ABSTRACT
OBJECTIVE: Our objective was to perform a meta-analysis examining the risk of ovarian cancer with different types and regimens (continuous or sequential) of hormone therapy (HT). METHODS: PubMed, Cochrane, and Embase databases were searched until December 2014 using the terms: HT, estrogen therapy (ET), ovarian cancer, postmenopausal, and menopausal. HT was considered unopposed ET, estrogen-progestin therapy (EPT), or ET+EPT (ET followed by EPT). RESULTS: Of 180 studies identified, 12 were included in the meta-analysis. Of the 12 studies, 9 were cohort studies including 2,350,546 women and 7,549 cases of ovarian cancer, and 3 were case-control studies including a total of 1,347 cases and 2,052 controls. ET, EPT, and ET+EPT were associated with an increased risk of ovarian cancer: pooled hazard ratio (HR)/relative risk (RR)â=1.37, 95% CI: 1.19 to 1.58, P<0.001; pooled HR/RR=1.27, 95% CI: 1.18 to 1.36, P<0.001; pooled HR/RR=1.55, 95% CI: 1.05 to 2.30, P=0.027, respectively. Continuous and sequential regimens were associated with an increased risk: pooled HR/RR=1.27, 95% CI: 1.04 to 1.54, P=0.018; pooled HR/RR=1.31, 95% CI: 1.08 to 1.58, P=0.006, respectively. HT was associated with an increased risk of serous ovarian cancer (pooled HR/RR=1.46, 95% CI=1.28-1.67, P<0.001), but not clear cell, endometrioid, or mucinous ovarian cancer. CONCLUSIONS: Hormone therapy, regardless of type or regimen, is associated with an increased ovarian cancer risk.
Subject(s)
Estrogen Replacement Therapy/adverse effects , Ovarian Neoplasms/epidemiology , Postmenopause , Case-Control Studies , Cohort Studies , Estrogens/adverse effects , Female , Humans , Menopause , Middle Aged , Progestins/adverse effects , Proportional Hazards Models , RiskABSTRACT
OBJECTIVE: Vascular endothelial growth factor (VEGF) interaction with its receptor, VEGFR-3/Flt-4, regulates lymphangiogenesis. VEGFR-3/Flt-4 expression in cancer cells has been correlated with clinical stage, lymph node metastasis, and lymphatic invasion. The objective of this study is to identify a VEGFR-3/Flt-4-interacting peptide that could be used to inhibit VEGFR-3 for ovarian cancer therapy. METHODS: The extracellular fragment of recombinant human VEGFR-3/Flt-4 (rhVEGFR-3/Flt-4) fused with coat protein pIII was screened against a phage-displayed random peptide library. Using affinity enrichment and enzyme-linked immunosorbent assay (ELISA) screening, positive clones of phages were amplified. Three phage clones were selected after four rounds of biopanning, and the specific binding of the peptides to rhVEGFR-3 was detected by ELISA and compared with that of VEGF-D. Immunohistochemistry and immunofluorescence analyses of ovarian cancer tissue sections was undertaken to demonstrate the specificity of the peptides. RESULTS: After four rounds of biopanning, ELISA confirmed the specificity of the enriched bound phage clones for rhVEGFR-3. Sequencing and translation identified three different peptides. Non-competitive ELISA revealed that peptides I, II, and III had binding affinities for VEGFR-3 with K(aff) (affinity constant) of 16.4±8.6 µg/mL (n=3), 9.2±2.1 µg/mL (n=3), and 174.8±31.1 µg/mL (n=3), respectively. In ovarian carcinoma tissue sections, peptide III (WHWLPNLRHYAS), which had the greatest binding affinity, also co-localized with VEGFR-3 in endothelial cells lining lymphatic vessels; its labeling of ovarian tumors in vivo was also confirmed. CONCLUSION: These finding showed that peptide III has high specificity and activity and, therefore, may represent a potential therapeutic approach to target VEGF-VEGFR-3 signaling for the treatment or diagnosis of ovarian cancer.
