Metastasis Of Ovarian Carcinoma Research Articles

MiR-200c Regulation of Metastases in Ovarian Cancer: Potential Role in Epithelial and Mesenchymal Transition

Among the gynecological malignancies, ovarian cancer is the most fatal due to its high mortality rate. Most of the identified cases are epithelial ovarian cancer (EOC) with five distinct subtypes: high-grade serous carcinoma, low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear-cell carcinoma. Lack of an early diagnostic approach, high incidence of tumor relapse and the heterogenous characteristics between each EOC subtypes contribute to the difficulties in developing precise intervention and therapy for the patients. MicroRNAs (miRNAs) are single-stranded RNAs that have been shown to function as tumor suppressors or oncomiRs. The miR-200 family, especially miR-200c, has been shown to be implicated in the metastasis and invasion of ovarian carcinoma due to its functional regulation of epithelial-to-mesenchymal transition (EMT). This mini review is aimed to summarize the recent findings of the miR-200c functional role as well as its validated targets in the metastasis cascade of ovarian cancer, with a focus on EMT regulation. The potential of this miRNA in early diagnosis and its dual expression status are also discussed.

A clinicopathological study of ascites with special reference to malignant etiology in a tertiary care hospital in Kolkata

Introduction: Ascites is one the most common presenting complaints in tertiary care hospitals. Cirrhosis accounts for majority of cases of ascites. Cardiac ascites, peritoneal carcinomatosis, and mixed ascites resulting from cirrhosis and its complications account for rest of the cases. Less common causes of ascites include massive hepatic metastasis, infection (tuberculosis, Chlamydia), pancreatitis, and renal disease (nephrotic syndrome). Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and alcoholic liver disease are the main causes of cirrhosis in India and rest of the world. Aim and objective: The aim of the study is to explore the etiopathology of ascites in the patients who were admitted to a tertiary care hospital in eastern India. Materials and methods: A hospital based cross-sectional study is conducted over a period of one year in Medical College and Hospital, Kolkata. 100 patients of ascites above 18yrs of age were studied. Clinico-pathological, hematological and biochemical parameters along with imaging findings were documented and were presented in tabular, graphical and statistical means. Results: In our study the most common causes of ascites found were alcoholism (36%) followed by malignant ascites (18%). It was also observed that most of the patients were between 40-60 years with male preponderance. Amongst malignant causes of ascites HCC (44.44%), ovarian carcinoma (33.33%),colon carcinoma(11.11%), both gastric carcinoma and massive liver metastasis accounts for 5.55% each. Conclusion: The study highlights alcohol as the common culprit cause for ascites, labels HCC as the most common cause of malignant ascites, and defines the clinico-pathological, biochemical and imaging characteristics of different etiologies of ascites.

Down-regulation of SIRT3 promotes ovarian carcinoma metastasis

Distant metastasis and local recurrence are still the major causes for failure of treatment in patients with ovarian carcinoma (OC), making it urgent to further elicit the molecular mechanisms of OC metastasis. Sirtuin-3 (SIRT3), a member of the NAD+-dependent Class III histone deacetylases, may function as different role depending on the cell-type and tumor-type. However, the function and mechanism of SIRT3 has been not explored in OC metastasis. Here, we found that SIRT3 was significantly down-regulated in the metastatic tissues and highly metastatic cell line of ovarian cancer. In addition, knockdown of SIRT3 enhanced the migration and invasion in vitro and the liver metastasis in vivo of ovarian cancer cell. By contrast, ectopic overexpression of SIRT3 dramatically suppressed cancer cell metastatic capability. Mechanistically, SIRT3 inhibits epithelial-to-mesenchymal transition (EMT) by down-regulating Twist in ovarian cancer cells. Furthermore, an interaction between SIRT3 and Twist was detected. In conclusion, our results demonstrated that SIRT3 plays a crucial suppressive role in the metastasis of ovarian cancer by down-regulating Twist, and that this novel SIRT3/Twist axis may be valuable to develop new strategies for treating OC patients with metastasis.

Utility of ovarian biopsy in pancreatic metastasis of high-grade serous ovarian carcinoma: A case report.

It is very rare that ovarian carcinoma metastasizes to the pancreas, and pathological diagnosis is required to confirm the primary site. The present study reported a 73-year-old woman with serous carcinoma of the ovary that metastasized to the tail of the pancreas. Metastasis was confirmed by pathological and immunohistochemical examination of a biopsy of the ovarian tumor, an endoscopic ultrasound-guided fine-needle aspiration biopsy of the pancreatic tumor and computerized tomography-guided paraaortic lymph node biopsy. A biopsy of the ovarian tumor is useful to make a precise diagnosis and to determine proper treatment when ovarian and pancreatic tumors are identified at the same time and the primary neoplasm is uncertain.

Human lymphatic endothelial cells contribute to epithelial ovarian carcinoma metastasis by promoting lymphangiogenesis and tumour cell invasion.

The microenvironment of a tumour is an important factor in ovarian cancer metastasis. The present study aimed to simulate the in vivo microenvironment of an ovarian carcinoma using a co-culture system consisting of human lymphatic endothelial cells (HLECs) and human ovarian carcinoma cells with directional high lymphatic metastasis (SKOV3-PM4s) in order to investigate the role of both cell types in ovarian carcinoma metastasis. The SKOV3-PM4s cultured in the HLEC-conditioned medium exhibited increased numbers of pseudopodia and mitotic figures, proliferated at a faster rate and exhibited enhanced invasion and migratory abilities. Furthermore, the HLECs cultured in SKOV3-PM4-conditioned medium exhibited significant morphological alterations and vacuolisation of the cytoplasm, as well as increased invasion, migratory and tube forming abilities. In addition, spontaneous fusion of the SKOV3-PM4s and HLECs was observed in the co-culture system using laser confocal microscopy. The gelatin zymography assay demonstrated that matrix metalloproteinase-2, which was downregulated in the SKOV3-PM4s, was upregulated in the co-culture system. The results of the present study suggested that the invasion ability of the SKOV3-PM4s was increased in the in vitro co-culture system of SKOV3-PM4 and HLECs. Therefore, alterations in the cell microenvironment may represent a novel strategy for ovarian cancer therapy.

MiR-23b targets cyclin G1 and suppresses ovarian cancer tumorigenesis and progression.

BackgroundIt has been proposed that cyclin G1 (CCNG1) participates in p53-dependent G1–S and G2 checkpoints and might function as an oncogenic protein in the initiation and metastasis of ovarian carcinoma. MicroRNA 23b (miR-23b) is a critical regulatory factor in the progression of many cancer cell types that targets the relevant genes.MethodsMiR-23b expression in ovarian tissues was quantified by quantitative reverse transcription–PCR. The ovarian cancer cell lines OVCAR3, HO8910-PM, and SKOV3/DDP were transfected with miR-23b, after we assayed the cell phenotype and expression of the relevant molecules. Dual-luciferase reporter assay and a xenograft mouse model were used to examine the expression of miR-23b and its target gene CCNG1.ResultsMIR23B mRNA expression was significantly lower in epithelial ovarian carcinoma and borderline tumors than in normal ovarian tissues and benign tumors, and miR-23b expression among ages and pathological subtypes was significantly different. CCNG1 mRNA expression was significantly lower in normal ovarian tissues than in benign tumors, borderline tumors, and ovarian carcinomas, and expression among pathological subtypes was significantly different. MiR-23b overexpression inhibited ovarian cancer cell proliferation, invasion, and migration, and induced apoptosis. Dual-luciferase reporter assay showed that miR-23b bound with the 3′ untranslated region of CCNG1. MiR-23b overexpression significantly downregulated CCNG1, urokinase, survivin, Bcl-xL, P70S6K, and matrix metallopeptidase-9 (MMP9) mRNA and protein expression. Furthermore, miR-23b inhibited tumor growth and suppressed CCNG1 expression in vitro.ConclusionsOur findings show that miR-23b may inhibit ovarian cancer tumorigenesis and progression by downregulating CCNG1 and the expression of the relevant genes. MiR-23b is a potentially novel application for regulating ovarian carcinoma progression.

Unexpected Metastasis of High Grade Serous Ovarian Cancer to Breast: Case Report and Literature Review

Introduction: Metastasis of ovarian serous carcinoma to breast and/or axillary lymph nodes represents an unusual event. Nevertheless, their detection and distinction from mammary carcinoma are of huge clinical importance because the treatment and prognosis diverge significantly. Case presentation: We report a case of a 47 year-old Caucasian female patient with unforeseen metastasis to the breast and to axillary lymph nodes due to ovarian serous carcinoma. Conclusion: In patients with history of OSC who present with axillary or breast mass, an accurate histological diagnosis should be obtained since this has a great impact on treatment outcomes.

Whole Genome Expression Profiling Analysis of Metastasis and Drug-resistance-related Genes in Epithelial Ovarian Cancer Cells

Objective To investigate the genes associated with higher ability of metastasis and chemotherapic resistance in epithelial ovarian carcinoma (EOC) by using Agilent whole genome oligonucleotide gene chip,with an attempt to further investigate the molecular mechanism of metastasis and chemotherapic resistance of EOC. Methods Oligonucleotide microarrays were used to determine whether gene expression profile might differentiate EOC cell lines (RMG-1-C,COC1 and HO8910) from their sub-lines (RMG-1-H,COC1/DDP and HO8910/PM) with higher ability of metastasis and chemotherapic resistance. Quantitative real-time polymerase chain reaction and immunohistochemical staining validated the microarray results. Results Gene expression profile identified 49 differentially expressed genes that showed≥2.0 fold change. All these differentially expressed genes were involved mainly in gene expression and biopolymer biosynthesis. Interaction network analysis predicted 21 genes participating in the regulatory connection. Highly differential expression of GCET2,CFTR,FOXP1 and GARS genes was validated by quantitative realtime polymerase chain reaction in all cell line samples,and the Results were consistent with microarray findings. Conclusion The change in the metastasis and chemotherapic resistance-associated gene expression profiles may provide a theoretical basis for studies on the molecular mechanisms of metastasis and chemotherapic resistance in EOC.

Abstract POSTER-TECH-1112: Quantitate epithelial-mesenchymal transition in ovarian cancer

Abstract Purpose: Metastases account for more than 90% of cancer deaths and hence, inhibiting metastasis is an attractive therapeutic option. Accumulating evidences show that invasion and metastasis of ovarian carcinoma could be driven by Epithelial-Mesenchymal Transition (EMT), a developmental program being employed during carcinoma progression. As EMT is a reversible process, inhibiting or reversing EMT thus emerges as a potential anti-metastasis strategy. EMT is a spectrum consisting of the binary epithelial and mesenchymal states as well as transitional intermediate states. Therefore, reversing EMT from the mesenchymal state would result in the sliding along an EMT Spectrum. Currently, there is no quantitative tool available to assess the EMT spectrum. In this study, we describe a bioinformatics method for quantitating EMT. Experimental procedure: By using immunofluorescence staining of E-cadherin and N-cadherin, we defined the most epithelial and most mesenchymal cells in a panel of ovarian carcinoma cell lines. We derived an EMT signature from Affymetrix gene expression microarrays of these cell lines. Subsequently, with a Kolmogorov-Smirnov-based method, we computed EMT score that assesses the similarity of an ovarian carcinoma cell transcriptome with the derived EMT signature. This method scores ovarian carcinoma cell lines in the range of [-1.0,+1.0] which corresponded to the extreme epithelial and mesenchymal states respectively along the EMT spectrum. We thus applied the EMT scoring to estimate EMT status in ovarian carcinoma tissues. Results: The EMT signature derived included known EMT inducers and markers such as ZEB1, ZEB2, SNAI2 and VIM. Expressions of selected markers such as ZEB1, VIM and FN1 were confirmed by immunofluorescence staining. Ovarian carcinoma cell lines displaying a mesenchymal morphology were accurately reflected as having high EMT scores. Cell lines with high EMT scores were anoikis resistant. In addition, ovarian carcinoma tissues displaying high EMT scores had poorer overall survival than those of low EMT scores. Correlation analysis of EMT scores and pathways revealed that ovarian carcinoma with high EMT scores are associated with increased TGFβ, WNT, NOTCH, and SRC signaling pathways. This suggested that inhibitors targeting these pathways could potentially reverse EMT. We thus treated mesenchymal ovarian carcinoma cell lines SKOV3, HEY, DOV13 with a SRC inhibitor, AZD0530. We observed a partial reversal of EMT evident by decreased EMT scores (-0.11 to -0.17) in these cells. Conclusions: EMT scoring could reflect both the EMT status of a sample and the transitional changes along the EMT spectrum upon intervening with inhibitors. Thus, EMT scoring presents a promising tool to assess the effectiveness of anti-EMT or EMT reversing compounds. Citation Format: Tuan Zea Tan, Ruby Yun-Ju Huang, Qing Hao Miow, Jieru Ye, Meng Kang Wong, Jieying Amelia Lau, Seiichi Mori, Jean Paul Thiery. Quantitate epithelial-mesenchymal transition in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1112.

Abstract 1679: Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian cancer

Abstract Ovarian carcinoma is the most crucial and difficult problem for therapeutic treatment in gynecological malignancies, which requires great efforts for an effective solution. Molecular studies have shown that chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 and its receptor CXCR4 are the key determinants of tumor initiation, progression and metastasis in ovarian carcinoma. It is also believed that blocking CXCR4-CXCL12 pathway plays potential roles in treating ovarian cancer patients. Recent studies also showed that the cytotoxic function of gamma delta (γ/δ) T lymphocytes could efficiently kill ovarian CSCs (cancer stem cells) and present a promising immunotherapy for ovarian cancer. To investigate how the CXCL12/CXCR4 pathway is involved in the regulation of ovarian cancer. We eliminated the expression of CXCR4 in different ovarian cancer cell lines using CXCR4 antagonist (e.g., AMD3100) and CXCR4 shRNA silencing to prevent the CXCR4/CXCL12 axis interaction. Besides, up to 78% of γ/δ T cells was expanded in-vitro using aminobisphosphonates plus low-dose interleukin-2 for the therapeutic investigating. The therapeutic effects following different treatments were measured. First, our results showed that blocking of Cxcr4/Cxcl12 axis by AMD3100 reduced around 37% on cell survival rate. Similar results were also observed in the CXCR4-shRNA silencing ovarian cancer cells. Additionally, the higher CXCR4-expressed cells were highly proliferation after CXCL12 stimulating compared to the CXCR4 non-expressed cells. Next, cancer cells treated with the exogenous activated γ/δ T cells showed a reduction of 35% on cell survival rate. Finally, the combined treatment strategy using AMD3100 plus γ/δ-T cells showed the most significant therapeutic effects in the high-grade ovarian cancer cells, and the cell survival rate was reduced almost to 50% after the cell cytotoxic assay. We therefore conclude that the limitation of CXCL12/CXCR4 activities combined with the γ/δ T cell cytotoxicity is a potent immunotherapy for treating ovarian cancer and would served as a promising new strategies for clinical translation. Citation Format: Chao Lien Liu, Tsui Lien Mao. Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian cancer. [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 1679. doi:10.1158/1538-7445.AM2015-1679

MiR-26b/KPNA2 axis inhibits epithelial ovarian carcinoma proliferation and metastasis through downregulating OCT4.

Karyopherin alpha 2 (KPNA2) is a nuclear transport protein upregulated in many cancers. Our previous study has identified KPNA2 overexpression in epithelial ovarian carcinoma (EOC) tissues, which predicts poor prognosis. However, the mechanism of KPNA2 overexpression in EOC remains unclear. This study aimed to examine the role of miRNA in KPNA2 dysregulation. Our results showed that miR-26b was downregulated in EOC samples, and correlated inversely with KPNA2 expression. Low expression of miR-26b was associated with advanced FIGO stage, poor differentiation, higher risk of distant metastasis and recurrence. Downregulation of miR-26b predicted poor disease-free survival and overall survival in EOC patients. KPNA2 was validated as a direct target of miR-26b. Knockdown of KPNA2 or ectopic expression of miR-26b could downregulate OCT4, vimentin and upregulate E-cadherin. Reintroduction of KPNA2 partially abrogated the suppression effect induced by miR-26b. We further verified that miR-26b/KPNA2/OCT4 axis inhibited EOC cell viability, migratory ability and sphere-forming capacity in vitro and in vivo. In conclusion, our results reveal that miR-26b is downregulated in EOC, and directly targets KPNA2. miR-26b/KPNA2 axis suppresses tumor proliferation and metastasis through decreasing OCT4 expression, which is indicative of the important role of miR-26b/KPNA2/OCT4 axis in EOC carcinogenesis and progression.

Effect of VTCN1 on progression and metastasis of ovarian carcinoma in vitro and vivo.

Through reducing immune response, VTCN1 could promote carcinoma indirectly. However, the direct effect of VTCN1 on carcinoma was not studied clearly, especially on ovarian carcinoma. In this paper, we verified the potential effect and mechanism of VTCN1 on ovarian carcinoma. The influence of high or low VTCN1 expression on the viability of ovarian cancer was detected by CKK-8 and annexin V-PI kit. The orthotopicxenograft tumor model was performed to evaluate the effect of VTCN1 on the promotion of tumor in vivo. Western blot was used to verify the signaling pathways predicted by bioinformatics analysis. Low expression of VTCN1 could inhibit the viability and metastasis of ovarian carcinoma directly in vitro and vivo; Information analysis demonstrated that cell cycle and JAK2/STAT were involved in the regulation of VTCN1. The CDK2/4 and CDC25C expression and phosphorylation of JAK2/STAT had a direct relationship with the reduction of VTCN1. VTCN1 could affect the viability and metastasis of ovarian carcinoma by reducing the expression of CDK2/4 and CDC25C and phosphorylation of JAK2/STAT. It indicated that VTCN1 was a potential target for treating ovarian carcinoma.

Breast Metastasis of Serous Ovarian Papillary Carcinoma: A Report of Two Cases Diagnosed by Fine-Needle Aspiration

Breast metastases from gynecologic cancer are infrequent and are mainly from the ovary. They usually appear in advanced stages and have poor survival rates after diagnosis. Two cases of breast metastasis of serous ovarian carcinoma are presented. In both cases fine-needle aspiration (FNA) study of breast revealed a lesion with morphologic characteristics of serous carcinoma, while one of them was with immunocytochemical study. Origin was confirmed by histological examination of this lesion.

Gene expression profile analysis identifies metastasis and chemoresistance-associated genes in epithelial ovarian carcinoma cells.

The purpose of this study was to identify genes that associated with higher ability of metastasis and chemotherapic resistance in epithelial ovarian carcinoma (EOC) cells. An oligonucleotide microarray with probe sets complementary to 41,000+ unique human genes and transcripts was used to determine whether gene expression profile may differentiate three epithelial ovarian cell lines (RMG-I-C, COC1 and HO8910) from their sub-lines (RMG-I-H, COCI/DDP and HO8910/PM) with higher ability of metastasis and chemotherapic resistance. Quantitative real-time PCR and immunohistochemical staining validated the microarray results. Hierarchic cluster analysis of gene expression identified 49 genes that exhibited ≥2.0-fold change and P value ≤0.05. Highly differential expression of GCET2, NLRP4, FOXP1 and SNX29 genes was validated by quantitative PCR in all cell line samples. Finally, FOXP1 was validated at the protein level by immunohistochemistry in paraffin embedded ovarian tissues (i.e., for metastasis, 15 primary EOC and 10 omental metastasis [OM]; for chemoresistance, 13 sensitive and 13 resistant EOC). The identification of higher ability of metastasis and chemotherapic resistance-associated genes may provide a foundation for the development of new type-specific diagnostic strategies and treatment for metastasis and chemotherapic resistance in epithelial ovarian cancer.

P08.05 * INTRACRANIAL METASTASES IN PATIENTS WITH OVARIAN CARCINOMA

Brain metastases in patients with ovarian carcinoma are extremely rare. Only 1.7% of these patients develop brain metastases. The prognosis in these patients appears to be poor.We report 4 female patients with intracranial single metastase who were treated in our institution within the last 2 years. The age of the patients at time of operation were 43, 66, 74 and 76 years. The interval between diagnosis of ovarian carcinoma and brain metastasis was 3 years in 2 patients, 4 and 7 years. Two patients had supratentorial metastasis in the frontal lobe and the other 2 were located infratentorially in the cerebellum. Histopathological examinations showed typical signs of metastasis of the primary carcinoma. Postoperative outcome was good and further radio- and chemotherapy was performed. Interdisciplinary management with the gynecologists is mandatory. Though brain metastases of ovarian cancer is very rare it has to be kept in mind in the preoperative differential diagnosis and planning of the operation. Mean average age is 54 years and mean interval between diagnosis of ovarian carcinoma and metastases is about 2 years. Median survival time postoperatively is about 6 months.

Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor

BackgroundWe previously reported that polyploid giant cancer cells (PGCCs) exhibit cancer stem cell properties and express cell cycle-related proteins. HEY PGCCs induced by cobalt chloride generated daughter cells and the daughter cells had a strong migratory and invasive ability. This study is to compare the expression of cyclin E, S-phase kinase-associated protein 2 (SKP2), and stathmin between PGCCs with budding and control HEY cells, and determine the clinicopathological significance of cell cycle-related protein expression in ovarian tumors.MethodsWe used western blot and immunocytochemical staining to compare the expression levels of cyclin E, SKP2 and stathmin between PGCC with budding daughter cells and control HEY cells. In addition, immunohistochemical staining for cyclin E, SKP2 and stathmin was performed on a total of 80 paraffin-embedded serous ovarian tumor tissue samples. The samples included 21 cases of primary high-grade carcinoma (group I) and their metastatic tumors (group II), 26 cases of primary low-grade carcinoma without metastasis (group III), and 12 cases of serous borderline cystadenoma (group IV).ResultsSingle PGCC with budding in the stroma showed high correlation with the metastasis of ovarian carcinoma. Group I had a significantly higher number of single PGCCs with budding in the stroma than group III (85.71% [18/21] vs. 23.08% [6/26] cases; χ2 = 18.240, P = 0.000). The expression of cyclin E, SKP2, and stathmin was compared among the four groups. The expression levels of cyclin E, SKP2, and stathmin increased with the malignant grade of ovarian tumors and group II had the highest expression levels. The expression of cyclin E (χ2 = 17.985, P = 0.000), SKP2 (χ2 = 12.384, P = 0.000), and stathmin (χ2 = 20.226, P = 0.000) was significantly different among the 4 groups.ConclusionsThese data suggest that the cell cycle-related proteins cyclin E, SKP2, and stathmin may be valuable biomarkers to evaluate the metastasis in patients with ovarian serous carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-576) contains supplementary material, which is available to authorized users.

A late, solitary brain metastasis of epithelial ovarian carcinoma

BackgroundBrain metastasis from epithelial ovarian cancer (EOC) is very rare with a reported incidence of less than 2%. It is usually associated with a poor prognosis that is related to several factors, the most important including: single vs multiple lesions, performance status, platinum-sensitive disease, tumor grade, extracranial disease, and multimodal approach treatment. At the time of diagnosis, an extracranial disease is found in over half of patients. The most common histology is the serous type. The median time from primary diagnosis to development of cerebral lesions is directly correlated to initial tumor grade and stage. Several therapeutic approaches can be proposed, including best supportive care +/- corticosteroids, surgery, radiotherapy and chemotherapy. A multimodal therapy approach may achieve an improved outcome and should therefore be utilized whenever applicable.Case presentationWe present the case of a patient with a solitary brain metastasis which appeared 11 years after a locally advanced and aggressive EOC (FIGO stage III C) and which totally regressed after surgery and adjuvant chemotherapy. Clinically, she showed progressive headaches, decreased visual acuity, balance and memory disorders associated with a confusional state. Brain CT scan and MRI documented a solitary, necrotic lesion in the left central parietal region with an important cerebral surrounding edema and initial cranial herniation. No other extracranial metastases were observed at the PET scan. Laboratory tests were in the normal range and CA 125 was moderatly increased at 81 UI/ml. The patient underwent surgical removal of tumor lesion, post-surgical whole-brain radiotherapy (WBRT) and systemic chemotherapy with carboplatin alone for six cycles. At a follow-up of 13 months, she is alive, in good clinical condition and tumor progression free.ConclusionThe peculiarity of this case relies on the isolated brain relapse of a BRCA-1/BRCA-2 non-mutated EOC, which is uncommon and rare, and to the very long time, of 11 years, from diagnosis of primary cancer and development of brain metastasis. A multimodal, aggressive approach of this isolated brain metastasis led to a complete and prolonged tumor control.

MACC1 induces metastasis in ovarian carcinoma by upregulating hepatocyte growth factor receptor c-MET.

Metastasis-associated in colon cancer 1 (MACC1) is a newly identified gene that has been shown to promote tumor cell invasion and metastasis. The present study investigated the effect of MACC1 downregulation on the biological characteristics of the ovarian cancer OVCAR3 cell line. In this study, MACC1 expression was blocked using the RNA interference technique. The downregulation of MACC1 mRNA and protein expression was confirmed using quantitative polymerase chain reaction and western blot analysis. The proliferative activity and adhesion rate of the cells were detected using cell counting kit-8 and a cell adhesion assay, while cell invasion was determined using a Matrigel invasion assay and migration capacity was observed using migration and wound-healing assays. A tube formation assay was also used to examine the angiogenic capacity of cells, and a luciferase assay was performed to assess whether MACC1 binds to the c-MET gene. The MACC1 mRNA and protein expression levels were significantly downregulated using sequence-specific small interfering RNA (siRNA). The inhibition of MACC1 expression markedly decreased the invasive, metastatic and angiogenic capacities of the cells, but only slightly inhibited growth and adhesion. In addition, a putative MACC1-binding site was identified in the 3′-untranslated region of c-MET. MACC1-siRNA was also found to significantly reduce the expression of the c-MET protein and a luciferase reporter assay confirmed that c-MET was the target gene of MACC1. These results demonstrated that the attenuation of MACC1 suppresses cell invasion and migration and that MACC1 may regulate cell metastasis through targeting the expression of c-MET. Inhibition of the function of MACC1 may represent a new strategy for treating ovarian cancer.

Splenic metastasis of ovarian clear cell adenocarcinoma: A case report and review of the literature

Splenic metastasis of ovarian cancer appears to be more common in serous cystadenocarcinomas. Splenic metastasis usually occurs postoperatively and simultaneously with dissemination to the greater omentum and pelvic cavity. Compared with other ovarian cancer subtypes, ovarian clear cell adenocarcinoma (OCCA) is rare, accounting for <5% of all ovarian malignancies. OCCA has a distinct histological type with poor prognosis and resistance to platinum-based chemotherapy. In the present study, a case of isolated splenic metastasis of OCCA was reported. A 53-year-old female presented with a mass in the left upper quadrant without any other clinical manifestations. Subsequent abdominal and pelvic computed tomography scans revealed multiple mixed cystic-solid lesions, potentially predicting ovarian malignancy. Pathological tests following ovarian cytoreductive surgery revealed primary OCCA with metastases to the spleen. The current study also reviewed recently published literature on splenic metastasis of ovarian carcinoma and demonstrated that the reported case was a rare case of isolated splenic metastasis of OCCA.

Clinicopathologic significance of claudin-6, occludin, and matrix metalloproteinases −2 expression in ovarian carcinoma

BackgroundTight junctions (TJs) are mainly composed of claudins, occludin, and tight junction adhesion molecules (JAM). The invasive and metastatic phenotype of highly invasive cancer cells has been related to abnormal structure and function of TJs, and with expression of activated matrix metalloproteinases (MMPs). The relevance of these mechanisms responsible for the invasion and metastasis of ovarian carcinoma is unclear. Similarly, it is not known if the expression of claudin-6, occludin and MMP2 is related with the clinical properties of these tumors.MethodsExpression of claudin-6, occludin, and MMP2 was detected in samples of human ovarian cancer tissues by immunohistochemistry and correlated with the clinical properties of the tumors.ResultsThe positive expression rates of claudin-6 and MMP-2 were higher in ovarian papillary serous carcinomas than n ovarian serous adenomas (P < 0.05). There were no differences in the expression of occludin (P > 0.05). The expression of claudin-6 and occludin in ovarian cancer was not correlated with patient age, pathological grade, clinical stage, and metastasis (P > 0.05). MMP-2 expression was enhanced with increased clinical stage and metastasis (P < 0.05), but was unrelated to patient age or tumor grade (P > 0.05). There were no apparent correlations between expression of claudin-6, occludin and MMP-2 in ovarian cancer tissue (P > 0.05).ConclusionsOur data suggest, for the first time, that the claudin-6 and MMP-2 are up-regulated in ovarian papillary serous carcinomas, MMP-2 expression was enhanced with increased clinical stage and metastasis. Claudin-6 and MMP-2 may play a positive role in the invasion and metastasis of ovarian cancer.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1775628454106511.