Paraneoplastic thrombocytosis in ovarian cancer

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p&gt

Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity <it>in vitro</it>. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.</p> <p>Methods</p> <p>To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition <it>in vitro </it>using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m²/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).</p> <p>Results</p> <p>Doxycyline <it>in vitro </it>completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.</p> <p>Conclusion</p> <p>Doxycycline can block MMP-2 and MMP-9 activities from glioma cells <it>in vitro</it>. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.</p

Decreased expression of RNA interference machinery, Dicer and Drosha, is associated with poor outcome in ovarian cancer patients

The clinical and functional significance of RNA interference (RNAi) machinery, Dicer and Drosha, in ovarian cancer is not known and was examined. Dicer and Drosha expression was measured in ovarian cancer cell lines (n=8) and invasive epithelial ovarian cancer specimens (n=111) and correlated with clinical outcome. Validation was performed with previously published cohorts of ovarian, breast, and lung cancer patients. Anti-Galectin-3 siRNA and shRNA transfections were used for in vitro functional studies. Dicer and Drosha mRNA and protein levels were decreased in 37% to 63% of ovarian cancer cell lines and in 60% and 51% of human ovarian cancer specimens, respectively. Low Dicer was significantly associated with advanced tumor stage (p=0.007), and low Drosha with suboptimal surgical cytoreduction (p=0.02). Tumors with both high Dicer and Drosha were associated with increased median patient survival (&gt;11 years vs. 2.66 years for other groups; p&lt;0.001). In multivariate analysis, high Dicer (HR=0.48; p=0.02), high-grade histology (HR=2.46; p=0.03), and poor chemoresponse (HR=3.95; p&lt;0.001) were identified as independent predictors of disease-specific survival. Findings of poor clinical outcome with low Dicer expression were validated in separate cohorts of cancer patients. Galectin-3 silencing with siRNA transfection was superior to shRNA in cell lines with low Dicer (78-95% vs. 4-8% compared to non-targeting sequences), and similar in cell lines with high Dicer. Our findings demonstrate the clinical and functional impact of RNAi machinery alterations in ovarian carcinoma and support the use of siRNA constructs that do not require endogenous Dicer and Drosha for therapeutic applications

Erythropoietin Stimulates Tumor Growth via EphB4

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

Molecular Clustering Based on ERα and EIG121 Predicts Survival in High-Grade Serous Carcinoma of the Ovary/Peritoneum

Assessment of estrogen receptor expression by immunohistochemistry has yielded inconsistent results as a prognostic indicator in ovarian carcinoma. In breast and endometrial carcinomas, panels of estrogen-induced genes have shown improved prognostic capability over the use of estrogen receptor immunohistochemistry alone. For both breast and endometrial cancer, over-expression of estrogen-induced genes is associated with better prognosis. We hypothesized that analysis of a panel of estrogen-induced genes can predict outcome in ovarian carcinoma and potentially differentiate between tumors of varying hormonal responsiveness. From a cohort of 219 women undergoing ovarian cancer surgery from 2004 −2007, 83 patients were selected for inclusion. All patients had advanced stage ovarian/primary peritoneal high-grade serous carcinoma and underwent primary surgical debulking followed by adjuvant treatment with platinum and taxane agents. The expression of ER α and six genes known to be induced by estrogen in the female reproductive tract ( EIG121, sFRP1, sFRP4, RALDH2, PR, IGF-1 ) was measured using qRT-PCR. Unsupervised cluster analyses were used to categorize patients as high or low gene expressors. Gene expression results were then compared to those for estrogen receptor immunohistochemistry. Clusters were compared using chi-square analyses, and Cox proportional hazards were used to evaluate survival outcomes. Median follow-up time was 38.7 months (range 1–68). A cluster defined by EIG121 and ER α segregated tumors into distinct groups of high and low gene expressors. Shorter overall survival was associated with high gene expression (HR 2.84 [1.11–7.30], p=0.03), even after adjustment for other covariates. No difference in estrogen receptor immunohistochemistry expression was noted between gene clusters. In contrast to other hormonally-driven cancers, high expression of ER α and the estrogen-induced gene EIG121 predicts shorter overall survival in patients with high-grade serous ovarian carcinoma. Such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population

Using Continuous Glucose Monitoring to Motivate Physical Activity in Overweight and Obese Adults: A Pilot Study

Background: Regular physical activity (PA) is associated with a lower risk of several types of cancers. However, two-thirds of overweight/obese adults are not sufficiently active; this, in combination with the unfavorable effect of excess body weight, puts them at a greater risk for cancer. One reason that these individuals do not engage in enough PA may be their lack of motivation to change their current behavior due to the perception of putting in effort for possible future gain without obvious short-term benefits. There is a need for innovative ways to help individuals recognize the immediate health benefits of PA and thus increase their motivation. Methods: This pilot intervention tested a PA education module that included a one-on-one counseling session highlighting the acute effects of PA on glucose patterns, followed by a 10-day self-monitoring period with a continuous glucose monitor (CGM) and a Fitbit tracker. Participants rated the acceptability of the education module on a 5-point Likert scale and completed surveys assessing stages of change for motivational readiness. Results: Nineteen overweight/obese adults (84% female) completed the study. Participants gave high ratings to the counseling session for improving their PA-related knowledge (mean 4.22), increasing motivation (mean 4.29), and providing personally relevant information (mean 4.35). The summary acceptability scores for the self-monitoring period were 4.46 for CGM and 4.51 -for Fitbit. Participants reported a significant decrease in the precontemplation stage and an increase in the action stage (P < 0.05). Conclusions: CGM is a feasible tool for PA interventions. Impact: Information from CGM could be used as biologicalbased feedback to motivate PA.12 month embargo; published online: 17 February 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]