RESUMEN
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.
Asunto(s)
Neoplasias de la Mama/inmunología , Carcinoma Hepatocelular/inmunología , Transformación Celular Neoplásica/inmunología , Glioblastoma/inmunología , Neoplasias Hepáticas/inmunología , Macrófagos/inmunología , Células Madre Mesenquimatosas/inmunología , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Quimiocinas/metabolismo , Medios de Cultivo Condicionados , Citocinas/metabolismo , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Terapia de Inmunosupresión , Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Macrófagos/metabolismo , Macrófagos/patología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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 tumor-associated 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.
Asunto(s)
Neoplasias de la Mama/prevención & control , Quimiocina CCL2/metabolismo , Difosfonatos/farmacología , Imidazoles/farmacología , Macrófagos/efectos de los fármacos , Trasplante de Células Madre Mesenquimatosas/métodos , Animales , Conservadores de la Densidad Ósea/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Células Cultivadas , Quimiocina CCL2/genética , Citocinas/genética , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Lectinas Tipo C/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Mediciones Luminiscentes/métodos , Macrófagos/metabolismo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/prevención & control , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Ratones Desnudos , Interferencia de ARN , Receptores de Superficie Celular/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido ZoledrónicoRESUMEN
Magnetic resonance imaging (MRI) is used extensively for clinical diagnoses. It is critical to design and develop highly efficient MR contrast agents with simple preparation procedure, low toxicity, and high biocompatibility. Here, we report a carbon quantum dots (CQDs)-stabilized gadolinium hybrid nanoprobe (Gd-CQDs) prepared via a one-pot hydrothermal treatment of the mixture of citrate acid, ethanediamine, and GdCl3 at 200 °C for 4 h. In vitro and in vivo tests confirmed their low toxicity and high biocompatibility. Gd-CQDs were observed to have a higher MR response than gadopentetic acid dimeglumine (Gd-DTPA) because of their high Gd content and hydrophilicity. Moreover, the fluorescence of CQDs was remained in Gd-CQDs. The in vivo MR and fluorescence dual-modality imaging of Gd-CQDs was confirmed with zebrafish embryo and mice as models. The modification of Gd-CQDs with arginine-glycine-aspartic acid (RGD) tripeptide provided a high affinity to U87 cancer cells for targeted imaging. Whereas the MR response showed a depth penetration and spatial visualization, fluorescence revealed the fine distribution of Gd-CQDs in tissues because of its high resolution and sensitivity. We found that Gd-CQDs distributed in the tissues in a heterogeneous mode: they entered into the tissue cells but were observed less in the extracellular matrix. The MR and fluorescence dual-modality imaging of Gd-CQDs makes them a potential contrast agent for clinic applications because of their simple preparation procedure, ease of functionalization, high contrast efficiency, low toxicity, and high biocompatibility.
Asunto(s)
Carbono/química , Gadolinio/química , Imagen por Resonancia Magnética/métodos , Sondas Moleculares , Puntos Cuánticos/química , Espectrometría de Fluorescencia/métodos , Animales , Ratones , Microscopía Electrónica de Transmisión , Distribución Tisular , Pez CebraRESUMEN
OBJECTIVE: To investigate whether electroacupuncture (EA) can promote cell survival and enhance heart function of mesenchymal stem cells (MSCs) therapy. METHODS: MSCs were isolated from bone marrow and expanded in Minimum Essential Medium Alpha (α-MEM). MI was induced in 72 Sprague-Dawley (S-D) rats by ligation of the left anterior descending coronary artery (LAD) for 30 min and reperfusion. MI rats randomly received injection of 1×10(6) DiI-labeled MSCs alone (n =24, MSC group), or plus electroacupuncture (EA) at Neiguan (PC6, n=24, EA+MSC group), or saline (n =24, saline group). EA treatment was performed for 4 days. Another 24 rats were subjected to chest-open surgery without LAD occlusion and treatment (sham group). Three time points, 4, 14 and 28 days (n =8 for each group) were included in this study. The survival of transplanted MSCs and the protective gene expression were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot at day 4 and 14. Left ventricular remodeling, cardiac function, infarction area, fibrosis and capillary density were analyzed at day 28. RESULTS: EA can enhance MSC survival (2.6-fold up) at day 4. Big capillary density was 53% higher in EA+MSC treated group than MSC alone group. Furthermore, the rats treated by EA reduced the fibrosis and had 36% smaller infarct size comparing to MSC alone. EA also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts at week 4. CONCLUSION: EA at Neiguan acupoint can promote the stem cell survival and improve ischemic heart function. EA could become a useful approach in stem cell therapy for ischemia heart diseases.