Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasion

Barbolina, Maria V.; Adley, Brian P.; Shea, Lonnie D.; Stack, M. Sharon

doi:10.1002/cncr.23341

Cited by 42 publications

(30 citation statements)

References 52 publications

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“…P53, SP17, NY-ESO-1, survivin, and WT1 are immunogenic target antigens in EOC. Rates of observed (over)expression of p53, SP17, survivin, and WT1 in 48.0%, 68.9%, 90.0%, and 56.3% of EOC patients, respectively, are in agreement with previous studies [16, 24, 40, 41]. NY-ESO-1 expression was seen in 11.0% of tumors in our cohort which is in agreement with the results of others [42, 43].…”

Section: Discussionsupporting

confidence: 93%

Potential Target Antigens for a Universal Vaccine in Epithelial Ovarian Cancer

Vermeij

Daemen

Bock

et al. 2010

Journal of Immunology Research

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The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a “universal” vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.

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Section: Discussionsupporting

confidence: 93%

Potential Target Antigens for a Universal Vaccine in Epithelial Ovarian Cancer

Vermeij

Daemen

Bock

et al. 2010

Journal of Immunology Research

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“…Our previous studies have shown that three-dimensional collagen I (3DCI) gels, a microenvironmental component relevant to that encountered by metastasizing ovarian carcinoma cells 11, 12, dramatically modulates cell behavior and promotes a pro-invasive phenotype 6, 7, 13-16. Specifically, our data demonstrate that 3DCI enhances the ability of cells to migrate through upregulation of membrane Wilms’ tumor gene product 1 17 and actinin alpha-4 13, and to digest extracellular matrix via upregulation of membrane type-1 matrix metalloproteinase 6, 7, 15. These findings led to the speculation that other cellular mechanisms pertinent to pro-invasive and migratory behavior, such as cell-matrix adhesion, may be altered through interaction of cells with 3DCI as well.…”

Section: Introductionmentioning

confidence: 60%

Downregulation of connective tissue growth factor by three‐dimensional matrix enhances ovarian carcinoma cell invasion

Barbolina

Adley

Kelly

et al. 2009

Intl Journal of Cancer

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Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancies, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intraperitoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hr of 3D collagen culture) coupled with confirmatory real-time reverse-transcriptase polymerase chain reaction, multiple 3D cell culture matrices, Western blot, immunostaining, adhesion, migration and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasionmimicking conditions (3D Type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n 5 41), but was present in 100% of normal ovarian epithelium samples (n 5 7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using a6b1 and a3b1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. ' UICCKey words: ovarian carcinoma; metastasis; invasion; adhesion; connective tissue growth factor Epithelial ovarian carcinoma (EOC) has the poorest survival of all gynecologic malignancies, 1 due predominantly to the presence of disseminated intraperitoneal metastasis.2 Successful metastatic spread requires concerted regulation of crucial cellular processes, including apoptosis, proliferation, cell-cell and cell-matrix adhesion, migration and breakdown of the extracellular matrix.3 A detailed understanding of these mechanisms is a prerequisite for the design of therapeutics essential for retardation or prevention of metastatic spread. The tumor microenvironment plays a major role in orchestrating the cell behavior. 4 The microenvironment in sites of EOC metastatic dissemination is predominantly comprised of interstitial collagens I and III, 5 which can be modeled experimentally to distinguish effects of the microenvironment on cell behavior. 6,7 Experimentally created 3D cultures recapitulate the in vivo cellular environment more closely than traditional cell culture on planar substrata. It has been demonstrated that these 3D culture models and organotypic cultures can accurately and reliably replicate certain conditions in the living organs and, therefore, can be used as a preliminary model to more closely understand the consequences of inte...

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“…This procedure was performed as previously described [40-42]. Antibodies were used at the following dilutions: 1:100 mouse anti-human-versican (clone 12C5) in 3% BSA in a solution of 50 mM tris-buffered saline, pH 7.4, 150 mM NaCl, and 0.05% Tween-20 (TBST) (Sigma; St. Louis, MO) and 1:200 mouse anti-human-β-tubulin in 3% BSA in TBST.…”

Section: Methodsmentioning

confidence: 99%

Versican regulates metastasis of epithelial ovarian carcinoma cells and spheroids

et al. 2014

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BackgroundEpithelial ovarian carcinoma is a deadly disease characterized by overt peritoneal metastasis. Individual cells and multicellular aggregates, or spheroids, seed these metastases, both commonly found in ascites. Mechanisms that foster spheroid attachment to the peritoneal tissues preceding formation of secondary lesions are largely unknown.MethodsCell culture models of SKOV-3, OVCAR3, OVCAR4, Caov-3, IGROV-1, and A2780 were used. In this report the role of versican was examined in adhesion of EOC spheroids and cells to peritoneal mesothelial cell monolayers in vitro as well as in formation of peritoneal tumors using an in vivo xenograft mouse model.ResultsThe data demonstrate that versican is instrumental in facilitating cell and spheroid adhesion to the mesothelial cell monolayers, as its reduction with specific shRNAs led to decreased adhesion. Furthermore, spheroids with reduced expression of versican failed to disaggregate to complete monolayers when seeded atop monolayers of peritoneal mesothelial cells. Failure of spheroids lacking versican to disaggregate as efficiently as controls could be attributed to a reduced cell migration that was observed in the absence of versican expression. Importantly, both spheroids and cells with reduced expression of versican demonstrated significantly impaired ability to generate peritoneal tumors when injected intraperitoneally into athymic nude mice.ConclusionsTaken together these data suggest that versican regulates the development of peritoneal metastasis originating from cells and spheroids.

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Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasion

Abstract: The data from the current study identify a novel regulatory mechanism for the control of WT1 expression and provide evidence for a functional role of WT1 protein in the control of cellular invasive activity.

Cited by 42 publications

References 52 publications

Potential Target Antigens for a Universal Vaccine in Epithelial Ovarian Cancer

Potential Target Antigens for a Universal Vaccine in Epithelial Ovarian Cancer

Downregulation of connective tissue growth factor by three‐dimensional matrix enhances ovarian carcinoma cell invasion

Versican regulates metastasis of epithelial ovarian carcinoma cells and spheroids

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