Ovarian tumor AND Ovarian functional and neoplastic tumors [keywords]
- Ovarian-Sparing Surgery in Pediatric Benign Ovarian Tumors. [JOURNAL ARTICLE]
- J Pediatr Adolesc Gynecol 2016 Oct; 29(5):506-510.
To evaluate outcomes of children after ovarian-sparing surgery (OSS) for non-neoplastic and benign neoplastic ovarian lesions.Retrospective cohort study from January 2003 to January 2012.Single, high-volume, tertiary care hospital.Children 18 years of age and younger.None.Postoperative complications and tumor recurrence after OSS.One hundred nine patients underwent OSS with a median age of 13.3 years (interquartile range [IQR], 11.4-15.1 years). Eighty-two patients were treated laparoscopically with 4 conversions to an open procedure. Postoperative complications included surgical site infections in 7 patients (6%). Pathology most commonly revealed functional ovarian cysts (n = 57) and mature teratomas (n = 37). Ninety-four patients (86%) were followed for a median of 10.4 months (IQR, 0.72-30.8 months). Fifty-five patients (60%) had subsequent imaging surveillance a median of 7.6 months postoperatively (IQR, 3.9-13 months). Ten patients (10%) developed a second ipsilateral lesion within a median time of 11 months (IQR, 7.7-24 months), of whom 5 girls had repeated surgery for mass enlargement or persistent abdominal pain at a median time of 10.5 months (IQR, 8.0-12.65 months). Fifty-eight patients (63%) began or resumed menses at their most recent follow-up. Three girls became pregnant after OSS at a median follow-up of 5 years (range, 2.4-6.7 years).Benign ovarian lesions in children can be treated successfully with OSS with low recurrence and repeat surgery rates.
- Possible relevance of tumor-related genes mutation to malignant transformation of endometriosis. [Journal Article]
- Eur J Gynaecol Oncol 2016; 37(1):89-94.
Despite studies have suggested that endometriosis has malignant potential, the molecular mechanism underlying the malignant transformation of endometriosis is poorly understood so far. Endometriosis-associated ovarian cancer (EAOC) or ovarian cancer arising from endometriosis (OCEM) may provide an ideal model for genetic studies. To investigate the genetic alterations during transformation of ovarian endometriosis into cancer, the authors analysed mutations of tumour-related genes (PTEN and p53) in EAOC cases (n=23, group 1), including 19 cases which were detected co-existence of endometriosis and cancer and four cases which fulfilled the histological criteria in malignant transformation of endometriosis (OCEMs), and in atypical hyperplasia ovarian endometriosis (aEMs) (n = 10, group 2), as well as in solitary ovarian endometriosis (EMs) (n = 20, group 3), simultaneously, to study the correlation of the two genes in the development and progression of the ovarian endometriosis malignancy.Each paraffin block was sliced into serial ten-µm-thick sections. Extracted DNA was amplified by nested PCR. Mutations of PTEN and p53 were examined by bidirectional DNA sequencing.It was acknowledged by experiments that the PTEN and p53 mutation frequency in EAOCs were significantly higher than that in aEMs and EMs. There was significant difference to compare EAOCs with EMs (p < 0.01, p < 0.05), and converse to compare with aEMs (p > 0.05), respectively. No definite involvement between the frequency of PTEN and p53 mutations in EAOCs and age difference, histological type, clinical stage, pathological grade, and whether accompanied by metastasis (p > 0.05); however, a decreasing trend of PTEN mutation with the increased age, decreased clinical stage and pathological grade, and when accompanied by metastasis was detected. Adversely, an increasing trend of p53 mutation was represented. In EAOCs group, the authors detected eight PTEN and four p53 mutation events, respectively. Moreover, one case occurred PTEN and p53 mutation simultaneously. With 23 EAOCs, two cases which fulfilled the histological criteria in malignant transformation of endometriosis, which may be a specific entity distinct from non-endometriosis-associated ovarian cancer, the authors named them the OCEMs, occurred PTEN or p53 mutation, respectively.The present study suggested that the mutation and functional incapacitation of certain tumor-related genes may be involved in malignant transformation of endometriosis. PTEN mutation is the pristine event, but p53 mutation is the late.
- Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.]
- Nat Commun 2016.:11150.
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.
- Procoagulant activity in gynaecological cancer patients; the effect of surgery and chemotherapy. [Journal Article, Research Support, Non-U.S. Gov't]
- Thromb Res 2016 Mar.:135-41.
Gynaecological cancers are associated with high rates of venous thromboembolism (VTE). Studies on ambulatory cancer patients do not support thromboprophylaxis during chemotherapy. Approximately 6-7% of gynaecological cancer patients suffer a postoperative VTE despite Low Molecular Weight Heparin prophylaxis (LMWH). Large cancer studies have shown that Calibrated Automated Thrombogram (CAT) and Microparticles (MP) assays may be useful in predicting VTE but data on gynaecological cancer patients is scarce.Our objective was to identify whether the CAT assay and MP functional assays have potential as biomarkers predictive of VTE in gynaecological cancer patients.Gynaecological cancer patients were investigated before surgery (n=146) and at 5, 14 and 42days post-surgery (n=78). Fourteen additional patients were investigated before chemotherapy and after 3 and 6 cycles of therapy. Thrombin generation was measured before and after addition of thrombomodulin.Patients with clear cell cancer (CCC) of the ovary and patients with endometrial cancer had higher ETP and peak thrombin compared with patients with benign disease. Patients who developed VTE (n=8) following surgery had enhanced thrombin generation prior to surgery which persisted during the post-operative period despite LMWH prophylaxis. Both neoadjuvant and adjuvant chemotherapy showed increased thrombin generation following addition of thrombomodulin. There were no differences in MP levels during the study.CAT assay shows potential as a promising biomarker for the prediction of VTE in gynaecological cancer patients. The identification of high risk patients combined with individualised LMWH prophylaxis might reduce VTE in this high risk group.
- BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin. [Journal Article, Research Support, Non-U.S. Gov't]
- Mutat Res 2016 Feb-Mar.:8-15.
Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) via direct protein-protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.
- Expression and Function of CD44 in Epithelial Ovarian Carcinoma. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Biomolecules 2015; 5(4):3051-66.
CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed.
- Oncogenic Signaling Adaptor Proteins. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review]
- J Genet Genomics 2015 Oct 20; 42(10):521-9.
Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
- Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-β-D-Digitoxosyl-Mithramycin SK (EC-8042). [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2015; 10(11):e0140786.
Demycarosyl-3D-β-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug.
- Confluence analysis of multiple omics on platinum resistance of ovarian cancer. [Journal Article]
- Eur J Gynaecol Oncol 2015; 36(5):514-9.
The study aimed to provide novel insight into the mechanism of platinum resistance of ovarian cancer.RNA-seq data ERP000710 were obtained from Gene Expression Omnibus database, including specimens from six platinum sensitive samples and six platinum tolerance samples. The author analyzed the data of the 12 samples as a whole because of the low flux sequencing. Single nucleotide polymorphisms (SNPs) were identified between platinum-sensitive and platinum-tolerant samples using VARSCAN, followed by functional prediction of the SNPs. After processed by Btrim software, the data were subjected to Cuffdiff for the identification of differentially expressed genes (DEGs), followed by function and pathway enrichment analysis. In addition, VARSCAN software was used to detect the specific mutations in platinum tolerance samples, combined with functional prediction of mutations.The author obtained 38 new SNPs after excluding 22 SNP from dbSNP database and 1000 Genomes Project and found ESRP1, LDHA, DDX5, and HEXA were associated with platinum resistance of ovarian cancer. Totally, 290 upregulated and 157 down-regulated genes were selected. Biological processes such as immune response, inflammatory response, and response to wounding and pathways such as cell adhesion molecules, calcium signaling, and NOD-like receptor signaling pathways were enriched with upregulated genes. Cell-cell signaling, cell morphogenesis, and basal cell carcinoma pathway were related to downregulated genes.Based on high-throughput RNA-seq data and confluence analysis of multiple omics, the author explored the biological mechanisms on platinum tolerance of ovarian cancer, which may provide new ideas and methods for further research.
- Synthesis, Anticancer Activity, and Genome Profiling of Thiazolo Arene Ruthenium Complexes. [Journal Article, Research Support, Non-U.S. Gov't]
- J Med Chem 2015 Nov 12; 58(21):8475-90.
Sixteen hydrazinyl-thiazolo arene ruthenium complexes of the general formula [(η(6)-p-cymene)Ru(N,N'-hydrazinyl-thiazolo)Cl]Cl were synthesized. All complexes were tested in vitro for their antiproliferative activity on three tumor cell lines (HeLa, A2780, and A2780cisR) and on a noncancerous cell line (HFL-1). A superior cytotoxic activity of the ruthenium complexes as compared to cisplatin and oxaliplatin, on both cisplatin-sensitive and cisplatin resistant ovarian cancer cells, was observed. In addition, the biological activity of two selected derivatives was evaluated using microarray gene expression assay and ingenuity pathway analysis. p53 signaling was identified as an important pathway modulated by both arene ruthenium compounds. New activated molecules such as FAS, ZMAT3, PRMT2, BBC3/PUMA, and PDCD4, whose overexpressions are correlated with overcoming resistance to cisplatin therapy, were also identified as potential targets. Moreover, the arene ruthenium complexes can be used in association with cisplatin to prevent cisplatin resistance development and synergistically to induce cell death in ovarian cancer cells.