preoperative evaluation of peritoneal deposits in epithelial ovarian cancer and prediction of surgical outcome with multidetector computed tomography

16515 Background: Peritoneal route is the most common form of spread in epithelial ovarian cancer (EOC) and in the management of EOC, optimum debulking surgery (residual tumour of 1 cm or less) is ...