Altered ovarian cancer metabolism increases neuronal n-acetylaspartate to promote tumor growth

Background: Altered metabolism is a well-established trait in many cancers, and is an emerging hallmark of cancer. Recent resurgence of cancer metabolism studies has identified dysregulated metabolic pathways that produce novel oncometabolites in various cancers. However, large scale studies of dysregualted high grade serous epithelial ovarian cancers (HGSOC) are unknown. Materials and Methods: Following IRB approval, metabolic profiling of 101 HGSOC patients and 15 normal ovaries were obtained using GC/LC mass spectrometry from 2 U.S. academic centers to identify highly up-regulated metabolites. Samples from a cohort of 135 and 208 patients from a single institution were evaluated for gene expression and protein expression of NAT8L, respectively. Gene expression of NAT8L and clinical outcomes were further investigated from publicly available databases from the cancer genomics atlas (TCGA) using www.cbioportal.org, and two previously published melanoma gene expression profiles. Reverse Phase Protein Array (RPPA) and gene expression array were evaluated in HeyA8 ovarian cancer cell lines to investigate the protein and gene expression changes associated with NAT8L siRNA. In vitro and in vivo v experiments of NAT8L siRNA were investigated to evaluate its effects on cancer proliferation, apoptosis, cell cycle, and invasion/migration. Results: A total of 313 metabolites were identified between these two groups, of which 172 were significantly altered (p HeyA8 and A2780 cell lines showed that NAT8L siRNA significantly increased total apoptosis compared to control (NT) siRNA by 38.53% (p Genomic analysis of HEYA8 cells transfected with NAT8L siRNA compared to NT siRNA showed 1961 significantly different gene expression data (p Conclusion: HGSOC metabolic profiling revealed highly altered metabolism compared to the normal ovary. NAA is one of the most up-regulated metabolites in HGSOC. High levels of NAA are associated with worse overall survival in HGSOC. Furthermore, high expression of its biosynthetic gene (NAT8L) is associated with vii worse overall survival in HGSOC, invasive breast, lung squamous, colon, uterine, melanoma and renal cell cancers. Inhibiting NAA production decreases tumor growth, and tilts the cancer cell to a more catabolic steady state. Therefore, our data indicate that targeting cancer’s NAA production maybe an effective therapeutic approach

SSRI use and clinical outcomes in epithelial ovarian cancer

Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001). Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications

Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy

Hematogenous Metastasis of Ovarian Cancer: Rethinking Mode of Spread

SummaryOvarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis

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

Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer

We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understoo

Autocrine Effects of Tumor-Derived Complement

We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications