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Jia X.-H.,CAS Institute of Automation | Du Y.,CAS Institute of Automation | Mao D.,Nankai University | Wang Z.-L.,Xidian University | And 7 more authors.
Oncotarget | Year: 2015

Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment. To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumorassociated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR. In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth. Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.

Jia X.-H.,CAS Institute of Automation | Feng G.-W.,Tianjin Medical University | Feng G.-W.,Nankai University | Wang Z.-L.,Xidian University | And 9 more authors.
Oncotarget | Year: 2016

Cancer development and progression is linked to tumor-associated macrophages (TAMs). Distinct TAMs subsets perform either protective or pathogenic effects in cancer. A protective role in carcinogenesis has been described for M1 macrophages, which activate antitumor mechanisms. By comparison, TAMs isolated from solid and metastatic tumors have a suppressive M2-like phenotype, which could support multiple aspects of tumor progression. Currently, it has not been clearly understood how macrophages in tumor-associated stroma could be hijacked to support tumor growth. Mesenchymal stem cells (MSCs) actively interact with components of the innate immune system and display both anti-inflammatory and pro-inflammatory effects. Here, we tested whether MSCs could favor the tumor to escape from immunologic surveillance in the presence of M1 macrophages. We found that MSCs educated by M1 condition medium (cMSCs) possessed a greatly enhanced ability in promoting tumor growth in vivo. Examination of cytokines/chemokines showed that the cMSCs acquired a regulatory profile, which expressed high levels of iNOS and MCP1. Consistent with an elevated MCP1 expression in cMSCs, the tumor-promoting effect of the cMSCs depended on MCP1 mediated macrophage recruitment to tumor sites. Furthermore, IL-6 secreted by the cMSCs could polarize infiltrated TAMs into M2- like macrophages. Therefore, when macrophages changed into M1 pro-inflammation type in tumor microenvironment, the MSCs would act as poor sensors and switchers to accelerate tumor growth.

Hu Z.,CAS Institute of Automation | Hu Z.,Beijing Key Laboratory of Molecular Imaging | Qu Y.,Chinese Peoples Armed Police forces Academy | Wang K.,CAS Institute of Automation | And 13 more authors.
Nature Communications | Year: 2015

Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications. © 2015 Macmillan Publishers Limited. All rights reserved.

Ma X.,CAS Institute of Automation | Ma X.,Stanford University | Ma X.,Beijing Key Laboratory of Molecular Imaging | Hui H.,CAS Institute of Automation | And 12 more authors.
Biomaterials | Year: 2016

SM5-1 is a humanized mouse monoclonal antibody, targeting an over-expressed membrane protein of approximately 230 kDa in hepatocellular carcinoma (HCC). SM5-1 can be used for target therapy in hepatocellular carinoma due to its ability of inhibiting cell growth and inducing apoptosis. However, the tumor inhibition efficacy of SM5-1 in HCC cancer treatment remains low. In this study, we synthesized SM5-1-conjugated gold nanoparticles (Au-SM5-1 NPs) and investigated their anticancer efficacy in HCC both in vitro and in vivo. The tumor inhibition rates of Au-SM5-1 NPs for subcutaneous tumor mice were 40.10% ± 4.34%, 31.37% ± 5.12%, and 30.63% ± 4.87% on day 12, 18, and 24 post-treatment as determined by bioluminescent intensity. In addition, we investigated the antitumor efficacy of Au-SM5-1 NPs in orthotopic HCC tumor models. The results showed that the inhibition rates of Au-SM5-1 NPs can reach up to 39.64% ± 4.87% on day 31 post-treatment determined by the bioluminescent intensity of the abdomen in tumor-bearing mice. Furthermore, three-dimensional reconstruction results of the orthotopic tumor revealed that Au-SM5-1 NPs significantly inhibited tumor growth compared with SM5-1 alone. Our results suggested that the developed Au-SM5-1 NPs has great potential as an antibody-based nano-drug for HCC therapy. © 2016 The Authors.

Shen W.,CAS Institute of Automation | Shen W.,Beijing Key Laboratory of Molecular Imaging | Zhou M.,Stanford University | Yang F.,Beijing Jiaotong University | And 10 more authors.
Pattern Recognition | Year: 2016

We investigate the problem of lung nodule malignancy suspiciousness (the likelihood of nodule malignancy) classification using thoracic Computed Tomography (CT) images. Unlike traditional studies primarily relying on cautious nodule segmentation and time-consuming feature extraction, we tackle a more challenging task on directly modeling raw nodule patches and building an end-to-end machine-learning architecture for classifying lung nodule malignancy suspiciousness. We present a Multi-crop Convolutional Neural Network (MC-CNN) to automatically extract nodule salient information by employing a novel multi-crop pooling strategy which crops different regions from convolutional feature maps and then applies max-pooling different times. Extensive experimental results show that the proposed method not only achieves state-of-the-art nodule suspiciousness classification performance, but also effectively characterizes nodule semantic attributes (subtlety and margin) and nodule diameter which are potentially helpful in modeling nodule malignancy. © 2016 Elsevier Ltd.

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