Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. More than 80% of patients present with advanced disease, with 5 year survival rates between 15% and 45%. ...In contrast, the survival rate for stage I disease, with malignancy confined to the ovary, is approximately 95%. Given the discrepancy in survival outcomes between early- and late-stage disease, strategies that would allow for the detection of ovarian cancer in its early stages would hold promise to significantly improve the mortality rate from ovarian cancer. Unfortunately, current screening methods for the detection of early stage ovarian cancer are inadequate. However, several recent proteomics-based biomarker discovery projects show promise for the development of highly sensitive and specific markers for gynecological malignancies, including ovarian cancer. In this review, we hope to provide an overview of the early detection ovarian cancer from traditional methods to recent promises in the proteomics pipeline.
We have previously reported the identification of three ovarian cancer biomarker panels comprised of SELDI-TOF-MS peaks representing 14 differentially expressed serum proteins for the diagnosis of ...ovarian cancer. Using micro-LC-MS/MS, we identified five m/z peaks as transthyretin (TTR 13.9 kDa, TTR fragment 12.9 kDa), beta-hemoglobin (Hb, 15.9 kDa), apolipoprotein AI (ApoAI, 28 kDa) and transferrin (TF, 79 kDa). Western and/or ELISA methods confirmed the differential expression of TTR, Hb, and TF, and multivariate analyses resulted in improving the detection of early stage ovarian tumors (low malignant potential and malignant; receiver operating characteristic, ROC 0.933) as compared to cancer antigen CA125 alone (ROC 0.833). Interestingly, when CA125 was included with our markers in the multivariate analysis, the ROC increased to 0.959. Furthermore, multivariate analysis with only the mucinous subtype of early stage ovarian tumors, showed our markers to greatly improve the detection of disease (ROC 0.959) as compared to CA125 alone (ROC 0.613). Interestingly, the combination of CA125 with our markers did not seem to further improve the detection of mucinous tumors (ROC 0.955). We conclude that TTR, Hb, ApoAI and TF, when combined with CA125 should significantly improve the detection of early stage ovarian cancer.
Objective The objective of this study was to determine the efficacy of 3 previously described ovarian cancer serum biomarkers (apolipoprotein-1 ApoA-I, prealbumin TTR, transferrin TF) in the ...detection of endometrioid and papillary serous adenocarcinoma of the endometrium. Study Design ApoA-I, TTR, and TF levels were measured in serum samples that were obtained from 433 individuals that included 90 women with normal endometrium, 210 women with early-stage endometrial cancer, and 133 women with late-stage endometrial cancer. Multivariate regression models were constructed to evaluate the usefulness of the biomarkers in the detection of endometrial cancer. Results ApoA-I, TTR, and TF distinguished normal samples from early-stage endometrial cancer with a sensitivity of 71% (specificity, 88%) and normal samples from late stage endometrial cancer with a sensitivity of 82% (specificity, 86%). Conclusion The biomarker panel that consists of ApoA-I, TTR, and TF may prove to be a useful clinical tool for the detection of endometrial cancer.
We recently reported that apoA‐I and apoA‐I mimetic peptides prevent the development of flank tumors in immunocompetent C57BL/6J mice. To delineate the mechanism(s) of action of apoA‐I mimetic ...peptides in tumor development, we examined the effect of D‐4F (an apoA‐I mimetic peptide) on the antioxidant status and on the gene expression and function of antioxidant enzymes in ID8 cells (a mouse epithelial ovarian cancer cell line) and in a mouse model. We demonstrate that D‐4F treatment significantly reduces the viability and proliferation of ID8 cells, with a concomitant improvement of the antioxidant status of ID8 cells as measured by lipid peroxidation, protein carbonyl, superoxide anion, and hydrogen peroxide levels. D‐4F treatment induces MnSOD (but not CuZnSOD) mRNA, protein, and activity. Inhibition of MnSOD in ID8 cells using shRNA vectors abrogates the inhibitory effects of D‐4F on ID8 cell viability and proliferation. Moreover, tumor development from ID8 cells carrying shRNA for MnSOD were unaffected by D‐4F treatment. Our results suggest that the inhibitory effects of D‐4F on ID8 cell proliferation and tumor development are mediated, at least in part, by the induced expression and activity of MnSOD.
We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased ...survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.
Multi-gene panel testing has expanded the genetic information available to cancer patients. The objective was to assess provider behaviors and attitudes and patient knowledge and attitudes towards ...genetic counseling and testing. An online survey was distributed to Society of Gynecologic Oncology members and a written questionnaire was administered to patients diagnosed with epithelial ovarian cancer at a tertiary care referral center. Most of the 233 (18% response rate) provider respondents were gynecologic oncologists. Access to a genetic counselor was reported by 87% of providers and 55% deferred all testing to genetic counselors. Of 53 ovarian cancer patient respondents, two-thirds had previously seen a genetic counselor or undergone testing. Patients’ attitudes about genetic counseling and/or testing were favorable with respect to themselves (70–81%) and their family members (94%). Less than 25% of patients indicated worrying about health care discrimination, lack of privacy, or high cost. Seventy-seven percent of patients demonstrated a desire to obtain genetic information even if the results were not currently actionable, and 20% of providers stated they test for only those genes with guideline-supported actionable results. Provider practice differences were identified in screening and prevention strategies for patients with deleterious non-
BRCA
mutations and variants of uncertain significance. The variation in clinical interpretation of results associated with poorly defined cancer risks signals a need for more comprehensive training and guidelines to ensure access to evidence-based care.
Omega-6 (ω-6) polyunsaturated fatty acids (PUFA), abundant in the Western diet, are precursors for a number of key mediators of inflammation including the 2-series of prostaglandins (PG). PGE2, a ...cyclooxygenase (COX) metabolite of arachidonic acid, a ω-6 PUFA, is a potent mediator of inflammation and cell proliferation. Dietary supplements rich in ω-3 PUFA reduce the concentrations of 2-series PG and increase the synthesis of 3-series PG (e.g., PGE3), which are believed to be less inflammatory. However, studies on cellular consequences of increases in 3-series PG in comparison to 2-series PG have not been reported. In this study, we compared the effects of PGE2and PGE3on (i) cell proliferation in NIH 3T3 fibroblasts, (ii) expression and transcriptional regulation of the COX-2 gene in NIH 3T3 fibroblasts, and (iii) the production of an inflammatory cytokine, IL-6, in RAW 264.7 macrophages. PGE3, unlike PGE2, is not mitogenic to NIH 3T3 fibroblasts. PGE2and PGE3both induce COX-2 mRNA via similar signaling mechanisms; however, compared with PGE2, PGE3is significantly less efficient in inducing COX-2 gene expression. Furthermore, although both PGE2and PGE3induce IL-6 synthesis in RAW 264.7 macrophages, PGE3is substantially less efficient compared with PGE2. We further show that increasing the ω-3 content of membrane phospholipid results in a decrease in mitogen-induced PGE2synthesis. Taken together, our data suggest that successful replacement of ω-6 PUFA with ω-3 PUFA in cell membranes can result in a decreased cellular response to mitogenic and inflammatory stimuli.
A novel approach to oral apoA-I mimetic therapy[S] Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg ...
Journal of lipid research,
April 2013, 2013-Apr, 2013-04-00, 20130401, 2013-04-01, Volume:
54, Issue:
4
Journal Article
Peer reviewed
Open access
Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to ...Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR−/−) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy.
Objective Ovarian cancer has the highest mortality of all the gynecologic malignancies with most patients diagnosed at late stages. Serum CA-125 is elevated in only half of patients with stages I-II. ...We identified 3 serum proteins (apolipoprotein A-1, transthyretin, and transferrin) for the detection of ovarian cancer and reported them combined with CA-125 to effectively detect early-stage mucinous tumors. The objectives of this study were to assess the effectiveness of the panel in detection of early-stage serous and endometrioid ovarian cancers. Study Design In all, 358 serum samples (control, benign adnexal masses, and early-stage and late-stage ovarian cancer) were obtained from the National Cancer Institute. The level of each marker was measured. Multiple logistic regression models were built to calculate sensitivity and specificity. Results When combined with CA-125, the panel detected early-stage cancer with a sensitivity of 96%. The highest sensitivity was seen for detection of endometrioid subtype of early-stage carcinomas (98%). Conclusion A panel of 4 serum biomarkers effectively detected early-stage ovarian cancers with the highest reported overall sensitivity of 96%. Endometrioid tumors were detected at early stages with a sensitivity of 98%. Prospective clinical analysis of the panel is needed to validate it as an effective screening tool for early-stage ovarian cancer.
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