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Special Issue "Cancer Molecules in Ovarian Cancer"

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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 November 2010)

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. The molecular etiology of ovarian cancer remains elusive and the attempts to develop effective early detection and treatment for ovarian cancer patients are empirical. Identification and characterization of ovarian cancer-associated genes are fundamental steps toward elucidating its pathogenesis and providing new opportunity for cancer detection and therapy. To this end, many research teams over the past several years have applied several new technologies to study the molecular landscape of ovarian cancer. This special issue timely honors these new advances and cordially invites the publications of new ovarian cancer-associated molecules and the pathways that may shed new light into the pathogenesis of this devastating disease. Specifically, we welcome the manuscripts that report molecules and pathways that i) may be involved in molecular etiology, ii) could be used as potential biomarkers for detections and diagnosis, and iii) may be served as promising molecular targets for new therapeutics in ovarian cancer. Review articles that succinctly summarize recent advances in the fields as mentioned above are also very welcome. Translational research such as applications of markers of ovarian cancer for differential diagnosis and prognostic prediction is also the focus in this special issue.

Ie-Ming Shih
Guest Editor

Related Journal

Cancers

Keywords

  • ovarian cancer
  • pathogenesis
  • pathology
  • markers
  • detection
  • Notch
  • diagnosis
  • target therapy
  • prognosis

Published Papers (11 papers)

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Research

Jump to: Review

Open AccessArticle Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation
Int. J. Mol. Sci. 2011, 12(2), 1334-1358; doi:10.3390/ijms12021334
Received: 17 January 2011 / Revised: 12 February 2011 / Accepted: 12 February 2011 / Published: 22 February 2011
Cited by 16 | PDF Full-text (1197 KB) | HTML Full-text | XML Full-text
Abstract
Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved
[...] Read more.
Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients’ ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients’ ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Expression and Clinical Role of Protein of Regenerating Liver (PRL) Phosphatases in Ovarian Carcinoma
Int. J. Mol. Sci. 2011, 12(2), 1133-1145; doi:10.3390/ijms12021133
Received: 18 November 2010 / Revised: 26 January 2011 / Accepted: 7 February 2011 / Published: 11 February 2011
Cited by 9 | PDF Full-text (462 KB) | HTML Full-text | XML Full-text
Abstract
The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was
[...] Read more.
The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Identification of Receptor Tyrosine Kinase, Discoidin Domain Receptor 1 (DDR1), as a Potential Biomarker for Serous Ovarian Cancer
Int. J. Mol. Sci. 2011, 12(2), 971-982; doi:10.3390/ijms12020971
Received: 20 December 2010 / Revised: 18 January 2011 / Accepted: 18 January 2011 / Published: 31 January 2011
Cited by 11 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis,
[...] Read more.
Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, and represent potential targets for anticancer therapies. In this study, we performed cDNA subtraction following polymerase chain reaction (PCR) using degenerate oligonucleotide primers to identify specifically overexpressed PTKs in ovarian cancer. Three PTKs, janus kinase 1, insulin-like growth factor 1 receptor, and discoidin domain receptor 1 (DDR1), were identified and only DDR1 was overexpressed in all ovarian cancer tissues examined for the validation by quantitative real-time PCR. The DDR1 protein was expressed in 63% (42/67) of serous ovarian cancer tissue, whereas it was undetectable in normal ovarian surface epithelium. DDR1 was expressed significantly more frequently in high-grade (79%) and advanced stage (77%) tumors compared to low-grade (50%) and early stage (43%) tumors. The expression of the DDR1 protein significantly correlated with poor disease-free survival. Although its functional role and clinical utility remain to be examined in future studies, our results suggest that the expression of DDR1 may serve as both a potential biomarker and a molecular target for advanced ovarian cancer. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Combined Effects of Cyclooxygenase-1 and Cyclooxygenase-2 Selective Inhibitors on Ovarian Carcinoma in Vivo
Int. J. Mol. Sci. 2011, 12(1), 668-681; doi:10.3390/ijms12010668
Received: 30 November 2010 / Revised: 28 December 2010 / Accepted: 10 January 2011 / Published: 18 January 2011
Cited by 24 | PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 selective
[...] Read more.
The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 selective inhibitor) alone, or SC-560/celecoxib by gavage, twice a day for three weeks. To test the mechanism of inhibition of tumor growth by COX selective inhibitors, the index of proliferating cells in tumor tissues was determined by immunostaining and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. The inhibitory rate on tumor growth in the combination group was 35.54% which is significant statistically compared with that of the control group (P < 0.05). In the combination group, the index of cell proliferation and apoptosis were 12.40% and 51.03% respectively, which are significant statistically compared with those of the control group (22.56%, 19.07%, all P < 0.05). These studies indicate that synergism between two COX inhibitors and inhibitor combination treatment has particular potential for chemoprevention of ovarian cancer growth. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Clinicopathological Significance of Loss of ARID1A Immunoreactivity in Ovarian Clear Cell Carcinoma
Int. J. Mol. Sci. 2010, 11(12), 5120-5128; doi:10.3390/ijms11125120
Received: 1 December 2010 / Revised: 8 December 2010 / Accepted: 8 December 2010 / Published: 13 December 2010
Cited by 54 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein
[...] Read more.
Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein and inactivation of the putative tumor suppressor. In this study, we determined the significance of loss of ARID1A immunoreactivity with respect to several clinicopathological features in a total of 149 OCCCs. First, we demonstrated that ARID1A immunohistochemistry showed concordance with the mutational status in 91% of cases with 100% sensitivity and 66% specificity. Specifically, among 12 OCCC cases for which ARIDA mutational status was known, ARIDIA immunoreactivity was undetectable in all 9 cases harboring ARID1A mutations and was undetectable in one of 3 cases with wild-type ARID1A. With respect to the entire cohort, ARID1A immunoreactivity was undetectable in 88 (59%) of 149 OCCCs. There was no significant difference between ARID1A negative and positive cases in terms of histopathologic features, age, clinical stage, or overall survival. In conclusion, this study provides further evidence that mutations in ARID1A resulted in loss of ARID1A protein expression in OCCC, although no significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Lewis (y) Antigen Overexpression Increases the Expression of MMP-2 and MMP-9 and Invasion of Human Ovarian Cancer Cells
Int. J. Mol. Sci. 2010, 11(11), 4441-4451; doi:10.3390/ijms11114441
Received: 25 October 2010 / Revised: 30 October 2010 / Accepted: 31 October 2010 / Published: 8 November 2010
Cited by 16 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
Lewis (y) antigen is a difucosylated oligosaccharide present on the plasma membrane, and its overexpression is frequently found in human cancers and has been shown to be associated with poor prognosis. Our previous studies have shown that Lewis (y) antigen plays a positive
[...] Read more.
Lewis (y) antigen is a difucosylated oligosaccharide present on the plasma membrane, and its overexpression is frequently found in human cancers and has been shown to be associated with poor prognosis. Our previous studies have shown that Lewis (y) antigen plays a positive role in the process of invasion and metastasis of ovarian cancer cells. However, the mechanisms by which Lewis (y) antigen enhances the invasion and tumor metastasis are still unknown. In this study, we established a stable cell line constitutively expressing Lewis (y) antigen (RMG-1-hFUT) by transfecting the cDNA encoding part of the human α1,2-fucosyltransferase (α1,2-FUT) gene into the ovarian cancer cell line RMG-1, and investigated whether Lewis (y) antigen regulates the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and tissue inhibitors of metalloproteinases (TIMP-1) and TIMP-2. We found that RMG-1-hFUT cells exhibited higher invasive capacities than their control cells. In addition, expression of TIMP-1 and TIMP-2 was down-regulated and expression of MMP-2 and MMP-9 was up-regulated. Anti-Lewis (y) antigen antibody treatment significantly reversed the expression of TIMP-1, TIMP-2, MMP-2 and MMP-9. Taken together, we provide the first evidence that down-regulation of TIMP-1 and TIMP-2 and up-regulation of MMP-2 and MMP-9 represents one of the mechanisms by which Lewis (y) antigen promotes cell invasion. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessArticle Lewis Y Promotes Growth and Adhesion of Ovarian Carcinoma-Derived RMG-I Cells by Upregulating Growth Factors
Int. J. Mol. Sci. 2010, 11(10), 3748-3759; doi:10.3390/ijms11103748
Received: 9 August 2010 / Revised: 13 September 2010 / Accepted: 16 September 2010 / Published: 29 September 2010
Cited by 6 | PDF Full-text (2471 KB) | HTML Full-text | XML Full-text
Abstract
Lewis y (LeY) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis. However, the effects of LeY on ovarian cancer are
[...] Read more.
Lewis y (LeY) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis. However, the effects of LeY on ovarian cancer are not yet clear. Previously, we transfected the ovarian cancer cell line RMG-I with the α1,2-fucosyltransferase gene to obtain stable transfectants, RMG-I-H, that highly express LeY. In the present study, we examined the proliferation, tumorigenesis, adhesion and invasion of the cell lines with treatment of LeY monoclonal antibody (mAb). Additionally, we examined the expression of TGF-β1, VEGF and b-FGF in xenograft tumors. The results showed that the proliferation and adhesion in vitro were significantly inhibited by treatment of RMG-I-H cells with LeY mAb. When subcutaneously inoculated in nude mice, RMG-I-H cells produced large tumors, while mock-transfected cells RMG-I-C and the parental cells RMG-I produced small tumors. Moreover, the tumor formation by RMG-I-H cells was inhibited by preincubating the cells with LeY mAb. Notably, the expression of TGF-β1, VEGF and b-FGF all increased in RMG-I-H cells. In conclusion, LeY plays an important role in promoting cell proliferation, tumorigenecity and adhesion, and these effects may be related to increased levels of growth factors. The LeY antibody shows potential application in the treatment of LeY-positive tumors. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

Review

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Open AccessReview Epigenetic Regulation of Cancer-Associated Genes in Ovarian Cancer
Int. J. Mol. Sci. 2011, 12(2), 983-1008; doi:10.3390/ijms12020983
Received: 15 December 2010 / Revised: 19 January 2011 / Accepted: 28 January 2011 / Published: 31 January 2011
Cited by 22 | PDF Full-text (621 KB) | HTML Full-text | XML Full-text
Abstract
The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except
[...] Read more.
The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Figures

Open AccessReview Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis
Int. J. Mol. Sci. 2011, 12(2), 1009-1029; doi:10.3390/ijms12021009
Received: 30 November 2010 / Revised: 28 January 2011 / Accepted: 29 January 2011 / Published: 31 January 2011
Cited by 44 | PDF Full-text (780 KB) | HTML Full-text | XML Full-text
Abstract
There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can
[...] Read more.
There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Open AccessReview MALDI Imaging Mass Spectrometry (MALDI-IMS)―Application of Spatial Proteomics for Ovarian Cancer Classification and Diagnosis
Int. J. Mol. Sci. 2011, 12(1), 773-794; doi:10.3390/ijms12010773
Received: 1 December 2010 / Revised: 10 January 2011 / Accepted: 17 January 2011 / Published: 21 January 2011
Cited by 49 | PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment
[...] Read more.
MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment where relative spatial abundance for potentially hundreds of analytes across virtually any tissue section can be measured. Crucially, imaging can be achieved without prior knowledge of tissue composition and without the use of antibodies. In effect MALDI-IMS allows generation of molecular data which complement and expand upon the information provided by histology including immuno-histochemistry, making its application valuable to both cancer biomarker research and diagnostics. The current state of MALDI-IMS, key biological applications to ovarian cancer research and practical considerations for analysis of peptides and proteins on ovarian tissue are presented in this review. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)
Figures

Open AccessReview Exploring the Immunoproteome for Ovarian Cancer Biomarker Discovery
Int. J. Mol. Sci. 2011, 12(1), 410-428; doi:10.3390/ijms12010410
Received: 30 November 2010 / Accepted: 12 January 2011 / Published: 14 January 2011
Cited by 2 | PDF Full-text (1380 KB) | HTML Full-text | XML Full-text
Abstract
Most scientific efforts towards early detection of ovarian cancer are commonly focused on the discovery of tumour-associated antigens (TAA). Autologous antibodies against TAA, however, may serve as more sensitive diagnostic markers. They circulate in the blood before TAA and are usually more abundant
[...] Read more.
Most scientific efforts towards early detection of ovarian cancer are commonly focused on the discovery of tumour-associated antigens (TAA). Autologous antibodies against TAA, however, may serve as more sensitive diagnostic markers. They circulate in the blood before TAA and are usually more abundant than the TAAs themselves as a result of amplification through the humoral immune response. Accumulating evidence also suggests that a humoral response already exists during malignant transformation when aberrant gene expression is translated into premalignant cellular changes. This article reviews the current knowledge about autoantibodies against TAA in ovarian cancer and presents current immunoproteomic approaches for their detection. Full article
(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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