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Special Issue "Cancer Molecules in Ovarian Cancer 2012"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 June 2012)

Special Issue Editor

Guest Editor
Prof. Dr. Ie-Ming Shih

Department of Pathology, Faculty in Pathobiology PhD Graduate Program, Johns Hopkins University, School of Medicine, CRB-II, Rm 305, 1550 Orleans Street, Baltimore, Maryland 21231, USA
Website | E-Mail
Fax: +1 410 502 7943
Interests: cancer pathogenesis; gene amplification; gene mutation; differential diagnosis; genome-wide analysis of human cancer

Special Issue Information

Dear Colleagues,

Ovarian cancer is a highly aggressive neoplastic disease in women. It is well accepted that identification and characterization of ovarian cancer-associated genes are fundamental toward elucidating its pathogenesis and providing new opportunity for cancer detection and therapy. Many investigators over the past several years have diligently applied several new technologies to study the molecular landscape of ovarian cancer. Importantly, the Cancer Genome Atlas (TCGA) project has recently deposited unprecedented amount of data on molecular characteristics of ovarian high-grade serous carcinoma. This special issue timely honors these new advances and cordially invites the publications of new cancer-associated molecules and the pathways that are important to understand the pathogenesis and provide new molecular landscape in designing targeted therapy in ovarian cancer. Specifically, we welcome the manuscripts that report molecules that are related to molecular etiology, biomarkers for detections and diagnosis, and molecular targets for new therapeutics. Manuscripts reporting analysis of the TCGA database and new revelation of molecular signatures pertaining to clinical outcome are specially encouraged to submit. Review articles that succinctly summarize recent advances in the fields as mentioned above are also very welcome.

Prof. Dr. Ie-Ming Shih
Guest Editor

Keywords

  • ovarian cancer
  • TCGA
  • pathogenesis
  • pathology
  • markers
  • detection
  • genomics
  • diagnosis
  • target therapy
  • prognosis

Published Papers (10 papers)

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Research

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Open AccessArticle NotI Microarrays: Novel Epigenetic Markers for Early Detection and Prognosis of High Grade Serous Ovarian Cancer
Int. J. Mol. Sci. 2012, 13(10), 13352-13377; doi:10.3390/ijms131013352
Received: 10 August 2012 / Revised: 12 September 2012 / Accepted: 12 September 2012 / Published: 18 October 2012
Cited by 13 | PDF Full-text (938 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Chromosome 3-specific NotI microarray (NMA) containing 180 clones with 188 genes was used in the study to analyze 18 high grade serous ovarian cancer (HGSOC) samples and 7 benign ovarian tumors. We aimed to find novel methylation-dependent biomarkers for early detection and
[...] Read more.
Chromosome 3-specific NotI microarray (NMA) containing 180 clones with 188 genes was used in the study to analyze 18 high grade serous ovarian cancer (HGSOC) samples and 7 benign ovarian tumors. We aimed to find novel methylation-dependent biomarkers for early detection and prognosis of HGSOC. Thirty five NotI markers showed frequency of methylation/deletion more or equal to 17%. To check the results of NMA hybridizations several samples for four genes (LRRC3B, THRB, ITGA9 and RBSP3 (CTDSPL)) were bisulfite sequenced and confirmed the results of NMA hybridization. A set of eight biomarkers: NKIRAS1/RPL15, THRB, RBPS3 (CTDSPL), IQSEC1, NBEAL2, ZIC4, LOC285205 and FOXP1, was identified as the most prominent set capable to detect both early and late stages of ovarian cancer. Sensitivity of this set is equal to (72 ± 11)% and specificity (94 ± 5)%. Early stages represented the most complicated cases for detection. To distinguish between Stages I + II and Stages III + IV of ovarian cancer the most perspective set of biomarkers would include LOC285205, CGGBP1, EPHB1 and NKIRAS1/RPL15. The sensitivity of the set is equal to (80 ± 13)% and the specificity is (88 ± 12)%. Using this technique we plan to validate this panel with new epithelial ovarian cancer samples and add markers from other chromosomes. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessArticle MUC16/CA125 in the Context of Modular Proteins with an Annotated Role in Adhesion-Related Processes: In Silico Analysis
Int. J. Mol. Sci. 2012, 13(8), 10387-10400; doi:10.3390/ijms130810387
Received: 19 June 2012 / Revised: 23 July 2012 / Accepted: 9 August 2012 / Published: 21 August 2012
PDF Full-text (194 KB) | HTML Full-text | XML Full-text
Abstract
Mucin 16 (MUC16) is a type I transmembrane protein, the extracellular portion of which is shed after proteolytic degradation and is denoted as CA125 antigen, a well known tumor marker for ovarian cancer. Regarding its polypeptide and glycan structures, as yet there is
[...] Read more.
Mucin 16 (MUC16) is a type I transmembrane protein, the extracellular portion of which is shed after proteolytic degradation and is denoted as CA125 antigen, a well known tumor marker for ovarian cancer. Regarding its polypeptide and glycan structures, as yet there is no detailed insight into their heterogeneity and ligand properties, which may greatly influence its function and biomarker potential. This study was aimed at obtaining further insight into the biological capacity of MUC16/CA125, using in silico analysis of corresponding mucin sequences, including similarity searches as well as GO (gene ontology)-based function prediction. The results obtained pointed to the similarities within extracellular serine/threonine rich regions of MUC16 to sequences of proteins expressed in evolutionary distant taxa, all having in common an annotated role in adhesion-related processes. Specifically, a homology to conserved domains from the family of herpesvirus major outer envelope protein (BLLF1) was found. In addition, the possible involvement of MUC16/CA125 in carbohydrate-binding interactions or cellular transport of protein/ion was suggested. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessArticle Chick Chorioallantoic Membrane (CAM) Assay as an In Vivo Model to Study the Effect of Newly Identified Molecules on Ovarian Cancer Invasion and Metastasis
Int. J. Mol. Sci. 2012, 13(8), 9959-9970; doi:10.3390/ijms13089959
Received: 2 July 2012 / Revised: 27 July 2012 / Accepted: 2 August 2012 / Published: 10 August 2012
Cited by 51 | PDF Full-text (221 KB) | HTML Full-text | XML Full-text
Abstract
The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Significant improvement in ovarian cancer survival will require the development of more effective molecularly targeted therapeutics. Commonly, mouse models are used for the in vivo assessment
[...] Read more.
The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Significant improvement in ovarian cancer survival will require the development of more effective molecularly targeted therapeutics. Commonly, mouse models are used for the in vivo assessment of potential new therapeutic targets in ovarian cancer. However, animal models are costly and time consuming. Other models, such as the chick embryo chorioallantoic membrane (CAM) assay, are therefore an attractive alternative. CAM assays have been widely used to study angiogenesis and tumor invasion of colorectal, prostate and brain cancers. However, there have been limited studies that have used CAM assays to assess ovarian cancer invasion and metastasis. We have therefore developed a CAM assay protocol to monitor the metastatic properties of ovarian cancer cells (OVCAR-3, SKOV-3 and OV-90) and to study the effect of potential therapeutic molecules in vivo. The results from the CAM assay are consistent with cancer cell motility and invasion observed in in vitro assays. Our results demonstrate that the CAM assay is a robust and cost effective model to study ovarian cancer cell metastasis. It is therefore a very useful in vivo model for screening of potential novel therapeutics. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessArticle Methods for Identification of CA125 from Ovarian Cancer Ascites by High Resolution Mass Spectrometry
Int. J. Mol. Sci. 2012, 13(8), 9942-9958; doi:10.3390/ijms13089942
Received: 15 May 2012 / Revised: 11 July 2012 / Accepted: 24 July 2012 / Published: 9 August 2012
Cited by 6 | PDF Full-text (589 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
CA125 is the most widely used tumour marker in ovarian cancer with unsatisfactory sensitivity and specificity especially at early stage. It is quantified by antibody-based immunoassays; however different molecular weight isoforms have been described in the literature which have never been validated by
[...] Read more.
CA125 is the most widely used tumour marker in ovarian cancer with unsatisfactory sensitivity and specificity especially at early stage. It is quantified by antibody-based immunoassays; however different molecular weight isoforms have been described in the literature which have never been validated by mass spectrometry, potentially affecting the diagnostic accuracy and clinical reliability of the test. In this study, CA125 was detected by Western blot and its identity confirmed by mass spectrometry. Two-dimensional (2D) gel electrophoresis in combination with mass spectrometry revealed that positive Western blot signals up to 500 kDa are most likely false-positive interactions of M11-like and OC125-like antibodies. Fibronectin, identified as one of these false-positive interaction partners, increased the reading for CA125 in a first generation ELISA significantly (p = 0.02). The existence of low-molecular weight isoforms of CA125 is therefore questionable and is most likely reflecting cross-reactivity of the antibodies with other proteins. This would explain the conflicting reports on the molecular structure of CA125 and also the inconsistency of CA125 levels by different ELISAs. Our results are also the first steps towards a mass spectrometric assay for CA125 quantification, which would improve sensitivity and reliability. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessArticle Effects of Cyclooxygenase Inhibitors in Combination with Taxol on Expression of Cyclin D1 and Ki-67 in a Xenograft Model of Ovarian Carcinoma
Int. J. Mol. Sci. 2012, 13(8), 9741-9753; doi:10.3390/ijms13089741
Received: 18 June 2012 / Revised: 22 July 2012 / Accepted: 27 July 2012 / Published: 3 August 2012
Cited by 5 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
The present study was designed to investigate the effects of cyclooxygenase (COX) inhibitors in combination with taxol on the expression of cyclin D1 and Ki-67 in human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 100 mg/kg celecoxib (a COX-2
[...] Read more.
The present study was designed to investigate the effects of cyclooxygenase (COX) inhibitors in combination with taxol on the expression of cyclin D1 and Ki-67 in human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 100 mg/kg celecoxib (a COX-2 selective inhibitor) alone, 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone by gavage twice a day, 20 mg/kg taxol alone by intraperitoneally (i.p.) once a week, or celecoxib/taxol, SC-560/celecoxib, SC-560/taxol or SC-560/celecoxib/taxol, for three weeks. To test the mechanism of the combination treatment, the index of cell proliferation and expression of cyclin D1 in tumor tissues were determined by immunohistochemistry. The mean tumor volume in the treated groups was significantly lower than control (p < 0.05), and in the three-drug combination group, tumor volume was reduced by 58.27% (p < 0.01); downregulated cell proliferation and cyclin D1 expression were statistically significant compared with those of the control group (both p < 0.01). This study suggests that the effects of COX selective inhibitors on the growth of tumors and decreased cell proliferation in a SKOV-3 cells mouse xenograft model were similar to taxol. The three-drug combination showing a better decreasing tendency in growth-inhibitory effect during the experiment may have been caused by suppressing cyclin D1 expression. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)

Review

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Open AccessReview Ovarian Cancer: In Search of Better Marker Systems Based on DNA Repair Defects
Int. J. Mol. Sci. 2013, 14(1), 640-673; doi:10.3390/ijms14010640
Received: 27 August 2012 / Revised: 14 December 2012 / Accepted: 24 December 2012 / Published: 4 January 2013
Cited by 10 | PDF Full-text (798 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer is the fifth most common female cancer in the Western world, and the deadliest gynecological malignancy. The overall poor prognosis for ovarian cancer patients is a consequence of aggressive biological behavior and a lack of adequate diagnostic tools for early detection.
[...] Read more.
Ovarian cancer is the fifth most common female cancer in the Western world, and the deadliest gynecological malignancy. The overall poor prognosis for ovarian cancer patients is a consequence of aggressive biological behavior and a lack of adequate diagnostic tools for early detection. In fact, approximately 70% of all patients with epithelial ovarian cancer are diagnosed at advanced tumor stages. These facts highlight a significant clinical need for reliable and accurate detection methods for ovarian cancer, especially for patients at high risk. Because CA125 has not achieved satisfactory sensitivity and specificity in detecting ovarian cancer, numerous efforts, including those based on single and combined molecule detection and “omics” approaches, have been made to identify new biomarkers. Intriguingly, more than 10% of all ovarian cancer cases are of familial origin. BRCA1 and BRCA2 germline mutations are the most common genetic defects underlying hereditary ovarian cancer, which is why ovarian cancer risk assessment in developed countries, aside from pedigree analysis, relies on genetic testing of BRCA1 and BRCA2. Because not only BRCA1 and BRCA2 but also other susceptibility genes are tightly linked with ovarian cancer-specific DNA repair defects, another possible approach for defining susceptibility might be patient cell-based functional testing, a concept for which support came from a recent case-control study. This principle would be applicable to risk assessment and the prediction of responsiveness to conventional regimens involving platinum-based drugs and targeted therapies involving poly (ADP-ribose) polymerase (PARP) inhibitors. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessReview Hyaluronan Synthase and Hyaluronidase Expression in Serous Ovarian Carcinoma is Related to Anatomic Site and Chemotherapy Exposure
Int. J. Mol. Sci. 2012, 13(10), 12925-12938; doi:10.3390/ijms131012925
Received: 3 August 2012 / Revised: 19 September 2012 / Accepted: 29 September 2012 / Published: 10 October 2012
Cited by 5 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The present study investigated the expression and clinical role of hyaluronan synthases (HAS1-3) and hyaluronidases (Hyal1-3) in serous ovarian carcinoma. HAS and HYAL mRNA expression was analyzed in 97 tumors (61 effusions, 27 primary carcinomas, 9 solid metastases) using PCR and further studied
[...] Read more.
The present study investigated the expression and clinical role of hyaluronan synthases (HAS1-3) and hyaluronidases (Hyal1-3) in serous ovarian carcinoma. HAS and HYAL mRNA expression was analyzed in 97 tumors (61 effusions, 27 primary carcinomas, 9 solid metastases) using PCR and further studied for association with clinicopathologic parameters, including survival. HAS1 mRNA was overexpressed in effusions compared to primary carcinomas and solid metastases (p < 0.001), and an alternatively spliced HAS1 was expressed only in effusions. HAS2 mRNA was overexpressed in solid metastases and primary carcinomas compared to effusions (p = 0.043), and HAS3 mRNA was overexpressed in primary carcinomas and effusions compared to solid metastases (p = 0.008). HYAL1 mRNA was absent in all specimens, whereas HYAL2 was expressed as two splice variants, of which HYAL2-var2 was overexpressed in solid metastases compared to effusions and primary carcinomas (p < 0.001). HYAL3 mRNA was expressed as wild-type and variant 1-3 form, the latter more highly in primary carcinomas and effusions compared to solid metastases (p = 0.006). HAS1 mRNA was overexpressed in pre- compared to post-chemotherapy effusions (p < 0.001), with opposite finding for HYAL2-var1 and HYAL3-WT (p = 0.016 and p = 0.024, respectively). Higher HYAL2-var1 and HAS1 splice variant mRNA expression in effusions was associated with longer (p = 0.033) and shorter (p = 0.047) overall survival, respectively. These data are the first to document a role for HAS and Hyal members in tumor progression in ovarian carcinoma, as evidenced by their differential expression as function of anatomic site and chemotherapy exposure, with a possible prognostic role for patients with malignant effusions. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessReview Mechanisms of Ovarian Cancer Metastasis: Biochemical Pathways
Int. J. Mol. Sci. 2012, 13(9), 11705-11717; doi:10.3390/ijms130911705
Received: 4 July 2012 / Revised: 31 August 2012 / Accepted: 3 September 2012 / Published: 18 September 2012
Cited by 11 | PDF Full-text (193 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with
[...] Read more.
Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with peritoneal dissemination. There is often no clearly identifiable precursor lesion; therefore, the events leading to metastatic disease are poorly understood. This article reviews metastatic suppressor genes, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment as they relate to ovarian cancer metastasis. Additionally, novel chemotherapeutic agents targeting the metastasis-related biochemical pathways are discussed. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessReview Deciphering the Molecular Nature of Ovarian Cancer Biomarker CA125
Int. J. Mol. Sci. 2012, 13(8), 10568-10582; doi:10.3390/ijms130810568
Received: 2 July 2012 / Revised: 3 July 2012 / Accepted: 13 August 2012 / Published: 22 August 2012
Cited by 13 | PDF Full-text (1013 KB) | HTML Full-text | XML Full-text
Abstract
The ovarian cancer biomarker CA125 has been extensively investigated over the last 30 years. The knowledge about the exact molecular nature of this protein, however, remains fragmented. This review provides an overview of the structural research regarding CA125, and presents an orthogonal verification
[...] Read more.
The ovarian cancer biomarker CA125 has been extensively investigated over the last 30 years. The knowledge about the exact molecular nature of this protein, however, remains fragmented. This review provides an overview of the structural research regarding CA125, and presents an orthogonal verification method to confirm the identity of this molecule. The need for independent identification of CA125 is exemplified by several reports where mutually exclusive data concerning the existence of isoforms and the glycan moieties is presented. Mass spectrometry can overcome the pitfalls of a single detection/identification method such as antibody probing. Independent verification of CA125 identity in characterization studies will help establish a refined model of its molecular structure that will promote the development of new approaches for diagnosis, prognosis and therapy of ovarian cancer. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)
Open AccessReview Transforming Growth Factor-Beta-Induced Protein (TGFBI)/(βig-H3): A Matrix Protein with Dual Functions in Ovarian Cancer
Int. J. Mol. Sci. 2012, 13(8), 10461-10477; doi:10.3390/ijms130810461
Received: 30 June 2012 / Revised: 3 August 2012 / Accepted: 16 August 2012 / Published: 21 August 2012
Cited by 20 | PDF Full-text (3264 KB) | HTML Full-text | XML Full-text
Abstract
Transforming growth factor-beta-induced protein (TGFBI, also known as βig-H3 and keratoepithelin) is an extracellular matrix protein that plays a role in a wide range of physiological and pathological conditions including diabetes, corneal dystrophy and tumorigenesis. Many reports indicate that βig-H3 functions as a
[...] Read more.
Transforming growth factor-beta-induced protein (TGFBI, also known as βig-H3 and keratoepithelin) is an extracellular matrix protein that plays a role in a wide range of physiological and pathological conditions including diabetes, corneal dystrophy and tumorigenesis. Many reports indicate that βig-H3 functions as a tumor suppressor. Loss of βig-H3 expression has been described in several cancers including ovarian cancer and promoter hypermethylation has been identified as an important mechanism for the silencing of the TGFBI gene. Our recent findings that βig-H3 is down-regulated in ovarian cancer and that high concentrations of βig-H3 can induce ovarian cancer cell death support a tumor suppressor role. However, there is also convincing data in the literature reporting a tumor-promoting role for βig-H3. We have shown βig-H3 to be abundantly expressed by peritoneal cells and increase the metastatic potential of ovarian cancer cells by promoting cell motility, invasion, and adhesion to peritoneal cells. Our findings suggest that βig-H3 has dual functions and can act both as a tumor suppressor or tumor promoter depending on the tumor microenvironment. This article reviews the current understanding of βig-H3 function in cancer cells with particular focus on ovarian cancer. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer 2012)

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