Resveratrol inhibits ovarian tumor growth in an in vivo mouse model.

BACKGROUND: Resveratrol inhibits the growth of ovarian carcinoma cells in vitro through the inhibition of glucose metabolism and the induction of both autophagy and apoptosis. In the current study, we investigated the metabolic and therapeutic effects of resveratrol in vivo. METHODS: A fluorescent xenograft mouse model of ovarian cancer was used. Mice were treated with cisplatin, resveratrol, or vehicle alone. Tumor burden was assessed using whole-body imaging. The effect of resveratrol on glucose uptake in vivo was determined using micro-positron emission tomography scanning. To determine whether resveratrol could inhibit tumor regrowth, tumor-bearing mice were treated with cisplatin followed by either daily resveratrol or vehicle. Autophagic response in resected tumors taken from mice treated with resveratrol was examined by transmission electron microscopy. Glycolysis and mitochondrial respiration in ovarian tumor cells after treatment with resveratrol was assessed. RESULTS: Mice treated with resveratrol and cisplatin were found to have a significantly reduced tumor burden compared with control animals (P<.001). Resveratrol-treated mice demonstrated a marked decrease in tumor uptake of glucose compared with controls. After treatment with cisplatin, "maintenance" resveratrol resulted in the suppression of tumor regrowth compared with mice receiving vehicle alone (P<.01). Tumors resected from mice treated with resveratrol exhibited autophagosomes consistent with the induction of autophagy. Treatment with resveratrol inhibited glycolytic response in ovarian tumor cells with high baseline glycolytic rates. CONCLUSIONS: Treatment with resveratrol inhibits glucose uptake and has a significant antineoplastic effect in a preclinical mouse model of ovarian cancer. Resveratrol treatment suppresses tumor regrowth after therapy with cisplatin, suggesting that this agent has the potential to prolong disease-free survival. Cancer 2016;122:722-729. © 2015 American Cancer Society.

Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells.

OBJECTIVES: Upregulation of glycolysis has been demonstrated in multiple tumor types. Glucose deprivation results in diminished intracellular ATP; this is counteracted by AMPK activation during energy deficiency to restore ATP levels. We sought to determine whether glucose deprivation could induce cytotoxicity in ovarian cancer cells through activation of AMPK, and whether AMPK activators could mimic glucose deprivation induced cytotoxicity. METHODS: Sensitivity to 2DG induced cytotoxicity and glucose deprivation was determined in a panel of ovarian cancer cells. Cellular growth rate, rate of glucose uptake, and response to glucose deprivation were determined. Expression of Glut-1, HIF1-α, AMPK and Akt was determined by immunoblotting. RESULTS: Incubation of ovarian cancer cells with glucose-free media, 2-DG and AMPK activators resulted in cell death. The glycolytic phenotype of ovarian cancer cells was present in both normoxic and hypoxic conditions, and did not correlate with HIF1-α expression levels. Sensitivity to glucose deprivation was independent of growth rate, rate of glucose uptake, and appeared to be dependent upon constitutive activation of Akt. Glucose deprivation resulted in activation of AMPK and inhibition of Akt phosphorylation. Treatment with AMPK activators resulted in AMPK activation, Akt inhibition, and induced cell death in ovarian cancer cells. CONCLUSIONS: Ovarian cancer cells are glycolytic as compared to normal, untransformed cells, and are sensitive to glucose deprivation. Because ovarian cancer cells are dependent upon glucose for growth and survival, treatment with AMPK activators that mimic glucose deprivation may result in broad clinical benefits to ovarian cancer patients.

Chemotherapy in pregnancy.

One in 1000 pregnancies is complicated with cancer with the most common tumors being breast cancer, cervical cancer, thyroid, leukemia, lymphoma, and ovarian cancer. It is often assumed that cancer during pregnancy necessitates sacrificing the well-being of the fetus but in most cases appropriate treatment can be offered to the mother without placing the fetus at serious risk. The care of a pregnant woman with cancer involves evaluation of competing maternal and fetal risks and benefits. Although it is rare to administer chemotherapy during pregnancy, the risks depend on the drugs used and the gestational age of the fetus. During the period of organogenesis (4 to 13 wk), administration of cytotoxic drugs carries an increased risk of fetal malformations and fetal loss. Chemotherapy in the second or third trimester is associated with intrauterine growth retardation, prematurity, and low birth weight and bone marrow toxicity in many exposed infants.

Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer.

BACKGROUND: Murine studies suggest that myeloid cells such as vascular leukocytes (VLC) and Tie2+ monocytes play a critical role in tumor angiogenesis and vasculogenesis. Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The elimination of these cells from the tumor microenvironment significantly restricts tumor growth in both spontaneous and xenograft murine tumor models. Thus animal studies indicate that myeloid cells are potential therapeutic targets for solid tumor therapy. Abundant VLC and Tie2+ monocytes have been reported in human cancer. Unfortunately, the importance of VLC in human cancer growth remains untested as there are no confirmed therapeutics to target human VLC. METHODS: We used FACS to analyze VLC in ovarian and non-ovarian tumors, and characterize the relationship of VLC and Tie2-monocytes. We performed qRT-PCR and FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Alemtuzumab. We assessed Alemtuzumab's ability to induce complement-mediated VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. RESULTS: Human VLC are present in ovarian and non-ovarian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potently induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti-CD52 immunotherapy targeting VLC restricts tumor angiogenesis and growth in murine ovarian cancer. CONCLUSION: These studies confirm VLC/myeloid cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogenic therapeutic in ovarian cancer. The identification of an FDA approved anti-VLC agent with a history of clinical use will allow immediate proof-of-principle clinical trials in patients with ovarian cancer.

Resveratrol inhibits glucose metabolism in human ovarian cancer cells.

OBJECTIVES: Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response. METHODS: Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment. RESULTS: We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis. CONCLUSIONS: Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.

Sexual Health, Mental Health, and Beliefs About Cancer Treatments Among Women Attending a Gynecologic Oncology Clinic.

INTRODUCTION: Sexual health is an important, yet overlooked, aspect of quality of life for gynecologic oncologic patients. Although patients with gynecologic cancer frequently report sexual health concerns, there are limited efforts to address these problems. A comprehensive understanding of the relationship between mental health and sexual health needs to be prioritized. AIM: To examine multiple components of sexual health in patients with gynecologic cancer. METHODS: For the present study, sexual health concerns (ie, sexual frequency, desire, response, and satisfaction; orgasm; and pain during sex; independent variables), beliefs about cancer treatments affecting sexual health (dependent variable), and mental health (ie, anxiety and depressive symptoms; dependent variables) of patients at a US gynecologic oncology clinic were assessed. MAIN OUTCOME MEASURES: Demographics; cancer diagnosis; positive screening results for cancer; sexual health histories including sexual frequency, desire, pain, orgasm, responsiveness, and satisfaction; and mental health including depression and anxiety symptoms. RESULTS: Most women reported experiencing at least one sexual health concern, and half the women screened positive for experiencing symptoms of depression and anxiety. Forty-nine percent of participants reported having no or very little sexual desire or interest in the past 6 months. Further, in mediation analyses, pain during sex was significantly and positively correlated with depressive symptoms (r = 0.42, P < .001), and this relationship was fully mediated by believing that cancer treatments affected one's sexual health (B = 0.16, 95% confidence interval = 0.01-0.48, P < .05). CONCLUSION: Findings emphasize the need to further address and incorporate sexual and mental health into standard care for patients attending gynecologic oncology clinics. Screening women for whether and to what extent they perceive cancer treatments affecting their sexual health could provide a brief, easily administrable, screener for sexual health concerns and the need for further intervention. Intervention development for patients with gynecologic cancer must include mental health components and addressing perceptions of how cancer treatments affect sexual health functioning. Eaton L, Kueck A, Maksut J, et al. Sexual Health, Mental Health, and Beliefs About Cancer Treatments Among Women Attending a Gynecologic Oncology Clinic. Sex Med 2017;5:e175-e183.

Coregistered photoacoustic and ultrasound imaging and classification of ovarian cancer: ex vivo and in vivo studies.

Most ovarian cancers are diagnosed at advanced stages due to the lack of efficacious screening techniques. Photoacoustic tomography (PAT) has a potential to image tumor angiogenesis and detect early neovascular changes of the ovary. We have developed a coregistered PAT and ultrasound (US) prototype system for real-time assessment of ovarian masses. Features extracted from PAT and US angular beams, envelopes, and images were input to a logistic classifier and a support vector machine (SVM) classifier to diagnose ovaries as benign or malignant. A total of 25 excised ovaries of 15 patients were studied and the logistic and SVM classifiers achieved sensitivities of 70.4 and 87.7%, and specificities of 95.6 and 97.9%, respectively. Furthermore, the ovaries of two patients were noninvasively imaged using the PAT/US system before surgical excision. By using five significant features and the logistic classifier, 12 out of 14 images (86% sensitivity) from a malignant ovarian mass and all 17 images (100% specificity) from a benign mass were accurately classified; the SVM correctly classified 10 out of 14 malignant images (71% sensitivity) and all 17 benign images (100% specificity). These initial results demonstrate the clinical potential of the PAT/US technique for ovarian cancer diagnosis.

Correlating optical coherence elastography based strain measurements with collagen content of the human ovarian tissue.

In this manuscript, the initial feasibility of a catheter based phase stabilized swept source optical coherence tomography (OCT) system was studied for characterization of the strain inside different human ovarian tissue groups. The ovarian tissue samples were periodically compressed with 500 Hz square wave signal along the axial direction between the surface of an unfocused transducer and a glass cover slide. The displacement and corresponding strain were calculated during loading from different locations for each tissue sample. A total of 27 ex vivo ovaries from 16 patients were investigated. Statistically significant difference (p < 0.001) was observed between the average displacement and strain of the normal and malignant tissue groups. A sensitivity of 93.2% and a specificity of 83% were achieved using 25 microstrain (µÎµ) as the threshold. The collagen content of the tissues was quantified from the Sirius Red stained histological sections. The average collagen area fraction (CAF) obtained from the tissue groups were found to have a strong negative correlation (R = -0.75, p < 0.0001) with the amount of strain inside the tissue. This indicates much softer and degenerated tissue structure for the malignant ovaries as compared to the dense, collagen rich structure of the normal ovarian tissue. The initial results indicate that the swept source OCT system can be useful for estimating the elasticity of the human ovarian tissue.

Asymptomatic postmenopausal simple ovarian cyst.

UNLABELLED: High-resolution transvaginal ultrasound frequently reveals incidental, simple ovarian cysts in asymptomatic postmenopausal women. Traditionally oophorectomy has been recommended for these women. However, evidence is emerging that most postmenopausal simple ovarian cysts are benign, allowing conservative management. Furthermore, many of these cysts will resolve spontaneously. Cancer antigen 125 (CA-125) and color Doppler may help differentiate benign from malignant cysts. When oophorectomy is favored, the laparoscopic approach may be considered, depending on the clinical situation. Nonoperative management of simple ovarian cysts in asymptomatic women is reasonable; regular follow-up with sonography should be performed. Because sonography is an operator-dependent test, it is imperative that the sonographer have expertise in ovarian imaging. Monitoring of CA-125 levels may be useful. Indications for removal during follow-up are increasing size, development of solid components, abnormal Doppler flow, CA-125 elevation, patient desire for removal of the cyst, and noncompliance with sonographic follow-up. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to estimate the prevalence of benign simple ovarian cysts in a postmenopausal population of women, to describe the natural history of a simple ovarian cyst, and outline the features consistent with a benign ovarian cyst on ultrasound.

A large cohort study of hypothyroidism and hyperthyroidism in relation to gynecologic cancers.

Background. Thyroid status may influence tumorigenesis of gynecologic cancers, yet epidemiologic studies of this relationship are limited and inconsistent. Methods. We evaluated the association of self-reported history of physician-diagnosed hypothyroidism and hyperthyroidism with medical-record confirmed endometrial (EC; all invasive adenocarcinomas) and ovarian cancer (OC; epithelial ovarian or peritoneal cancers) in Nurses' Health Study (NHS) from 1976 to 2010 and NHSII from 1989 to 2011. Cox proportional hazard models were used to estimate multivariable rate ratios (RRs) and 95% confidence intervals based on pooled cohort data. Results. We confirmed 1314 incident cases of EC and 1150 cases of OC. Neither a history of hypothyroidism nor hyperthyroidism was significantly associated with risk of EC or OC. However, having a history of hypothyroidism for 8+ years (median) was nonsignificantly inversely associated with EC (RR = 0.81; 95% CI = 0.63-1.04; P-trend with history duration = 0.11) and OC (RR = 0.87, 95% CI = 0.66-1.15; P-trend = 0.13). Having a history of hyperthyroidism for 6+ years (median) was non-significantly positively associated with EC (RR = 1.69; 95% CI = 0.86-3.30; P-trend = 0.12) but not OC (RR = 1.12; 95% CI = 0.46-2.72; P-trend = 0.95). Conclusions. A history of hypothyroidism or hyperthyroidism was not significantly associated with risk of EC or OC.

Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival.

Markers that reliably identify cancer stem cells (CSC) in ovarian cancer could assist prognosis and improve strategies for therapy. CD133 is a reported marker of ovarian CSC. Aldehyde dehydrogenase (ALDH) activity is a reported CSC marker in several solid tumors, but it has not been studied in ovarian CSC. Here we report that dual positivity of CD133 and ALDH defines a compelling marker set in ovarian CSC. All human ovarian tumors and cell lines displayed ALDH activity. ALDH(+) cells isolated from ovarian cancer cell lines were chemoresistant and preferentially grew tumors, compared with ALDH(-) cells, validating ALDH as a marker of ovarian CSC in cell lines. Notably, as few as 1,000 ALDH(+) cells isolated directly from CD133(-) human ovarian tumors were sufficient to generate tumors in immunocompromised mice, whereas 50,000 ALDH(-) cells were unable to initiate tumors. Using ALDH in combination with CD133 to analyze ovarian cancer cell lines, we observed even greater growth in the ALDH(+)CD133(+) cells compared with ALDH(+)CD133(-) cells, suggesting a further enrichment of ovarian CSC in ALDH(+)CD133(+) cells. Strikingly, as few as 11 ALDH(+)CD133(+) cells isolated directly from human tumors were sufficient to initiate tumors in mice. Like other CSC, ovarian CSC exhibited increased angiogenic capacity compared with bulk tumor cells. Finally, the presence of ALDH(+)CD133(+) cells in debulked primary tumor specimens correlated with reduced disease-free and overall survival in ovarian cancer patients. Taken together, our findings define ALDH and CD133 as a functionally significant set of markers to identify ovarian CSCs.