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1.
J Nanobiotechnology ; 17(1): 87, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387604

RESUMO

BACKGROUND: Adoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach. However, in vivo-administered T cells tend to disperse, with only a small proportion reaching the tumour. To remedy this, magnetic targeting of T cells has been recently explored. Magnetic nanoparticles (MNPs) functionalised with antibodies were attached to effector T cells and magnetically recruited to tumour sites under MRI guidance. In this study, we investigated whether 3-aminopropyl-triethoxysilane (APS)-coated MNPs directly attached to CD8+ T cell membranes could also magnetically target and accumulate tumour-specific CD8+ T cells in solid tumours using an external magnetic field (EMF). As it has been shown that T cells associated with APS-coated MNPs are retained in lymph nodes (LNs), and tumour-draining LNs are the most common sites of solid-tumour metastases, we further evaluated whether magnetic targeting of APS-MNP-loaded CD8+ T cells could cause them to accumulate in tumour-draining LNs. RESULTS: First, we show that antigen-specific CD8+ T cells preserve their antitumor activity in vitro when associated with APS-MNPs. Next, we demonstrate that the application of a magnetic field enhanced the retention of APS-MNP-loaded OT-I CD8+ T cells under flow conditions in vitro. Using a syngeneic mouse model, we found similar numbers of APS-MNP-loaded OT-I CD8+ T cells and OT-I CD8+ T cells infiltrating the tumour 14 days after cell transfer. However, when a magnet was placed near the tumour during the transfer of tumour-specific APS-MNP-loaded CD8+ T cells to improve tumour infiltration, a reduced percentage of tumour-specific T cells was found infiltrating the tumour 14 days after cell transfer, which was reflected in a smaller reduction in tumour size compared to tumour-specific CD8+ T cells transferred with or without MNPs in the absence of a magnetic field. Nonetheless, magnet placement near the tumour site during cell transfer induced infiltration of activated tumour-specific CD8+ T cells in tumour-draining LNs, which remained 14 days after cell transfer. CONCLUSIONS: The use of an EMF to improve targeting of tumour-specific T cells modified with APS-MNPs reduced the percentage of these cells infiltrating the tumour, but promoted the retention and the persistence of these cells in the tumour-draining LNs.


Assuntos
Transferência Adotiva , Linfócitos T CD8-Positivos/transplante , Linfonodos/patologia , Linfócitos do Interstício Tumoral/imunologia , Nanopartículas de Magnetita/química , Neoplasias Experimentais/terapia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Linfonodos/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/patologia , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Propilaminas/química , Silanos/química
2.
Anticancer Res ; 39(8): 4065-4071, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366489

RESUMO

BACKGROUND: Surgical orthotopic implantation of human colon cancer tissue to the ceca of mice has been used to mimic behavior of cancer in human patients for the development of precision cancer medicine. However, with the current method of serosal surface implantation (SSI) of pieces of human colon cancer tissue, cancer cells are exposed to the peritoneum, which can artificially increase the rate of peritoneal carcinomatosis (PC) during the disease course. The objective of the present study was to introduce a tumor-sealing method (TSM) and compare it with SSI for the ability to produce clinically-relevant metastases without artificial PC. MATERIALS AND METHODS: HCT116 colon cancer cells transfected with green fluorescence protein (GFP) were cultured and then injected into the subcutaneous layer of athymic nude mice. Subcutaneous tumors were allowed to grow sufficiently to supply adequate tumor for orthotopic implantation. For SSI, a 1 mm3-sized tumor fragment was sutured to partially torn serosa of the cecum. For TSM, the blind end of the cecum was folded over the tumor fragment and sealed with sutures. At 20 days after implantation, all mice were opened to visualize PC by intravital fluorescence imaging. At necropsy, distant metastasis was investigated using frozen section of whole blocks of organs. RESULTS: At 20 days after implantation, PC rates in the SSI group and the TSM group were 80% (12/15) and 20% (3/15), respectively (p<0.001). The liver metastasis rate was 41.7% (5/12) in the SSI group and 50% (5/10) in the TSM group (p=0.696). The lung metastasis rate was 0% (0/12) in the SSI group and 10% (1/10) in the TSM group (p=0.201). The mean survival of mice without PC on the 20th day was significantly longer than that of mice with PC on the 20th day (69.1±14.7 vs. 44.5±12.4 days, p=0.001). CONCLUSION: These results suggest that TSM might be a more patient-like and useful method as a model of metastatic colon cancer than SSI.


Assuntos
Carcinogênese/genética , Neoplasias do Colo/patologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/patologia , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/química , Células HCT116 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Transplante de Neoplasias/métodos , Imagem Óptica , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Gene ; 715: 144015, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357025

RESUMO

Tripartite Motif Containing 13 (TRIM13), a member of TRIM proteins, is deleted in multiple tumor types, especially in B-cell chronic lymphocytic leukemia and multiple myeloma. The present study explored the expression and potential role of TRIM13 in non-small-cell lung carcinoma (NSCLC). We found that TRIM13 mRNA and protein expression was reduced in NSCLC tissues and cell lines in comparison to paired non-cancerous tissues and a human normal bronchial epithelial cell line, respectively. Overexpression of TRIM13 in NCI-H1975 and SPC-A-1 cells hampered cell proliferation. Additionally, TRIM13 overexpression increased the levels of cleaved caspase-3. TRIM13-induced NSCLC cell apoptosis was attenuated by a caspase-3 inhibitor Ac-DEVD-CHO, suggesting that TRIM13 induced cell apoptosis partially through a caspase-3-dependent pathway. Moreover, it has been reported that TRIM13 can regulate nuclear factor kappaB (NF-κB) activity. Our data showed that TRIM13 overexpression inactivated NF-κB as indicated by the increased cytosolic NF-κB and decreased nuclear NF-κB. Exposure to an NF-κB inhibitor PDTC significantly blocked the impact of TRIM13 knockdown on cell proliferation and apoptosis, indicating the functions of TRIM13 in NSCLC cells were mediated by the NF-κB pathway. Finally, we demonstrated that TRIM13 overexpression suppressed tumor growth and induced cell apoptosis in vivo by using a xenograft mouse model. Collectively, our results indicate that TRIM13 behaves as a tumor suppressor in NSCLC through regulating NF-κB pathway. Our findings may offer a promising therapeutic target for NSCLC.


Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ligação a DNA/genética , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , NF-kappa B/genética , Transplante de Neoplasias , Transdução de Sinais , Proteínas Supressoras de Tumor/genética
4.
J Nanobiotechnology ; 17(1): 78, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269964

RESUMO

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Dissulfetos/química , Portadores de Fármacos/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/química , Hipertermia Induzida , Raios Infravermelhos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Fotoquimioterapia/métodos
5.
Gene ; 711: 143949, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31255735

RESUMO

As a transcriptional repressor, Chromobox 8 (CBX8) overexpression is found to be associated with tumorigenesis in several cancers. However, its role in radiotherapy resistance remains poorly characterized. Our study is the first to explore the correlation between CBX8 and radioresistance. We report here that CBX8 is upregulated in Esophageal Squamous Cell Carcinoma (ESCC) tissues and cells and serves as an indicator of poor prognosis for ESCC patients. CBX8 knockdown inhibits cell proliferation, colony formation capability, DNA repair and promotes cell apoptosis. Moreover, the transcriptome sequencing analysis demonstrates that CBX8 downregulates the expression of Apoptotic protease activating factor 1 (APAF1), which is the core protein that mediates mitochondrial apoptotic pathways. APAF1 depletion could abrogate apoptosis induced by CBX8 knockdown in irradiated ESCC cells. Our results provide novel insight into CBX8 as a therapeutic target to improve the radiosensitivity of ESCC.


Assuntos
Fator Apoptótico 1 Ativador de Proteases/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Complexo Repressor Polycomb 1/metabolismo , Tolerância a Radiação , Animais , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Complexo Repressor Polycomb 1/genética , Prognóstico , Regulação para Cima
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 491-497, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292052

RESUMO

Objective To investigate the effect of tumor microenvironment on the metabolism and function of myeloid-derived suppressor cells (MDSCs). Methods The spleen-derived MDSCs of lung cancer xenograft mice were isolated by immunomagnetic beads. After treated by Lewis tumor cell conditioned medium (TCCM) for 48 hours, real-time PCR was used to detect the mRNA levels of lactate dehydrogenase A (LDHA), glucose transporter-1 (GLUT1) and hypoxia-inducible factor 1α (HIF-1α). The hexokinase (HK) method was used to detect the concentration of glucose; the lactic acid test kit was used to detect the content of lactic acid which was the final production of glycolysis; and the 5, 6-carboxyfluorescein diacetate succinimiyl ester (CFSE) staining combined with flow cytometry was used to detect the immunosuppressive function of MDSCs on the proliferation of CD4+ T cells. Arginase kit was used to detect arginase 1 (ARG1) activity of MDSCs, and nitric oxide kit was used to detect the level of inducible nitric oxide synthase (iNOS). Results Compared with the untreated group, the mRNA levels of LDHA, GLUT1 and HIF-1α were up-regulated; the activity of ARG1 and the level of iNOS significantly increased; the immunosuppressive function of MDSCs on the proliferation of CD4+ T cells was significantly enhanced after the treatment of TCCM. Conclusion TCCM can activate the glycolytic pathway, up-regulate the immunosuppressive function on the proliferation of CD4+ T cells and the release of immunosuppressive effector molecule of MDSCs.


Assuntos
Meios de Cultivo Condicionados/química , Glicólise , Imunossupressão , Células Supressoras Mieloides/citologia , Microambiente Tumoral , Animais , Linfócitos T CD4-Positivos/citologia , Neoplasias Pulmonares , Camundongos , Transplante de Neoplasias
7.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288458

RESUMO

BACKGROUND/AIM: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers. METHODS: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model. RESULTS: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, 1H-NMR and 13C-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 µg/mL, respectively. CONCLUSION: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.


Assuntos
Alpinia/química , Antineoplásicos Fitogênicos/química , Extratos Vegetais/química , Pironas/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorofórmio/química , Flores/química , Xenoenxertos , Humanos , Malondialdeído/metabolismo , Metanol/química , Camundongos , Transplante de Neoplasias , Extratos Vegetais/farmacologia , Plantas Medicinais , Pironas/farmacologia , Solventes , Superóxido Dismutase/metabolismo
8.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288488

RESUMO

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Radioisótopos de Gálio/química , Glioblastoma/diagnóstico por imagem , Oligopeptídeos/química , Compostos Radiofarmacêuticos/química , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Feminino , Radioisótopos de Flúor , Glioblastoma/metabolismo , Humanos , Camundongos SCID , Transplante de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Tomografia Computadorizada por Raios X
9.
Zhongguo Zhong Yao Za Zhi ; 44(13): 2827-2834, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31359697

RESUMO

In this paper,the effects of active fractions of Ferula ferulaeoides on the growth and apoptosis of human gastric cancer cell MGC-803 transplantation tumor were systematically studied. The subcutaneous ectopic transplantation tumor model was established in human gastric cancer MGC-803 nude mice by cell suspension implantation method. The anti-tumor rate and organ index were used to evaluate the anti-tumor effect of the active fractions of F. ferulaeoides on the tumor-bearing nude mice. HE staining,TUNEL staining,RT-PCR,Western-blot and ELISA were used for pathological examination,apoptosis observation,and detection of apoptosis-related genes,proteins and cytokines expression. The results showed that as compared with the model group,the low,medium and high doses of the active fraction of F. ferulaeoides had inhibitory effects on xenografts in nude mice,respectively,in a dose-dependent manner; the apoptotic ratio was increased with the increase of drug concentration. As compared with the model group,F. ferulaeoides could down-regulate the expression of survivin mRNA in nude mice,and the protein expression levels of Bax,Bcl-2,caspase-3 and caspase-9 in tumor tissues of nude mice could be increased to different degrees in F. ferulaeoides groups. The contents of IL-10 and TGF-ß1 in plasma of nude mice were decreased in high dose group of F. ferulaeoides active fractions. The results indicated that F. ferulaeoides can significantly inhibit the growth of human gastric cancer MGC-803 subcutaneously transplanted tumor,and its mechanism may be related with down-regulating the expression of survivin mRNA,and up-regulating the expression of apoptosis-related proteins Bax,caspase-3 and caspase-9.


Assuntos
Apoptose , Ferula/química , Extratos Vegetais/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Caspase 3/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
10.
Nat Commun ; 10(1): 2510, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175290

RESUMO

Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis-promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Primárias Múltiplas/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Células HEK293 , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Mucinas/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Transplante de Neoplasias , Neoplasias Primárias Múltiplas/patologia , RNA Mensageiro/metabolismo , Carga Tumoral
11.
Nat Commun ; 10(1): 2484, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171773

RESUMO

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Citofagocitose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Antígenos de Neoplasias/metabolismo , Linfócitos B , Linhagem Celular Tumoral , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de IgG , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Anticancer Res ; 39(6): 2721-2727, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177107

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D50). RESULTS: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D50 values for these tumours were higher than for the simulated tumours without vessel collapse. CONCLUSION: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia.


Assuntos
Vasos Sanguíneos/lesões , Vasos Sanguíneos/efeitos da radiação , Neoplasias da Mama/radioterapia , Radiocirurgia/efeitos adversos , Animais , Vasos Sanguíneos/diagnóstico por imagem , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/diagnóstico por imagem , Hipóxia Celular , Linhagem Celular Tumoral , Fracionamento da Dose de Radiação , Feminino , Humanos , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Modelos Biológicos , Transplante de Neoplasias , Resultado do Tratamento
13.
Anticancer Res ; 39(6): 2739-2747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177109

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-ß. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.


Assuntos
Antígenos CD34/metabolismo , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Astragalus propinquus/química , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Medicina Tradicional Chinesa , Camundongos , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos
14.
Nat Commun ; 10(1): 2399, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160585

RESUMO

Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD's stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos/genética , Superóxido Dismutase/genética , Acetilação , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Técnicas In Vitro , Lisina/metabolismo , Células MCF-7 , Camundongos , Mutação , Transplante de Neoplasias , Peroxidase/metabolismo , Estrutura Quaternária de Proteína/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Tamoxifeno/uso terapêutico , Proteínas Supressoras de Tumor
15.
Nat Commun ; 10(1): 2406, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160622

RESUMO

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.


Assuntos
Líquido Ascítico , Carcinoma/secundário , Adesão Celular , Hidrodinâmica , Células-Tronco Neoplásicas/metabolismo , Oligossacarídeos/metabolismo , Neoplasias Ovarianas/patologia , Selectina-P/metabolismo , Neoplasias Peritoneais/secundário , Animais , Carcinoma/metabolismo , Linhagem Celular Tumoral , Epitélio/metabolismo , Feminino , Fucosiltransferases/metabolismo , Células HEK293 , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Peritônio/metabolismo , Receptor IGF Tipo 1/metabolismo , Estresse Mecânico
16.
Nat Commun ; 10(1): 2532, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182717

RESUMO

Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/metabolismo , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Knockout , Camundongos Nus , Mutação , Transplante de Neoplasias , Multimerização Proteica , Quinases raf/antagonistas & inibidores , Quinases raf/genética , Proteínas ras/metabolismo
17.
Nat Commun ; 10(1): 2416, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186412

RESUMO

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL9/metabolismo , Fator Inibidor de Leucemia/imunologia , Macrófagos/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/metabolismo , Epigênese Genética , Humanos , Memória Imunológica , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , Transplante de Neoplasias , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/imunologia
18.
Anticancer Res ; 39(6): 2729-2737, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177108

RESUMO

BACKGROUND/AIM: Salivary adenoid cystic carcinoma (SACC) is the most common malignancy of the salivary gland with a poor prognosis and survival. The present study aimed to investigate the role of histone methyltransferase WHSC1 in SACC. MATERIALS AND METHODS: Human SACC specimens were evaluated for WHSC1 expression by RT-PCR and immunohistochemistry. The effects of WHSC1 knockdown on SACC cells proliferation, cell cycle, clone and tumorsphere formation, and apoptosis as well as on the expression of related genes were examined. A xenograft mouse model of SACC was used to evaluate the in vivo effects of WHSC1 knockdown on SACC tumorigenesis. RESULTS: WHSC1 expression was up-regulated in human SACC tissues (p<0.01). WHSC1 knockdown in SACC cells significantly inhibited cell proliferation, clone and tumorsphere formation (p<0.05). Cell distribution at the S and G2/M phases was significantly reduced by WHSC1 knockdown (p<0.05). WHSC1 knockdown significantly increased apoptosis of SACC cells (p<0.05). c-Myc, survivin, Bcl-2 and cyclin B1 genes were significantly down-regulated by WHSC1 knockdown cells (p<0.05). WHSC1 knockdown significantly reduced H3K36me2 modification of the MYC gene promoter in SACC cells and tumorigenesis of SACC cells in vivo (p<0.05). CONCLUSION: Knockdown of WHSC1 inhibited cell proliferation, induced apoptosis and affected tumorigenesis in SACC.


Assuntos
Carcinoma Adenoide Cístico/patologia , Técnicas de Silenciamento de Genes/métodos , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Neoplasias das Glândulas Salivares/patologia , Regulação para Cima , Animais , Apoptose , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Transdução de Sinais
19.
Gene ; 711: 143941, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31242453

RESUMO

Inorganic arsenic is a well-known carcinogen associated with several types of cancer, but the mechanisms involved in arsenic-induced carcinogenesis are not fully understood. Recent evidence points to epigenetic dysregulation as an important mechanism in this process; however, the effects of epigenetic alterations in gene expression have not been explored in depth. Using microarray data and applying a multivariate clustering analysis in a Gaussian mixture model, we describe the alterations in DNA methylation around the promoter region and the impact on gene expression in HaCaT cells during the transformation process caused by chronic exposure to arsenic. Using this clustering approach, the genes were grouped according to their methylation and expression status in the epigenetic landscape, and the changes that occurred during the cellular transformation were identified adequately. Thus, we present a valuable method for identifying epigenomic dysregulation.


Assuntos
Arsênico/toxicidade , Transformação Celular Neoplásica/patologia , Metilação de DNA/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Neoplasias Cutâneas/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética
20.
Eur J Med Chem ; 177: 425-447, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158755

RESUMO

Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC50 of 0.10 ±â€¯0.01 µM than Regorafenib (IC50 = 0.16 ±â€¯0.04 µM). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Antineoplásicos/uso terapêutico , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Proteína da Polipose Adenomatosa do Colo/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/farmacologia , Transplante de Neoplasias , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Fatores de Troca de Nucleotídeo Guanina Rho/química , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
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