RESUMEN
Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a "professional" transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular "pilot" of tumor cell migration by locally amplifying PI3K-AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration-proliferation paradox of cancer cells that characterizes many cancers.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Fibrosarcoma/patología , Neoplasias Pulmonares/patología , Neoplasias Cutáneas/patología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Dietilnitrosamina/efectos adversos , Femenino , Fibrosarcoma/inducido químicamente , Fibrosarcoma/genética , Fibrosarcoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Vía de Señalización Hippo , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Metilcolantreno/efectos adversos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismoRESUMEN
For decades, proteases have been associated with cancer progression due to the ability of some members of this large group of enzymes to degrade tumor cell surroundings, thereby facilitating cancer invasion and dissemination. However, the generation of mouse models deficient in proteases has revealed the existence of a great variety of functions among proteolytic enzymes in cancer biology, including important tumor-suppressive roles. Therefore, in this chapter, we describe methods to chemically induce different types of cancer (lung adenocarcinoma, hepatocellular carcinoma, oral and esophageal carcinoma, colorectal carcinoma, skin cancer, and fibrosarcoma) in genetically modified mouse models to efficiently evaluate the specific pro- or antitumoral function of proteases in cancer.
Asunto(s)
Carcinoma/genética , Fibrosarcoma/genética , Neoplasias Experimentales/genética , Neoplasias/genética , Péptido Hidrolasas/genética , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Carcinoma/inducido químicamente , Carcinoma/patología , Femenino , Fibrosarcoma/inducido químicamente , Fibrosarcoma/patología , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/inducido químicamente , Neoplasias/patología , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patologíaRESUMEN
Vaccines are important for providing protection from infectious diseases. Vaccination initiates a process that stimulates development of a robust and long-lived immune response to the disease agents in the vaccine. Side effects are sometimes associated with vaccination. These vary from development of acute hypersensitivity responses to vaccine components to local tissue reactions that are annoying but not significantly detrimental to the patient. The pathogenesis of these responses and the consequent clinical outcomes are discussed. Overstimulation of the immune response and the potential relationship to autoimmunity is evaluated in relation to genetic predisposition.
Asunto(s)
Enfermedades de los Gatos/inducido químicamente , Enfermedades de los Perros/inducido químicamente , Vacunación/veterinaria , Vacunas/efectos adversos , Anafilaxia/inducido químicamente , Anafilaxia/veterinaria , Animales , Reacción de Arthus/inducido químicamente , Reacción de Arthus/veterinaria , Autoinmunidad/efectos de los fármacos , Autoinmunidad/genética , Gatos , Enfermedades de los Perros/genética , Perros , Fibrosarcoma/inducido químicamente , Fibrosarcoma/veterinaria , Enfermedades de los Caballos/inducido químicamente , Caballos , Inmunidad Colectiva , Inmunoglobulina E/inmunología , Vacunación/efectos adversosRESUMEN
Diagnosis of cancer and photothermal therapy using optoelectronic properties of noble metal nanoparticles (NPs) has established a new therapeutic approach for treating cancer. Here we address the intrinsic properties of noble metal NPs (gold and silver) as well as the mechanism of their potential antitumor activity. For this, the study addresses the functional characterization of tumor associated macrophages (TAMs) isolated from murine fibrosarcoma induced by a chemical carcinogen, 3-methylcholanthrene (MCA). We have previously shown antitumor activity of both gold nanoparticles (AuNPs) and silver nanoparticle (AgNPs) in vivo in a murine fibrosarcoma model. In the present study, it has been seen that AuNPs and AgNPs modulate the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, suppressing the antioxidant system of cells (TAMs). Moreover, the antioxidant-mimetic action of these NPs maintain the ROS and RNS levels in TAMs which act as second messengers to activate the proinflammatory signaling cascades. Thus, while there is a downregulation of tumor necrosis factor-α (TNF-α) and Interleukin-10 (IL-10) in the TAMs, the proinflammatory cytokine Interleukin-12 (IL-12) is upregulated resulting in a polarization of TAMs from M2 (anti-inflammatory) to M1 (pro-inflammatory) nature.
Asunto(s)
Fibrosarcoma/inmunología , Macrófagos/fisiología , Nanopartículas del Metal/administración & dosificación , Animales , Diferenciación Celular , Células Cultivadas , Fibrosarcoma/inducido químicamente , Oro/química , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Masculino , Nanopartículas del Metal/química , Metilcolantreno/toxicidad , Ratones , Estrés Oxidativo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Plata/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
USP15 is a deubiquitinase that negatively regulates activation of naive CD4(+) T cells and generation of IFN-γ-producing T helper 1 (Th1) cells. USP15 deficiency in mice promotes antitumor T cell responses in a transplantable cancer model; however, it has remained unclear how deregulated T cell activation impacts primary tumor development during the prolonged interplay between tumors and the immune system. Here, we find that the USP15-deficient mice are hypersensitive to methylcholantrene (MCA)-induced fibrosarcomas. Excessive IFN-γ production in USP15-deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet(+) regulatory T cells and CD11b(+)Gr-1(+) myeloid-derived suppressor cells at tumor site. Mixed bone marrow adoptive transfer studies further reveals a T cell-intrinsic role for USP15 in regulating IFN-γ production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-γ, which promotes an immunosuppressive tumor microenvironment during MCA-induced primary tumorigenesis.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Interferón gamma/metabolismo , Células TH1/metabolismo , Proteasas Ubiquitina-Específicas/genética , Animales , Anticuerpos Neutralizantes/inmunología , Antígeno B7-H1/metabolismo , Antígeno CD11b/metabolismo , Linfocitos T CD4-Positivos/inmunología , Línea Celular Tumoral , Quimiocina CXCL12/metabolismo , Fibrosarcoma/inducido químicamente , Fibrosarcoma/mortalidad , Fibrosarcoma/patología , Factores de Transcripción Forkhead/metabolismo , Interferón gamma/inmunología , Metilcolantreno/toxicidad , Ratones , Ratones Noqueados , Transducción de Señal , Tasa de Supervivencia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Microambiente Tumoral , Proteasas Ubiquitina-Específicas/deficienciaRESUMEN
Foxp3(+) regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3(+) T-bet(+) 'TH1-like' Tregs which are thymus-derived Helios(+) cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the TH1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69(+) Tregs are more suppressive than their CD69- counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.
Asunto(s)
Proliferación Celular , Fibrosarcoma/metabolismo , Interleucina-2/metabolismo , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/metabolismo , Sarcoma Experimental/metabolismo , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fibrosarcoma/inducido químicamente , Fibrosarcoma/genética , Fibrosarcoma/inmunología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-2/antagonistas & inhibidores , Interleucina-2/inmunología , Activación de Linfocitos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Metilcolantreno , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Sarcoma Experimental/inducido químicamente , Sarcoma Experimental/genética , Sarcoma Experimental/inmunología , Transducción de Señal , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Microambiente TumoralRESUMEN
The present study aimed to assess the antitumor effect of glycosphingolipid-incorporated liposomes (glycosphingosomes) in combination with liposomal doxorubicin (Lip-Dox) in a mouse model of fibrosarcoma. Glycosphingosomes were prepared by incorporating glycosphingolipids isolated from Sphingomonas paucimobilis into the liposomes of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, and cardiolipin. Tumors were induced by administering dimethyl-α-benzanthracene, and tumor-bearing mice were treated with various formulations of Dox, including free Dox, Lip-Dox, or glycosphingosomes + Lip-Dox. Mice were observed for 90 days to monitor their survival and tumor size. Free Dox, but not Lip-Dox or a combination of glycosphingosomes and Lip-Dox, caused the substantial depletion of leukocytes and significantly increased the levels of lactate dehydrogenase and creatinine kinase in mice. Tumor-bearing mice treated with a combination of glycosphingosomes and Lip-Dox showed restricted tumor growth and increased survival when compared to those treated with free Dox or Lip-Dox. The results of the present study suggest that a combination of glycosphingosomes and Lip-Dox may prove to be very effective in the treatment of tumors.
Asunto(s)
1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Doxorrubicina/análogos & derivados , Fibrosarcoma/inducido químicamente , Fibrosarcoma/tratamiento farmacológico , 1,2-Dipalmitoilfosfatidilcolina/química , Animales , Proliferación Celular/efectos de los fármacos , Química Farmacéutica , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Fibrosarcoma/patología , Ratones , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Análisis de SupervivenciaRESUMEN
Epidemiologic studies depict a negative correlation between caffeine consumption and incidence of tumors in humans. The main pharmacological effects of caffeine are mediated by antagonism of the adenosine receptor, A2AR. Here, we examine whether the targeting of A2AR by caffeine plays a role in anti-tumor immunity. In particular, the effects of caffeine are studied in wild-type and A2AR knockout (A2AR(-/-)) mice. Tumor induction was achieved using the carcinogen 3-methylcholanthrene (3-MCA). Alternatively, tumor cells, comprised of 3-MCA-induced transformed cells or B16 melanoma cells, were inoculated into animal footpads. Cytokine release was determined in a mixed lymphocyte tumor reaction (MLTR). According to our findings, caffeine-consuming mice (0.1% in water) developed tumors at a lower rate compared to water-consuming mice (14% vs. 53%, respectively, p=0.0286, n=15/group). Within the caffeine-consuming mice, tumor-free mice displayed signs of autoimmune alopecia and pronounced leukocyte recruitment intocarcinogen injection sites. Similarly, A2AR(-/-) mice exhibited reduced rates of 3-MCA-induced tumors. In tumor inoculation studies, caffeine treatment resulted in inhibition of tumor growth and elevation in proinflammatory cytokine release over water-consuming mice, as depicted by MLTR. Addition of the adenosine receptor agonist, NECA, to MLTR resulted in a sharp decrease in IFNγ levels; this was reversed by the highly selective A2AR antagonist, ZM241385. Thus, immune response modulation through either caffeine or genetic deletion of A2AR leads to a Th1 immune profile and suppression of carcinogen-induced tumorigenesis. Taken together, our data suggest that the use of pharmacologic A2AR antagonists may hold therapeutic potential in diminishing the rate of cancer development.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Cafeína/farmacología , Fibrosarcoma/inducido químicamente , Neoplasias Experimentales/inducido químicamente , Receptor de Adenosina A2A/metabolismo , Animales , Línea Celular Tumoral , Ciclopentanos/toxicidad , Fibrosarcoma/genética , Fibrosarcoma/metabolismo , Fibrosarcoma/prevención & control , Ratones , Ratones Noqueados , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/prevención & control , Receptor de Adenosina A2A/efectos de los fármacos , Receptor de Adenosina A2A/genética , Triazinas/farmacología , Triazoles/farmacologíaRESUMEN
Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.
Asunto(s)
Citotoxinas/farmacología , Fibrosarcoma/terapia , Depleción Linfocítica , Linfopenia/terapia , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Cisplatino/farmacología , Ciclofosfamida/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Resistencia a Medicamentos/inmunología , Etopósido/farmacología , Femenino , Fibrosarcoma/inducido químicamente , Fibrosarcoma/inmunología , Fibrosarcoma/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfopenia/inducido químicamente , Linfopenia/inmunología , Linfopenia/patología , Metilcolantreno , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Paclitaxel/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patología , Células Tumorales Cultivadas , Vidarabina/análogos & derivados , Vidarabina/farmacología , Irradiación Corporal Total , GemcitabinaRESUMEN
A TAT47-57 peptide was modified on the N-terminus by elongation with a 2,3-diaminopropionic acid residue and then by coupling of two histidine residues on its N-atoms. This branched peptide could bind to Ni under physiological conditions as a 1 : 1 complex. We demonstrated that the complex was quantitatively taken up by human fibrosarcoma cells, in contrast to Ni(2+) ions. Ni localization (especially at the nuclei) was confirmed by imaging using both scanning X-ray fluorescence microscopy and Newport Green fluorescence. A competitive assay with Newport Green showed that the latter displaced the peptide ligand from the Ni-complex. Ni(2+) delivered as a complex with the designed peptide induced substantially more DNA damage than when introduced as a free ion. The availability of such a construct opens up the way to investigate the importance of the nucleus as a target for the cytotoxicity, genotoxicity or carcinogenicity of Ni(2+).
Asunto(s)
Núcleo Celular/metabolismo , Fibrosarcoma/inducido químicamente , Fibrosarcoma/metabolismo , Níquel/metabolismo , Níquel/toxicidad , Fragmentos de Péptidos/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Secuencia de Aminoácidos , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/toxicidad , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/patología , Daño del ADN/efectos de los fármacos , Fibrosarcoma/genética , Fibrosarcoma/patología , Humanos , Níquel/administración & dosificación , Imagen Óptica , Fragmentos de Péptidos/química , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/químicaRESUMEN
Matrix metalloproteinase (MMP)-9 degrades type IV collagen in the basement membrane and plays crucial roles in several pathological implications, including tumorigenesis and inflammation. In this study, we analyzed the effect of flavonols on MMP-9 expression in phorbol-12-myristate-13-acetate (PMA)-induced human fibrosarcoma HT-1080 cells. Galangin and kaempferol efficiently decreased MMP-9 secretion, whereas fisetin only weakly decreased its secretion. Galangin and kaempferol did not affect cell viability at concentrations up to 30 µM. Luciferase reporter assays showed that galangin and kaempferol decrease transcription of MMP-9 mRNA. Moreover, galangin and kaempferol strongly reduce IκBα phosphorylation and significantly decrease JNK phosphorylation. These results indicate that galangin and kaempferol suppress PMA-induced MMP-9 expression by blocking activation of NF-κB and AP-1. Therefore, these flavonols could be used as chemopreventive agents to lower the risk of diseases involving MMP-9.
Asunto(s)
Fibrosarcoma/genética , Flavonoides/farmacología , Quempferoles/farmacología , Metaloproteinasa 9 de la Matriz/genética , Acetato de Tetradecanoilforbol/análogos & derivados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibrosarcoma/inducido químicamente , Fibrosarcoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas I-kappa B/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidor NF-kappaB alfa , Fosforilación , Transducción de Señal/efectos de los fármacos , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
The frequency of CD4(+) Foxp3(+) regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumour-infiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4(+) Foxp3(-) and CD4(+) Foxp3(+) T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines (CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3CL1), reflected by an enrichment of activated Foxp3(-) and Foxp3(+) T cells expressing T helper type 1-associated chemokine receptors. Notably, we found that CXCR3(+) T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3(-) and Foxp3(+) T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3(+) cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours.
Asunto(s)
Carcinógenos/toxicidad , Quimiocinas/inmunología , Fibrosarcoma/inducido químicamente , Fibrosarcoma/inmunología , Proteínas de Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Movimiento Celular/inmunología , Quimiocinas/genética , Femenino , Fibrosarcoma/genética , Fibrosarcoma/patología , Humanos , Metilcolantreno/toxicidad , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Linfocitos T Reguladores/patología , Células TH1/inmunología , Células TH1/patologíaRESUMEN
Tumor recognition by immune effector cells is mediated by antigen receptors and a variety of adhesion and costimulatory molecules. The evidence accumulated since the identification of CD155 and CD112 as ligands for DNAM-1 in humans and mice has suggested that the interactions between DNAM-1 and its ligands play an important role in T cell- and natural killer (NK) cell-mediated recognition and lysis of tumor cells. We have previously demonstrated that methylcholanthrane (MCA) accelerates tumor development in DNAM-1-deficient mice, and the Cd155 level on MCA-induced tumors is significantly higher in DNAM-1-deficient mice than in wild-type (WT) mice. By contrast, Cd112 expression on the tumors is similar in WT and DNAM-1-deficient mice, suggesting that CD155 plays a major role as a DNAM-1 ligand in activation of T cells and NK cells for tumor immune surveillance. To address this hypothesis, we examined MCA-induced tumor development in CD155-deficient mice. Unexpectedly, we observed no significant difference in tumor development between WT and CD155-deficient mice. Instead, we found that Cd112 expression was significantly higher in the MCA-induced tumors of CD155-deficient mice than in those of WT mice. We also observed higher expression of DNAM-1 and lower expression of an inhibitory receptor, TIGIT, on CD8+ T cells in CD155-deficient mice. These results suggest that modulation of the expression of receptors and CD112 compensates for CD155 deficiency in immune surveillance against MCA-induced tumors.
Asunto(s)
Antígenos de Neoplasias/genética , Moléculas de Adhesión Celular/genética , Fibrosarcoma/inducido químicamente , Fibrosarcoma/patología , Metilcolantreno/toxicidad , Proteínas de Neoplasias/genética , Animales , Antígenos de Diferenciación de Linfocitos T/genética , Citocinas/genética , Citocinas/metabolismo , Fibrosarcoma/genética , Humanos , Subunidad beta del Receptor de Interleucina-2/genética , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nectinas , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Linfocitos T/metabolismoRESUMEN
Immune suppression is well documented during tumor progression, which includes loss of effect of T cells and expansion of T regulatory (Treg) cells. IL-7 plays a key role in the proliferation, survival and homeostasis of T cells and displays a potent antitumor activity in vivo. In the present study, we investigated the antitumor effect of IL-7 in Meth A model. IL-7 inhibited tumor growth and prolonged the survival of tumor-bearing mice with corresponding increases in the frequency of CD4 and CD8 T cells, Th1 (CD4(+)IFN-γ(+)), Tc1 (CD8(+)IFN-γ(+)) and T cells cytolytic activity against Meth A cells. Neutralization of CD4 or CD8 T cells reversed the antitumor benefit of IL-7. Furthermore, IL-7 decreased regulatory T Foxp3 as well as cells suppressive activity with a reciprocal increase in SMAD7. In addition, we observed an increase of the serum concentrations of IL-6 and IFN-γ, and a significant decrease of TGF-ß and IL-10 after IL-7 treatment. Taken together, these results indicate that IL-7 augments T cell-mediated antitumor immunity and improves the effect of antitumor in Meth A model.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Citocinas/biosíntesis , Fibrosarcoma/terapia , Interleucina-7/administración & dosificación , Neoplasias Cutáneas/terapia , Linfocitos T Reguladores/efectos de los fármacos , Animales , Anticuerpos Bloqueadores/administración & dosificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Citocinas/sangre , Citocinas/genética , Citotoxicidad Inmunológica/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Fibrosarcoma/inducido químicamente , Fibrosarcoma/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , Metilcolantreno/metabolismo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/inmunología , Proteína smad7/genética , Proteína smad7/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Phorbol ester (PMA or TPA), a tumor promoter, can cause either proliferation or cell cycle arrest, depending on cellular context. For example, in SKBr3 breast cancer cells, PMA hyper-activates the MEK/MAPK pathway, thus inducing p21 and cell cycle arrest. Here we showed that PMA-induced arrest was followed by conversion to cellular senescence (geroconversion). Geroconversion was associated with active mTOR and S6 kinase (S6K). Rapamycin suppressed geroconversion, maintaining quiescence instead. In this model, PMA induced arrest (step one of a senescence program), whereas constitutively active mTOR drove geroconversion (step two). Without affecting Akt phosphorylation, PMA increased phosphorylation of S6K (T389) and S6 (S240/244), and that was completely prevented by rapamycin. Yet, T421/S424 and S235/236 (p-S6K and p-S6, respectively) phosphorylation became rapamycin-insensitive in the presence of PMA. Either MEK or mTOR was sufficient to phosphorylate these PMA-induced rapamycin-resistant sites because co-treatment with U0126 and rapamycin was required to abrogate them. We next tested whether activation of rapamycin-insensitive pathways would shift quiescence towards senescence. In HT-p21 cells, cell cycle arrest was caused by IPTG-inducible p21 and was spontaneously followed by mTOR-dependent geroconversion. Rapamycin suppressed geroconversion, whereas PMA partially counteracted the effect of rapamycin, revealing the involvement of rapamycin-insensitive gerogenic pathways. In normal RPE cells arrested by serum withdrawal, the mTOR/pS6 pathway was inhibited and cells remained quiescent. PMA transiently activated mTOR, enabling partial geroconversion. We conclude that PMA can initiate a senescent program by either inducing arrest or fostering geroconversion or both. Rapamycin can decrease gero-conversion by PMA, without preventing PMA-induced arrest. The tumor promoter PMA is a gero-promoter, which may be useful to study aging in mammals.
Asunto(s)
Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/patología , Carcinógenos/farmacología , Senescencia Celular/efectos de los fármacos , Fibrosarcoma/inducido químicamente , Fibrosarcoma/patología , Acetato de Tetradecanoilforbol/farmacología , Neoplasias de la Mama/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Interacciones Farmacológicas , Femenino , Fibrosarcoma/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación , Sirolimus/farmacologíaRESUMEN
Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-α. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function.
Asunto(s)
Fibrosarcoma/inmunología , Macrófagos Peritoneales/inmunología , Papiloma/inmunología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Neoplasias Cutáneas/inmunología , Receptor Toll-Like 4/inmunología , 9,10-Dimetil-1,2-benzantraceno/administración & dosificación , Animales , Carcinogénesis , Movimiento Celular/efectos de los fármacos , Fibrosarcoma/inducido químicamente , Fibrosarcoma/genética , Genotipo , Factor de Crecimiento de Hepatocito/metabolismo , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Metilcolantreno/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Papiloma/inducido químicamente , Papiloma/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/genética , Balance Th1 - Th2 , Activación Transcripcional/genética , TranscriptomaRESUMEN
This work reports the chemopreventive property of hydroalcoholic extract of the Trichosanthes dioica root (TDA) against 3-methylcholanthrene (3-MC)-induced carcinogenesis in Swiss albino mice. TDA was administered orally at 2 and 4 mg/kg for 45 days after 24 hours of a single subcutaneous administration of 3-MC (200 µg) in mice. The mice were observed for 15 weeks to record tumor incidence (fibrosarcoma) and survival. After 15 weeks the mice were killed for the evaluation of hematological profiles and hepatic biochemical parameters viz lipid peroxidation, reduced glutathione, glutathione-S-transferase, superoxide dismutase, and catalase. TDA treatment markedly reduced tumor incidence and prolonged the life span of sarcoma-bearing mice compared with 3-MC control mice. Hematological profiles of TDA-treated mice were restored significantly to normal levels. TDA treatment significantly modulated the liver biochemical parameters compared with 3-MC control. Therefore, TDA possesses remarkable cancer chemopreventive efficacy plausibly mediated by multiple mechanisms in Swiss albino mice.
Asunto(s)
Fibrosarcoma/inducido químicamente , Fibrosarcoma/prevención & control , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/prevención & control , Metilcolantreno/efectos adversos , Extractos Vegetales/uso terapéutico , Raíces de Plantas , Trichosanthes , Animales , Catalasa/metabolismo , Quimioprevención/métodos , Modelos Animales de Enfermedad , Fibrosarcoma/metabolismo , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Fitoterapia/métodos , Extractos Vegetales/farmacología , Superóxido Dismutasa/metabolismo , Resultado del TratamientoRESUMEN
The NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response upon infectious insults or tissue injury and damage. However, the role of the NLRP3 inflammasome in natural killer (NK) cell-mediated control of tumor immunity is poorly understood. Here, we show in a model of chemical-induced carcinogenesis and a series of experimental and spontaneous metastases models that mice lacking NLRP3 display significantly reduced tumor burden than control wild-type (WT) mice. The suppression of spontaneous and experimental tumor metastases and methylcholanthrene (MCA)-induced sarcomas in mice deficient for NLRP3 was NK cell and IFN-γ-dependent. Focusing on the amenable B16F10 experimental lung metastases model, we determined that expression of NLRP3 in bone marrow-derived cells was necessary for optimal tumor metastasis. Tumor-driven expansion of CD11b(+)Gr-1(intermediate) (Gr-1(int)) myeloid cells within the lung tumor microenvironment of NLRP3(-/-) mice was coincident with increased lung infiltrating activated NK cells and an enhanced antimetastatic response. The CD11b(+)Gr-1(int) myeloid cells displayed a unique cell surface phenotype and were characterized by their elevated production of CCL5 and CXCL9 chemokines. Adoptive transfer of this population into WT mice enhanced NK cell numbers in, and suppression of, B16F10 lung metastases. Together, these data suggested that NLRP3 is an important suppressor of NK cell-mediated control of carcinogenesis and metastases and identify CD11b(+)Gr-1(int) myeloid cells that promote NK cell antimetastatic function.
Asunto(s)
Proteínas Portadoras/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Animales , Antígeno CD11b/inmunología , Quimiocina CCL5/inmunología , Quimiocina CXCL9/inmunología , Fibrosarcoma/inducido químicamente , Fibrosarcoma/inmunología , Fibrosarcoma/patología , Inflamasomas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Masculino , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/secundario , Metilcolantreno , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Metástasis de la Neoplasia , Neoplasias Experimentales/patología , Neoplasias Experimentales/secundario , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patologíaRESUMEN
Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy.
Asunto(s)
Carcinógenos Ambientales/toxicidad , Fibrosarcoma/inducido químicamente , Exposición Materna/efectos adversos , Petróleo/toxicidad , Neoplasias Retroperitoneales/inducido químicamente , Neoplasias de los Tejidos Blandos/inducido químicamente , Muslo , Femenino , Fibrosarcoma/congénito , Humanos , Recién Nacido , Masculino , Exposición Paterna/efectos adversos , Neoplasias Retroperitoneales/congénito , Neoplasias de los Tejidos Blandos/congénito , España , Encuestas y CuestionariosRESUMEN
Cancer immunoediting, the process by which the immune system controls tumor growth and shapes tumor immunogenicity, consists of 3 stages: elimination, equilibrium, and escape. The molecular mechanisms that underlie the equilibrium phase, during which the immune system maintains tumor dormancy, remain incompletely defined. Here, we investigated the length of the equilibrium phase during immune control of methylcholanthrene (MCA)-induced or p53 mutant cancers and showed the critical and opposing roles of interleukin (IL)-23 and IL-12 in maintaining cancer cells in a state of immune-mediated dormancy. Inhibition of IL-23p19 was shown to reduce the malignant potential of lesions established by MCA inoculation, whereas inhibition of IL-12/23p40 enhanced tumor outgrowth. Furthermore, agonistic anti-CD40 antibody treatment mimicked the effects of anti-IL-23p19 monoclonal antibody treatment. Other cytokines such as IL-4, IL-17, TNF, and IFNαß, which are known to play important roles either in MCA tumorigenesis or in the elimination phase of cancer immunoediting, did not play critical roles in maintaining the equilibrium phase. Taken together, our findings show opposing roles for IL-23 and IL-12 in determining the outgrowth versus dormancy of occult neoplasia and suggest a potential long-term danger in using IL-12/23p40 antibodies for treating human autoimmune inflammatory disorders.