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Key Points Several factors make ovarian cancer a difficult disease to treat effectively. Although many patients experience symptoms, these often overlap with other ailments, and many patients are diagnosed after the cancer has metastasized. Ovarian cancer is also heterogeneous — multiple genetic and epigenetic changes are evident in patients with ovarian cancer; however, how such changes are selected for during tumorigenesis is not yet clear. Mutation and loss of TP53 function is one of the most frequent genetic abnormalities in ovarian cancer and is observed in 60–80% of both sporadic and familial cases. Of the 16 candidate tumour suppressor genes identified to date in ovarian cancer, 3 are imprinted genes. Several growth inhibitory genes are also silenced by methylation or imprinting. Inheritance of DNA repair defects contributes to as many as 10–15% of ovarian cancers. The lifetime risk of developing ovarian cancer in mutation carriers varies with the genetic defect (for BRCA1 30–60%, for BRCA2 15–30% and for hereditary non-polyposis colon cancer 7%). At least 15 oncogenes have been implicated in ovarian cancers, and DNA copy number abnormalities have also been found in loci that are known to contain non-coding microRNAs. At least seven signalling pathways are activated in >50% of ovarian cancers, and mutations that affect cell proliferation, apoptosis and autophagy are also evident. Ovarian cancer can be split into two groups on the basis of genetic changes: low-grade tumours with mutations in KRAS, BRAF and PIK3CA , loss of heterozygosity (LOH) on chromosome Xq, microsatellite instability and expression of amphiregulin; and high-grade tumours with aberrations in TP53 and potential aberrations in BRCA1 and BRCA2 , as well as LOH on chromosomes 7q and 9p. Changes in cell adhesion and motility also contribute to disease development and metastasis. Adhesion of ovarian cancer cells to the mesothelial cells and to the underlying stroma is mediated by CD44, CA125 and b1 intergrin on the surface of ovarian cancer cells that bind to mesothelin and hyaluronic acid on mesothelial cells, or to fibronectin, laminin and type IV collagen in the underlying matrix. A crucial goal is to identify patients who would benefit from particular targeted therapies. Given the complexity of crosstalk between protein signalling pathways, predicting the impact and efficacy of any one signalling inhibitor is difficult. Inhibition of multiple pathways will almost certainly be required to substantially affect ovarian cancer growth. Effective methods for early detection are needed. Given the prevalence of ovarian cancer, strategies for early detection must have a high sensitivity for early-stage disease (>75%), but an extremely high specificity (99.6%) to attain a positive predictive value of at least 10% (ten operations for each case of ovarian cancer). Using rising values of serum biomarkers such as CA125 to trigger transvaginal sonography is a promising approach. Ovarian cancer is a heterogeneous disease, making it difficult to provide standard regimens that are effective for all patients. Can increases in long-term survival be achieved by translating recent insights at the molecular and cellular levels into individual strategies for treatment and optimal early detection? Over the past two decades, the 5-year survival for ovarian cancer patients has substantially improved owing to more effective surgery and treatment with empirically optimized combinations of cytotoxic drugs, but the overall cure rate remains approximately 30%. Many investigators think that further empirical trials using combinations of conventional agents are likely to produce only modest incremental improvements in outcome. Given the heterogeneity of this disease, increases in long-term survival might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.

This Opinion article outlines nine major recommendations for improving our understanding of ovarian cancer and the outcomes of women with this group of diseases. There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

The role of autophagy in oncogenesis remains ambiguous, and mechanisms that induce autophagy and regulate its outcome in human cancers are poorly understood. The maternally imprinted Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI; also known as DIRAS3) is downregulated in more than 60% of ovarian cancers, and here we show that re-expression of ARHI in multiple human ovarian cancer cell lines induces autophagy by blocking PI3K signaling and inhibiting mammalian target of rapamycin (mTOR), upregulating ATG4, and colocalizing with cleaved microtubule-associated protein light chain 3 (LC3) in autophagosomes. Furthermore, ARHI is required for spontaneous and rapamycin-induced autophagy in normal and malignant cells. Although ARHI re-expression led to autophagic cell death when SKOv3 ovarian cancer cells were grown in culture, it enabled the cells to remain dormant when they were grown in mice as xenografts. When ARHI levels were reduced in dormant cells, xenografts grew rapidly. However, inhibition of ARHI-induced autophagy with chloroquine dramatically reduced regrowth of xenografted tumors upon reduction of ARHI levels, suggesting that autophagy contributed to the survival of dormant cells. Further analysis revealed that autophagic cell death was reduced when cultured human ovarian cancer cells in which ARHI had been re-expressed were treated with growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix proteins found in xenografts. Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.

ObjectiveTo present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer.MethodsSystematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation.ResultsBecause of its low sensitivity (50–62% for early stage epithelial ovarian cancer) and limited specificity (94–98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery.ConclusionsAt present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.

Salt‐inducible kinase 2 (SIK2; also known as serine/threonine‐protein kinase SIK2) is overexpressed in several cancers and has been implicated in cancer progression. However, the mechanisms by which SIK2 regulates cancer cell motility, migration and metastasis in ovarian cancer have not been fully discovered. Here, we identify that SIK2 promotes ovarian cancer cell motility, migration and metastasis in vitro and in vivo. Mechanistically, SIK2 regulated cancer cell motility and migration by myosin light chain kinase, smooth muscle (MYLK)‐meditated phosphorylation of myosin light chain 2 (MYL2). SIK2 directly phosphorylated MYLK at Ser343 and activated its downstream effector MYL2, promoting ovarian cancer cell motility and metastasis. In addition, we found that adipocytes induced SIK2 phosphorylation at Ser358 and MYLK phosphorylation at Ser343, enhancing ovarian cancer cell motility. Moreover, SIK2 protein expression was positively correlated with the expression of MYLK‐pS343 in ovarian cancer cell lines and tissues. The co‐expression of SIK2 and MYLK‐pS343 was associated with reduced median overall survival in human ovarian cancer samples. Taken together, SIK2 positively regulates ovarian cancer motility, migration and metastasis, suggesting that SIK2 is a potential candidate for ovarian cancer treatment. SIK2 is overexpressed in several cancers and has been implicated in cancer progression. However, the mechanisms by which SIK2 regulates cancer cell motility and metastasis in ovarian cancer (OC) have not been fully described. Here, we have identified that SIK2 promotes OC cell motility and metastasis by phosphorylating MYLK/MYL2, suggesting that SIK2 may serve as a potential target in OC treatment.

Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent fibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer.

Background Multiple antigens, autoantibodies (AAb), and antigen-autoantibody (Ag-AAb) complexes were compared for their ability to complement CA125 for early detection of ovarian cancer. Methods Twenty six biomarkers were measured in a single panel of sera from women with early stage (I-II) ovarian cancers ( n  = 64), late stage (III-IV) ovarian cancers (186), benign pelvic masses (200) and from healthy controls (502), and then split randomly (50:50) into a training set to identify the most promising classifier and a validation set to compare its performance to CA125 alone. Results Eight biomarkers detected ≥ 8% of early stage cases at 98% specificity. A four-biomarker panel including CA125, HE4, HE4 Ag-AAb and osteopontin detected 75% of early stage cancers in the validation set from among healthy controls compared to 62% with CA125 alone ( p  = 0.003) at 98% specificity. The same panel increased sensitivity for distinguishing early-stage ovarian cancers from benign pelvic masses by 25% ( p  = 0.0004) at 95% specificity. From 21 autoantibody candidates, 3 AAb (anti-p53, anti-CTAG1 and annt-Il-8) detected 22% of early stage ovarian cancers, potentially lengthening lead time prior to diagnosis. Conclusion A four biomarker panel achieved greater sensitivity at the same specificity for early detection of ovarian cancer than CA125 alone.

Purpose of ReviewBoth conventional and novel approaches to early detection of ovarian cancer are reviewed in the context of new developments in our understanding of ovarian cancer biology.Recent FindingsWhile CA125 as a single value lacks adequate specificity or sensitivity for screening, large studies have shown that a 2-stage strategy which tracks CA125 change over time and prompts transvaginal ultrasound (TVS) for a small subset of women with abnormally rising biomarker values achieves adequate specificity and detects a higher fraction of early-stage disease. Sensitivity could clearly be improved in both blood tests and in imaging. Metastasis can occur from ovarian cancers too small to increase blood levels of protein antigens and a significant fraction of ovarian cancers arise from the fimbriae of fallopian tubes that cannot be imaged with TVS. Autoantibodies, miRNA, ctDNA, DNA methylation in blood, and cervical mucus might improve sensitivity of the initial phase and magnetic relaxometry and autofluorescence could improve imaging in the second phase.SummaryEnhancing the sensitivity of two-stage strategies for early detection could reduce mortality from ovarian cancer.