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1.  Role of CTGF in sensitivity to hyperthermia in ovarian and uterine cancers 
Cell reports  2016;17(6):1621-1631.
Summary
Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits of and predictors of sensitivity of cancer to hyperthermia are poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures in and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF siRNA treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia resistant cancers.
doi:10.1016/j.celrep.2016.10.020
PMCID: PMC5123842  PMID: 27806300
Hyperthermia; ovarian cancer; CTGF; DOPC-liposome; thermosensitivity; copper sulfide nanoparticle
2.  Host Factors and Cancer Progression: Biobehavioral Signaling Pathways and Interventions 
Journal of Clinical Oncology  2010;28(26):4094-4099.
Whereas evidence for the role of psychosocial factors in cancer initiation has been equivocal, support continues to grow for links between psychological factors such as stress, depression, and social isolation and progression of cancer. In vitro, in vivo, and clinical studies show that stress- related processes can impact pathways implicated in cancer progression, including immuno-regulation, angiogenesis, and invasion. Contributions of systemic factors, such as stress hormones to the crosstalk between tumor and stromal cells, appear to be critical in modulating downstream signaling pathways with important implications for disease progression. Inflammatory pathways may also be implicated in fatigue and other factors related to quality of life. Although substantial evidence supports a positive effect of psychosocial interventions on quality of life in cancer, the clinical evidence for efficacy of stress-modulating psychosocial interventions in slowing cancer progression remains inconclusive, and the biobehavioral mechanisms that might explain such effects are still being established. This article reviews research findings to date and outlines future avenues of research in this area.
doi:10.1200/JCO.2009.26.9357
PMCID: PMC2940426  PMID: 20644093
3.  Fundamental Principles of Cancer Biology: Does it have relevance to the perioperative period? 
Current anesthesiology reports  2015;5(3):250-256.
Malignant tumors are characterized by their ability to metastasize, which is the main cause of cancer-related mortality. Besides intrinsic alternations in cancer cells, the tumor microenvironment plays a pivotal role in tumor growth and metastasis. Ample evidence suggests that the perioperative period and the excision of the primary tumor can promote the development of metastases and can influence long-term cancer patient outcomes. The role of cancer biology and its impact on the perioperative period are of increasing interest. This review will present evidence regarding fundamental principles of cancer biology, especially tumor microenvironment, and discuss new therapeutic opportunities in the perioperative timeframe. We will also discuss the regulatory signaling that could be relevant to various aspects of surgery and surgical responses, which could facilitate the metastatic process by directly or indirectly affecting malignant tissues and the tumor microenvironment. We address the influences of surgery-related stress, anesthetic and analgesic agents, blood transfusion, hypothermia, and β-adrenergic blockade administration on tumor growth and metastasis. Through an improved understanding of these processes, we will provide suggestions for potential new perioperative approaches aimed at improving treatment outcomes of cancer patients.
doi:10.1007/s40140-015-0122-9
PMCID: PMC4570734  PMID: 26388704
Perioperative; cancer biology; therapeutics
4.  Dual metronomic chemotherapy with nab-paclitaxel and topotecan has potent anti-angiogenic activity in ovarian cancer 
Molecular cancer therapeutics  2015;14(12):2677-2686.
There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique anti-angiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-α, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8-MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase 3), and angiogenesis (microvessel density) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, p < 0.01 and 96% in the HeyA8 model, p < 0.03) compared with vehicle (p < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (p < 0.03). The greatest reduction in microvessel density (p <0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared to other groups (p < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development.
doi:10.1158/1535-7163.MCT-14-0630
PMCID: PMC4674355  PMID: 26516159
nab-paclitaxel; topotecan; angiogenesis; metronomic; ovarian carcinoma
5.  Erythropoietin Stimulates Tumor Growth via EphB4 
Cancer cell  2015;28(5):610-622.
SUMMARY
While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.
doi:10.1016/j.ccell.2015.09.008
PMCID: PMC4643364  PMID: 26481148
6.  Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy 
JCI Insight  null;1(17):e87754.
Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer-associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer-associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2–targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular-targeted therapy.
Chitosan-thioaptamer nanoparticles deliver miRNA-inhibitors selectively to the tumor vasculature, restore tight junction function, improve the delivery of paclitaxel, and reduce tumor growth.
doi:10.1172/jci.insight.87754
PMCID: PMC5070952  PMID: 27777972
7.  Interleukin-6, Cortisol, and Depressive Symptoms in Ovarian Cancer Patients 
Journal of Clinical Oncology  2008;26(29):4820-4827.
Purpose
Inflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients.
Patients and Methods
Patients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP).
Results
Advanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P < .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P = .008) and ascites (P = .024), but affective depression was unrelated to IL-6. Elevations in total depression (P = .026) and vegetative depression (P = .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values < .005).
Conclusion
These results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.
doi:10.1200/JCO.2007.14.1978
PMCID: PMC2653140  PMID: 18779606
8.  Targeting c-MYC in platinum-resistant ovarian cancer 
Molecular cancer therapeutics  2015;14(10):2260-2269.
The purpose of this study was to investigate the molecular and therapeutic effects of small-interfering RNA (siRNA)-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient’s data extracted from The Cancer Genome Atlas (TCGA) portal showed that the progression free- (PFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared to their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell cycle progression, and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer cells. Significant inhibition of cell growth and viability, cell cycle arrest, and activation of apoptosis, were observed upon siRNA-mediated c-MYC depletion. In addition, single weekly doses of c-MYC-siRNA incorporated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000)-based nanoliposomes resulted in significant reduction in tumor growth. These findings identify c-MYC as a potential therapeutic target for ovarian cancers expressing high levels of this oncoprotein.
doi:10.1158/1535-7163.MCT-14-0801
PMCID: PMC4596776  PMID: 26227489
c-MYC; siRNA; nanoliposomes; ovarian cancer; cisplatin
9.  MicroRNA deregulation in cancer cells and the tumor microenvironment 
Cancer discovery  2016;6(3):235-246.
MicroRNAs (miRNAs) are a key component of the noncoding RNA family. The underlying mechanisms involved in the interplay between the tumor microenvironment and cancer cells involve highly dynamic factors such as hypoxia and cell types such as cancer-associated fibroblasts and macrophages. Although miRNA levels are known to be altered in cancer cells, recent evidence suggests a critical role for the tumor microenvironment in regulating miRNA biogenesis, methylation, and transcriptional changes. Here, we discuss the complex pro-tumorigenic symbiotic role between tumor cells, the tumor microenvironment, and miRNA deregulation.
doi:10.1158/2159-8290.CD-15-0893
PMCID: PMC4783232  PMID: 26865249
MicroRNAs; Hypoxia; DICER; Drosha; miRNA biogenesis; tumor progression
10.  Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression 
Oncogene  2016;35(33):4312-4320.
MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer, and resulting in increased tumor growth and metastasis. Here, we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using DOPC nanoliposomes resulted in increased tumor growth and metastasis and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line based overexpression of sense or anti-sense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer.
doi:10.1038/onc.2015.492
PMCID: PMC4931989  PMID: 26725326
miRNAs; Dicer; Hypoxia; miRNA-630; Metastasis
11.  FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal 
The Journal of Clinical Investigation  null;126(5):1885-1896.
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
doi:10.1172/JCI85086
PMCID: PMC4855933  PMID: 27064283
12.  XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A 
Purpose
XPO1 inhibitors have shown promise for cancer treatment and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1.
Experimental design
We used proteomic analysis in XPO1 inhibitor treated ovarian cancer cell lines, and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents.
Results
XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO-independent. Significant anti-tumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (p < 0.001) and breast (p < 0.001) cancer mouse models, with further decrease in tumor burden observed in combination with topotecan or paclitaxel (p <0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels.
Conclusion
We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials.
doi:10.1158/1078-0432.CCR-14-1953
PMCID: PMC4506247  PMID: 25878333
XPO1; Exportin; CRM1; eIF5A; IGF2BP1
13.  Nanotechnology: Future of Oncotherapy 
Recent advances in nanotechnology have established its importance in several areas including medicine. The myriad of applications in oncology range from detection and diagnosis to drug delivery and treatment. Although nanotechnology has attracted a lot of attention, the practical application of nanotechnology to clinical cancer care is still in its infancy. This review summarizes the role that nanotechnology has played in improving cancer therapy, its potential for affecting all aspects of cancer care, and the challenges that must be overcome to realize its full promise.
doi:10.1158/1078-0432.CCR-14-1189
PMCID: PMC4505622  PMID: 26180057
14.  Metastasis regulation by PPARD expression in cancer cells 
JCI Insight  null;2(1):e91419.
Peroxisome proliferator–activated receptor–δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer.
PPARD in cancer cells is critical for metastasis development in in-vivo models, and high PPARD expression in human cancers is associated with increased metastasis risk.
doi:10.1172/jci.insight.91419
PMCID: PMC5214933  PMID: 28097239
15.  YAP1 and TAZ Activates mTORC1 Pathway by Regulating Amino Acid Transporters in hepatocellular carcinoma 
Hepatology (Baltimore, Md.)  2015;63(1):159-172.
Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma (HCC). Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. YAP1 and TAZ are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters SLC38A1 and SLC7A5. Subsequently, increased uptake of amino acids by the transporters activates mTORC1, a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in HCC patients. Furthermore, inhibition of the transporters and mTORC1 significantly block YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism’s potential clinical implications for treating HCC.
Conclusion
YAP1 and TAZ regulate cancer metabolism and mTOCR1 through regulation of amino acid transportation and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets.
doi:10.1002/hep.28223
PMCID: PMC4881866  PMID: 26389641
HCC; Hippo pathway; mTOR pathway; Amino acid transporters; metabolism; genomics
16.  Depression and oropharynx cancer outcome 
Psychosomatic medicine  2016;78(1):38-48.
Background
Studies have shown a modest relationship between depression and mortality in cancer patients. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following patients for a sufficient period of time.
Methods
We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit. All patients were optimally treated with radiation and sometimes chemotherapy. After adjusting for tumor stage, treatment, comorbidities, smoking, excessive alcohol use, and demographic factors, we assessed the effects of baseline self-reported depression on overall survival and recurrence.
Results
One hundred thirty participants were followed for a median of 5 years. The average age was 56 years, and 83% were male. Eighteen participants died during the study and 15 experienced disease recurrence. Self-reported depression was associated with decreased overall survival duration (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.2-10.8), and disease recurrence (HR = 3.8; 95% CI = 1.2-12.2) in multivariate analysis. In addition, smoking was associated with disease recurrence.
Conclusion
Patients with oropharyngeal cancer may benefit from depression screening and evidence-based treatments, if appropriate. Future studies are needed to determine whether depression is an independent prognostic factor of outcome and to elucidate biobehavioral mechanisms involved in patients with oropharyngeal cancer.
Precis
This prospective study evaluated the impact of self-reported depression on outcomes of patients diagnosed with oropharyngeal cancer and treated with radiation (with or without chemotherapy). After following one hundred thirty participants for a median of 5 years, we found that patients' self-reported depression was associated with decreased overall survival duration and disease recurrence.
doi:10.1097/PSY.0000000000000256
PMCID: PMC4696911  PMID: 26632757
Oropharynx; Depression; Survival; Recurrence
17.  PTEN expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer 
Molecular cancer therapeutics  2015;14(6):1466-1475.
PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN mutated and PTEN-wild type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared to Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared to the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to treatment FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development.
doi:10.1158/1535-7163.MCT-14-1077
PMCID: PMC4458384  PMID: 25833835
Focal adhesion kinase; PTEN; Uterine cancer
18.  Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis 
Oncogene  2015;35(18):2390-2397.
Adrenergic stimulation adversely affects tumor growth and metastasis, but the underlying mechanisms are not well understood. Here, we uncovered a novel mechanism by which catecholamines induce inflammation by increasing prostaglandin E2 (PGE2) levels in ovarian cancer cells. Metabolic changes in tumors isolated from patients with depression and mice subjected to restraint stress showed elevated PGE2 levels. Increased metabolites and PTGS2 and PTGES protein levels were found in Skov3-ip1 and HeyA8 cells treated with norepinephrine, and these changes were shown to be mediated by ADRB2 receptor signaling. Silencing PTGS2 resulted in significantly decreased migration and invasion in ovarian cancer cells in the presence of norepinephrine and decreased tumor burden and metastasis in restraint stress orthotopic models. In human ovarian cancer samples, concurrent increased ADRB2, PTGS2 and PTGES expression was associated with reduced overall and progression-free patient survival. In conclusion, increased adrenergic stimulation results in increased PGE2 synthesis via ADRB2-Nf-kB-PTGS2 axis, which drives tumor growth and metastasis.
doi:10.1038/onc.2015.302
PMCID: PMC4749473  PMID: 26257064
19.  Rac1/Pak1/p38/MMP-2 axis regulates angiogenesis in ovarian cancer 
Purpose
Zoledronic acid (ZA) is being increasingly recognized for its anti-tumor properties, but the underlying functions are not well understood. In this study, we hypothesized that ZA inhibits ovarian cancer (OC) angiogenesis preventing Rac1 activation.
Experimental Design
The biological effects of ZA were examined using a series of in vitro (cell invasion, cytokine production, Rac1 activation, reverse-phase protein array and in vivo (orthotopic mouse models) experiments.
Results
There was significant inhibition of OC (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of pro-angiogenic cytokines in response to ZA treatment. Furthermore, ZA inactivated Rac1 and decreased the levels of Pak1/p-38/matrix metalloproteinase-2 in OC cells. In vivo, ZA reduced tumor growth, angiogenesis and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel.
Conclusion
ZA has robust anti-tumor and anti-angiogenic activity and merits further clinical development as OC treatment.
doi:10.1158/1078-0432.CCR-14-2279
PMCID: PMC4417466  PMID: 25595279
Ovarian cancer; Angiogenesis; Rac1; Zoledronic acid
20.  Assessment of in vivo siRNA delivery in cancer mouse models 
RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs as cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discuss in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo.
doi:10.1007/978-1-4939-3378-5_15
PMCID: PMC5142631  PMID: 26721492
siRNA; Ovarian Cancer; Delivery; Cancer Therapy; stem-loop RT-PCR
21.  Morph-X-Select: Morphology-based tissue aptamer selection for ovarian cancer biomarker discovery 
BioTechniques  2016;61(5):249-259.
High affinity aptamer-based biomarker discovery has the advantage of simultaneously discovering an aptamer affinity reagent and its target biomarker protein. Here, we demonstrate a morphology-based tissue aptamer selection method that enables us to use tissue sections from individual patients and identify high-affinity aptamers and their associated target proteins in a systematic and accurate way. We created a combinatorial DNA aptamer library that has been modified with thiophosphate substitutions of the phosphate ester backbone at selected 5′dA positions for enhanced nuclease resistance and targeting. Based on morphological assessment, we used image-directed laser microdissection (LMD) to dissect regions of interest bound with the thioaptamer (TA) library and further identified target proteins for the selected TAs. We have successfully identified and characterized the lead candidate TA, V5, as a vimentin-specific sequence that has shown specific binding to tumor vasculature of human ovarian tissue and human microvascular endothelial cells. This new Morph-X-Select method allows us to select high-affinity aptamers and their associated target proteins in a specific and accurate way, and could be used for personalized biomarker discovery to improve medical decision-making and to facilitate the development of targeted therapies to achieve more favorable outcomes.
doi:10.2144/000114473
PMCID: PMC5136366  PMID: 27839510
morphology-based tissue aptamer selection; thioaptamer; laser microdissection; targeted protein; ovarian cancer
22.  A Framework for personalized surgical approach to ovarian cancer 
Nature reviews. Clinical oncology  2015;12(4):239-245.
The standard therapeutic approach for advanced ovarian cancer is upfront cytoreductive surgery followed by a combination of platinum and taxane-based chemotherapy. The degree of residual disease following upfront cytoreductive surgery correlates with objective response to adjuvant chemotherapy, rate of pathological complete response at second-look assessment operations, progression-free survival and overall survival. Contemporary data and meta-analyses have documented a continuous relationship between volume of residual disease and patient outcomes with those patients undergoing complete gross resection having the best outcomes, thereby focusing attention of surgical effort to remove as much disease as possible with the metric of “optimal” cytoreduction being R0 disease. Since patients with R0 resection appear to have the best overall outcomes, efforts to spare unnecessary primary debulking surgery by pre- or intra-operative assessment have abounded without external validity to incorporate into general practice. Serum CA125, physical examination and CT imaging have lacked accuracy in determining if disease can be optimally debulked. Therefore, an algorithm that identifies patients likely to achieve complete gross resection at primary surgery would be expected to improve patient survival. Herein, we review contemporary definitions of “optimal” residual disease, and discuss opportunities to personalize surgical therapy and improve the quality of surgical care delivered to patients with advanced ovarian cancer.
doi:10.1038/nrclinonc.2015.26
PMCID: PMC4528308  PMID: 25707631
23.  Depression and Risk of Epithelial Ovarian Cancer: Results from Two Large Prospective Cohort Studies 
Gynecologic oncology  2015;139(3):481-486.
Objectives
While emerging evidence supports a possible link between depression and ovarian cancer progression, no prospective studies have explored the association with ovarian cancer risk.
Methods
We prospectively followed 77 451 women from the Nurses' Health Study (1992-2010) and 106 452 women from the Nurses' Health Study II (1993-2011). Depression was defined as having one or more of the following: a 5-item Mental Health Index (MHI-5) score≤52, antidepressant use, or physician-diagnosed depression. Multivariate-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between depression and incident ovarian cancer.
Results
We documented 698 incident cases of epithelial ovarian cancer during follow-up. In multivariable analyses, depression assessed 2-4 years before cancer diagnosis was associated with a modestly higher incidence of ovarian cancer (HR=1.30, 95% CI1.05-1.60). Compared to women with persistent negative depression status, the adjusted HRs were 1.34 (95% CI 1.01-1.76) for women with persistent positive depression status and 1.28 (95% CI 0.88-1.85) for women with worsening depression status over follow-up. The association did not appear to vary by ovarian cancer risk factors or tumor characteristics.
Conclusions
Our findings suggest that depression may be associated with a modestly increased risk of ovarian cancer. Given the relatively high prevalence of depression in women, future work in larger prospective human studies is needed to confirm our results.
doi:10.1016/j.ygyno.2015.10.004
PMCID: PMC4679423  PMID: 26449316
depression; ovarian cancer; chronic stress; repeated measures; latency period; etiology
24.  Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches 
Cancer metastasis reviews  2015;34(1):19-40.
Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by antiangiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies.
doi:10.1007/s10555-014-9538-9
PMCID: PMC4369424  PMID: 25544368
Ovarian cancer; targeted therapy; angiogenesis; anti-vascular agent; resistance to anti-VEGF therapy
25.  New ways to successfully target tumor vasculature in ovarian cancer 
Purpose of review
The aim of this paper was to review the recent literature on potential therapeutic strategies for overcoming resistance to anti-VEGF drugs in ovarian cancer.
Recent findings
Although clinical benefits of anti-VEGF therapy were observed in ovarian cancer treatment trials, this use yielded only modest improvement in progression-free survival, and with the exception of cediranib no effect on overall survival. Adaptive resistance and escape from anti-angiogenesis therapy is likely a multifactorial process, including induction of hypoxia, vascular modulators and the immune response. New drugs targeting the tumor vasculature or other components of the surrounding microenvironment have shown promising results.
Summary
When to start and end antiangiogenesis therapy and the choice of optimal treatment combinations remain controversial. Further evaluation of personalized novel angiogenesis-based therapy is warranted. Defining the critical interaction of these agents and pathways and the appropriate predictive markers will become an increasingly important objective for effective treatment.
doi:10.1097/GCO.0000000000000136
PMCID: PMC4529067  PMID: 25502429
Angiogenesis; adaptive resistance; ovarian cancer

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