Vascular endothelial growth factor receptor-1 mRNA overexpression in peripheral blood as a useful prognostic marker in breast cancer

INTRODUCTION: Identification of useful markers associated with poor prognosis in breast cancer patients is critically needed. We previously showed that expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful to predict distant metastasis in gastric cancer patients. However, expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood of breast cancer patients has not yet been studied. METHODS: Real-time reverse transcriptase-PCR was used to analyze vascular endothelial growth factor receptor-1 mRNA expression status with respect to various clinical parameters in 515 patients with breast cancer and 25 controls. RESULTS: Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood was higher in breast cancer patients than in controls. Increased vascular endothelial growth factor receptor-1 mRNA expression was associated with large tumor size, lymph node metastasis and clinical stage. Patients with high vascular endothelial growth factor receptor-1 mRNA expression also experienced a poorer survival rate than those with low expression levels, including those patients with triple-negative type and luminal-HER2(-) type disease. CONCLUSIONS: Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful for prediction of poor prognosis in breast cancer, especially in patients with triple-negative type and luminal-HER2(-) type disease

Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14+ monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients

IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway

Myeloid-derived suppressor cells (MDSCs) are immune negative regulators in the tumour microenvironment. Interleukin (IL)-11, a member of IL-6 family cytokines, functions through the unique receptor IL-11 receptor α coupled with the common signal transducer gp130. IL-11-gp130 signalling causes activation of the JAK/STAT3 pathway. IL-11 is highly upregulated in many types of cancers and one of the most important cytokines during tumourigenesis and metastasis. However, the precise effect of IL-11 on differentiation into MDSCs is still unknown. Here, we found that CD11b+CD14+ monocytic MDSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence of IL-11. IL-11-conditioned PBMCs induced higher expression of immunosuppressive molecules such as arginase-1. A reduction of T-cell proliferation was observed when MDSCs generated in the presence of IL-11 were co-cultured with CD3/CD28-stimulated, autologous T cells of healthy donors. Culture of normal PBMCs with IL-11 led to STAT3 phosphorylation and differentiation into MDSCs via STAT3 activation. We confirmed expressions of both IL-11 and phosphorylated STAT3 in tumour tissues of colorectal cancer patients. These findings suggest that monocytic MDSCs may be induced by IL-11 in the tumour microenvironment. Thus, IL-11-mediated regulation in functional differentiation of MDSCs may serve as a possible target for cancer immunotherapy

Pressure induced phase transformation of Ba8Ga16Ge30 clathrate studied by x-ray diffraction and Raman spectroscopy

The phase transition and the vibrational properties of Ba8Ga16Ge30 have been investigated at high pressures up to 40 GPa at room temperature. The combined study of the high-pressure Raman and synchrotron powder x-ray diffraction (XRD) experiments revealed the occurrence of a first-order phase transition at 33 GPa, on which a volume decrease of about 3% was found. Rietveld refinements of the XRD data demonstrated the atomic displacements precursory to the phase transition, allowing us to discuss the mechanism of the phase transition. In the Raman experimental data, anomalies were observed in the spectral feature and the guest vibration around 17 GPa. By combining the Raman results with the XRD ones, the vibrational frequency of the guest Ba was investigated as a function of the host cage size. As a result, a linear relation between guest vibrational frequency and the guest-host distance was identified

IL6 modulates the immune status of the tumor microenvironment to facilitate metastatic colonization of colorectal cancer cells

It is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL-6, a proinflammatory cytokine produced in tumor-bearing states, promotes the metastatic colonization of colon cancer cells in association with dysfunctional anti-tumor immunity. In IL-6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the anti-tumor effector function of CD8+ T cells as well as IL-12 production by CD11c+ dendritic cells were augmented in vivo. Furthermore, IL-6-deficient mice exhibited enhanced IFNAR1- mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. In vivo injection of anti-PD-L1 antibody effectively suppressed the metastatic colonization of CT26 cells in Il6-/- but not Il6+/+ mice. Finally, we confirmed that colorectal cancer patients with low IL-6 levels in their primary tumors showed prolonged disease-free survival. These findings suggest IL-6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy

Design and characterization of mesoscopic dielectric cuboid antenna for operation in WR-3.4 waveguide bandwidth (220–330 GHz)

Abstract We designed a mesoscopic dielectric cuboid antenna connected to a flangeless WR-3.4 open-ended waveguide, and the antenna characteristics at 300 GHz were examined through simulations and experiments. Simulations confirmed that the flangeless design eliminated the flange-induced ripples in the radiation pattern, whose shape varied with frequency, and that the antenna operated in the full bandwidth of the WR-3.4 waveguide (220–330 GHz). Prototypes were then fabricated based on the simulation findings. A prototype with an antenna aperture area of 1.5 mm $$\times$$ × 1.5 mm and an antenna length of 2.35 mm exhibited an antenna gain of 17.2 dBi at 300 GHz and a voltage standing wave ratio of less than 1.5 throughout the WR-3.4 waveguide bandwidth. The level of the side lobes at about $$\pm 30$$ ± 30 degrees in the E-plane pattern was approximately $$-10$$ - 10 dB that of the main lobe. Therefore, the proposed antenna, connected to a flangeless waveguide, is a promising antenna for use in future short-range high-speed terahertz wireless applications such as kiosk downloads and board-to-board communication