Obstetrics and Gynaecology - Research Publications
Permanent URI for this collection
Search Results
1 - 4 of 4
-
ItemValidating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium(NATURE PUBLISHING GROUP, 2009-01-22)The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
-
ItemAn immunohistochemical perspective of PPARβ and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumours(NATURE PUBLISHING GROUP, 2008-04-22)Peroxisome proliferator-activated receptor beta (PPAR beta) is a member of the nuclear hormone receptor family and is a ligand-activated transcription factor with few known molecular targets including 3-phosphoinositide-dependent protein kinase 1(PDK1). In view of the association of PPAR beta and PDK1 with cancer, we have examined the expression of PPAR beta and PDK1 in normal ovaries and different histological grades of ovarian tumours. Normal ovaries, benign, borderline, grades 1, 2 and 3 ovarian tumours of serous, muciuous, endometrioid, clear cell and mixed subtypes were analysed by immunohistochemistry for PPAR beta and PDK1 expression. All normal ovarian tissues, benign, borderline and grade 1 tumours showed PPAR beta staining localised in the epithelium and stroma. Staining was predominantly nuclear, but some degree of cytoplasmic staining was also evident. Approximately 20% of grades 2 and 3 tumours lacked PPAR beta staining, whereas the rest displayed some degree of nuclear and cytoplasmic staining of the scattered epithelium and stroma. The extent of epithelial and stromal PPAR beta staining was significantly different among the normal and the histological grades of tumours (chi(2)=59.25, d.f.=25, P<0.001; chi(2)=64.48, d.f.=25, P<0.001). Significantly different staining of PPAR beta was observed in the epithelium and stroma of benign and borderline tumours compared with grades 1, 2 and 3 tumours (chi(2)=11.28, d.f.=4, P<0.05; chi(2)=16.15, d.f.=4, P<0.005). In contrast, PDK1 immunostaining was absent in 9 out of 10 normal ovaries. Weak staining for PDK1 was observed in one normal ovary and 40% of benign ovarian tumours. All borderline and malignant ovarian tumours showed positive cytoplasmic and membrane PDK1 staining. Staining of PDK1 was confined to the epithelium and the blood vessels, and no apparent staining of the stroma was evident. Significantly different PDK1 staining was observed between the benign/borderline and malignant ovarian tumours (chi(2)=22.45, d.f.=5, P<0.001). In some borderline and high-grade tumours, staining of the reactive stroma was also evident. Our results suggest that unlike the colon, the endometrial, head and neck carcinomas, overexpression of PPAR beta does not occur in ovarian tumours. However, overexpression of PDK1 was evident in borderline and low- to high-grade ovarian tumours and is consistent with its known role in tumorigenesis.
-
ItemCRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?(BMC, 2009-11-30)The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy.
-
ItemAlpha2beta1 integrin affects metastatic potential of ovarian carcinoma spheroids by supporting disaggregation and proteolysis.(Medknow, 2007-06-14)BACKGROUND: Ovarian cancer is characterized by a wide-spread intra-abdominal metastases which represents a major clinical hurdle in the prognosis and management of the disease. A significant proportion of ovarian cancer cells in peritoneal ascites exist as multicellular aggregates or spheroids. We hypothesize that these cellular aggregates or spheroids are invasive with the capacity to survive and implant on the peritoneal surface. This study was designed to elucidate early inherent mechanism(s) of spheroid survival, growth and disaggregation required for peritoneal metastases METHODS: In this study, we determined the growth pattern and adhesive capacity of ovarian cancer cell lines (HEY and OVHS1) grown as spheroids, using the well established liquid overlay technique, and compared them to a normal ovarian cell line (IOSE29) and cancer cells grown as a monolayer. The proteolytic capacity of these spheroids was compared with cells grown as a monolayer using a gelatin zymography assay to analyze secreted MMP-2/9 in conditioned serum-free medium. The disaggregation of cancer cell line spheroids was determined on extracellular matrices (ECM) such as laminin (LM), fibronectin (FN) and collagen (CI) and the expression of alpha2, alpha3, alphav, alpha6 and beta1 interin was determined by flow cytometric analysis. Neutralizing antibodies against alpha2, beta1 subunits and alpha2beta1 integrin was used to inhibit disaggregation as well as activation of MMPs in spheroids. RESULTS: We demonstrate that ovarian cancer cell lines grown as spheroids can sustain growth for 10 days while the normal ovarian cell line failed to grow beyond 2 days. Compared to cells grown as a monolayer, cancer cells grown as spheroids demonstrated no change in adhesion for up to 4 days, while IOSE29 cells had a 2-4-fold loss of adhesion within 2 days. Cancer cell spheroids disaggregated on extracellular matrices (ECM) and demonstrated enhanced expression of secreted pro-MMP2 as well as activated MMP2/MMP9 with no such activation of MMP's observed in monolayer cells. Flow cytometric analysis demonstrated enhanced expression of alpha2 and diminution of alpha6 integrin subunits in spheroids versus monolayer cells. No change in the expression of alpha3, alphav and beta1 subunits was evident. Conversely, except for alphav integrin, a 1.5-7.5-fold decrease in alpha2, alpha3, alpha6 and beta1 integrin subunit expression was observed in IOSE29 cells within 2 days. Neutralizing antibodies against alpha2, beta1 subunits and alpha2beta1 integrin inhibited disaggregation as well as activation of MMPs in spheroids. CONCLUSION: Our results suggest that enhanced expression of alpha2beta1 integrin may influence spheroid disaggregation and proteolysis responsible for the peritoneal dissemination of ovarian carcinoma. This may indicate a new therapeutic target for the suppression of the peritoneal metastasis associated with advanced ovarian carcinomas.