Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR\u27s tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Student's t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours

Ovarian cancer modulates the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells via glutamine metabolism

OBJECTIVE: Immature CD11b(+)Gr1(+) myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study\u27s objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: Depletion of Gr1(+) immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b(+)Gr1(+) myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b(+)Gr1(+) myeloid cells. CD11b(+)Gr1(+) myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b(+)Gr1(+) myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer

The Analysis of Receptor-binding Cancer Antigen Expressed on SiSo Cells (RCAS1) immunoreactivity within the microenvironment of the ovarian cancer lesion relative to the applied therapeutic strategy

RCAS1 is involved in generating the suppressive profile of the tumor microenvironment that helps cancer cells evade immune surveillance. The status of the cells surrounding the cancer nest may affect both the progression of the cancer and the development of metastases. In cases of ovarian cancer, a large number of patients do not respond to the applied therapy. The patient’s response to the applied therapy is directly linked to the status of the tumor microenvironment and the intensity of its suppressive profile. We analyzed the immunoreactivity of RCAS1 on the cells present in the ovarian cancer microenvironment in patients with the disease; these cells included macrophages and carcinoma-associated fibroblasts. Later we analyzed the immunoreactivity levels within these cells, taking into consideration the clinical stage of the cancer and the therapeutic strategy applied, such as the number of chemotherapy regiments, primary cytoreductive surgery, or the presence of advanced ascites. In the patients who did not respond to the therapy we observed significantly higher immunoreactivity levels of RCAS1 within the cancer nest than in those patients who did respond; moreover, in the non-responsive patients we found RCAS1 within both macrophages and carcinoma-associated fibroblasts. RCAS1 staining may provide information about the intensity of the immuno-suppressive microenvironment profile found in cases of ovarian cancer and its intensity may directly relate to the clinical outcome of the disease

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Depletion of immunosuppressive myeloid-derived suppressor cells impedes ovarian cancer growth.

Objective: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are increased in tumors and create an immunosuppressive environment by inhibiting the T cell function. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Increased MDSC accumulation in epithelial ovarian cancer (EOC) has been associated with poor prognosis. Our aim was to investigate whether depletion of MDSCs influences EOC progression. Method: The intraperitoneal ID8 syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study. The ID8 tumorbearing mice were treated once a week with either the anti-Gr1 specific antibody (Ab) that targets and depletes MDSCs or its isotype IgG2b Ab as control (100 μg/dose/mouse). Mice were sacrificed at day 60 for tumor burden evaluation. Quantification of various immune cells in blood, spleen, bone marrow, and ascites was performed by fluorescence-activated cell sorter (FACS) using specific cell surface markers and by immunohistochemistry (IHC). Cytokine levels were measured by ELISA. Results: ID8 tumor-bearing mice exhibited significantly higher levels of granulocytic (CD11b+Gr1high) and monocytic (CD11b+Gr1low) MDSCs (P b 0.001) in bone marrow, blood, and spleen compared to control mice with no tumors. When compared to MDSCs retrieved from the spleens of control nontumor-bearing mice, MDSCs isolated from tumor-bearing mice exhibited higher ability to suppress T cell proliferation (P b 0.01) and function as reflected by lower IFNgamma production (P b 0.01). Depletion of MDSCs using anti-Gr1 antibody significantly retarded the progression of ovarian cancer in mice as reflected by decreased ascites volume (P b 0.001) and tumor burden at diaphragm, peritoneal cavity, and other organs. Ascitic fluid from tumor-bearing mice treated with anti-Gr1 showed decreased MDSC counts associated with an increase in the number of IFN-gamma producing CD4 and CD8 T cells (P b 0.01). Conclusion: Our data suggest that reducing MDSCs can improve the antitumor immune response and AIDS in containing EOC progression. Thus targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies including T cell-based therapies