RESUMO
Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.
Assuntos
Neoplasias Associadas a Colite/etiologia , Granulócitos/patologia , Interleucina-17/fisiologia , Fator de Transcrição STAT1/fisiologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/fisiopatologia , Progressão da Doença , Feminino , Granulócitos/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Microambiente Tumoral/imunologiaAssuntos
Adaptação Fisiológica/fisiologia , Neoplasias Pulmonares/diagnóstico , Pulmão/patologia , Neoplasias Experimentais/diagnóstico , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal , Animais , Carcinógenos/toxicidade , Progressão da Doença , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/fisiopatologia , Camundongos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Fatores de Tempo , Uretana/toxicidadeRESUMO
BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model.
Assuntos
Caquexia/etiologia , Carcinoma 256 de Walker/fisiopatologia , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Neoplasias Experimentais/fisiopatologia , Proteoglicanas/metabolismo , Animais , Líquido Ascítico/química , Caquexia/metabolismo , Carcinoma 256 de Walker/química , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos , Mioblastos , Proteoglicanas/isolamento & purificação , Ratos , Ratos WistarRESUMO
La asociación entre cáncer e inflamación en un órgano o tejido se encuentra sólidamente establecida. En efecto, se sabe que en sitios de inflamación crónica, existe una mayor probabilidad de que se origine un tumor y que procesos inflamatorios locales pueden acelerar el crecimiento de tumores preexistentes en animales y seres humanos. Por otro lado, la relación entre cáncer e inflamación sistémica ha sido menos estudiada. En este trabajo, demostramos que el crecimiento de un fibrosarcoma de ratón (MC-C) fue acompañado por inflamación sistémica, evidenciada por neutrofilia y por un aumento de la concentración sérica de las citoquinas pro-inflamatorias interleuquina-1 beta (IL-1 beta), interleuquina-6 (IL-6) y factor de necrosis tumoral-alfa (TNF-alfa) y de las proteínas de fase aguda C reactiva (CRP) y A amieloide (SAA). Hubo un pico de estas moléculas poco después de la inoculación del tumor, que cayó a valores normales después de la primera semana, para luego comenzar a incrementarse progresivamente en función del tamaño tumoral. Una variación similar fue vista en el porcentaje de neutrófilos polimorfonucleares (PMN) circulantes. En ratones portadores de tumores grandes la mayoría de los PMN exhibían activación evidenciada por aumento en la generación de especies reactivas del oxígeno y alta expresión de los marcadores Gr1+/Mac1+. La inoculación de tioglicolato, que produce una inflamación sistémica transitoria, aceleró el crecimiento de MC-C, mientras que el tratamiento anti-inflamatorio con indometacina revirtió ese efecto. Esto sugiere que MC-C podría utilizar el fenómeno de inflamación sistémica que genera por sí mismo, como parte de su estrategia de crecimiento.
The link between cancer and inflammation in an organ or tissue has firmly been established on the basis that cancer tends to occur at sites of chronic inflammation and that local inflammatory processes can accelerate the growth of preexisting tumors in both animals and human beings. In contrast, the relationship between cancer and systemic inflammation has been less studied. In this work, we demonstrated that the growth of the murine fibrosarcoma MC-C, was accompanied by manifestations of systemic inflammation, as demonstrated by an increase in both the number of circulating polymorphonuclear neutrophils (PMN) and the serum concentration of the proinflammatory cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) and the acute phase proteins C reactive (CRP) and serum A amyloid (SAA). Two temporally separate peaks of systemic inflammation were detected during tumor development. The first was displayed during the first week after tumor inoculation. The second peak began around day 14 and its intensity was proportional to tumor size. In mice bearing a large MC-C tumor, a high number of circulating PMN and myeloid precursors were evident. Most of these cells exhibited activation evidenced by an increased reactive oxygen species generation and high expression of the Gr1+/Mac1+ markers. Inoculation of thioglycolate -which generates a transient systemic inflammation- accelerated the growth of MC-C tumor and reciprocally, inhibition of such systemic inflammation by using indomethacin, prevented that enhancing effect. This suggests that the systemic inflammation that the tumor generates on its own, could be part of its growth strategy.
Assuntos
Animais , Camundongos , Citocinas/sangue , Fibrossarcoma/patologia , Inflamação/patologia , Neoplasias Experimentais/fisiopatologia , Fibrossarcoma/sangue , Fibrossarcoma/fisiopatologia , Inflamação/sangue , Inflamação/fisiopatologia , Interleucina-1beta/sangue , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/sangue , Proteína Amiloide A Sérica/análise , Biomarcadores Tumorais/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
The gene p53 has been fashioned as the guardian of the genome and as prototype of the tumour suppressor gene (TSG) whose function must be inactivated in order for tumours to develop. The ubiquitous expression of truncated p53 protein isoforms, results in "premature ageing" of laboratory mouse strains engineered for expressing such isoforms. These facts have been construed in the argument that p53 evolved in order to protect organisms with renewable tissues from developing cancer yet, because p53 is also an inducer of cellular senescence or apoptosis after extensive DNA damage, it becomes a limiting factor for tissue renewal by depleting tissues from stem/precursor cells thus leading to whole-organism ageing. From that point of view p53 displays antagonist pleiotropy contributing to the establishment of degenerative diseases and ageing. Therefore, tumour suppression becomes a balancing act between cancer prevention and ageing. Nevertheless, here we present current evidence showing that the aforementioned argument is rather inconsistent and unwarranted on evolutionary grounds. The evolutionary perspective indicates that p53 evolved so as to play a subtle but very important role during development while its role as a TSG is only important in animals that are protected from most sources of extrinsic mortality, thus suggesting that p53 was primarily selected for its developmental role and not as a TSG. Therefore no real antagonist pleiotropy can be attached to p53 functions and their relationship with whole-organism ageing might be a laboratory artefact.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Evolução Molecular , Neoplasias Experimentais/metabolismo , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Animais , Humanos , Neoplasias/mortalidade , Neoplasias/fisiopatologia , Neoplasias Experimentais/mortalidade , Neoplasias Experimentais/fisiopatologia , Proteína Supressora de Tumor p53/antagonistas & inibidoresRESUMO
A variety of chemicals can adversely affect the immune system and influence tumor development. The modifying potential of chemical carcinogens on the lymphoid organs and cytokine production of rats submitted to a medium-term initiation-promotion bioassay for carcinogenesis was investigated. Male Wistar rats were sequentially initiated with N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4hydroxybutyl)nitrosamine (BBN), dihydroxy-di-n-propylnitrosamine (DHPN), and 1,2-dimethylhydrazine (DMH) during 4 weeks. Two initiated groups received phenobarbital (PB) or 2-acetylaminofluorene (2-AAF) for 25 weeks and two noninitiated groups received only PB or 2-AAF. A nontreated group was used as control. Lymphohematopoietic organs, liver, kidneys, lung, intestines, and Zymbal's gland were removed for histological analysis. Interleukin (IL)-2, IL-12, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), IL-10, and transforming growth factor beta1 (TGF-beta1) levels were determined by ELISA in spleen cell culture supernatants. At the fourth week, exposure to the initiating carcinogens resulted in cell depletion of the thymus, spleen and bone marrow, and impairment of IL-2, IL-12, and IFN-gamma production. However, at the 30th week, no important alterations were observed both in lymphoid organs and cytokine production in the different groups. The results indicate that the initiating carcinogens used in the present protocol exert toxic effects on the lymphoid organs and affect the production of cytokines at the initiation step of carcinogenesis. This early and reversible depression of the immune surveillance may contribute to the survival of initiated cells facilitating the development of future neoplasia.
Assuntos
Bioensaio/métodos , Carcinógenos/toxicidade , Modelos Animais de Doenças , Tecido Linfoide/efeitos dos fármacos , Mutagênicos/toxicidade , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias da Medula Óssea/induzido quimicamente , Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/fisiopatologia , Carcinógenos/administração & dosagem , Citocinas/biossíntese , Tecido Linfoide/patologia , Tecido Linfoide/fisiopatologia , Masculino , Mutagênicos/administração & dosagem , Neoplasias Experimentais/fisiopatologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Neoplasias Esplênicas/induzido quimicamente , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/fisiopatologia , Neoplasias do Timo/induzido quimicamente , Neoplasias do Timo/patologia , Neoplasias do Timo/fisiopatologiaRESUMO
En las últimas décadas la medicina evolucionó hacia un enfoque molecular en la búsqueda de blancos específicos que permitan seguir adecuadamente la progresión de las patologías neoplásicas y desarrollar terapias exitosas. El conocimiento y comprensión de que la matriz extracelular (MEC) que rodea a un tumor influye sobre el comportamiento del mismo, reveló la importancia que cumplen las metaloproteinasas (MMPs) en la regulación de los componentes de la MEC, y por lo tanto en el desarrollo tumoral. Es por ello que actualmente se está evaluando la eficacia de inhibidores sintéticos de estas enzimas en ensayos clínicos, algunos ya en fase clínica III de investigación. También se propone que estas MMPs podrían ser utilizadas como marcadores bioquímicos, permitiendo evaluar la progresión de la enfermedad en pacientes que sufren patologías neoplásicas, e incluso dar un valor pronóstico. Es en este punto en que el laboratorio de análisis clínicos cumplirá un papel fundamental y deberá contar con los conocimientos y las herramientas necesarias para evaluar la presencia y actividad de estas enzimas. En este trabajo se expone el conocimiento actual de la estructura y funciones biológicas de las MMPs así como los antecedentes que muestran el papel que cumplen en las enfermedades neoplásicas, en especial en leucemias y linfomas (AU)
Assuntos
Humanos , Biomarcadores Tumorais , Neoplasias/fisiopatologia , Neoplasias Experimentais/fisiopatologia , Leucemia/fisiopatologia , Linfoma/fisiopatologia , Neovascularização Patológica/etiologia , Fatores de Crescimento Endotelial/sangue , Neoplasias/enzimologia , Neoplasias/irrigação sanguínea , Neoplasias Experimentais/enzimologia , Leucemia/enzimologia , Linfoma/enzimologia , Progressão da Doença , Neovascularização Patológica/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/fisiopatologia , Transtornos Linfoproliferativos , Metástase Neoplásica/fisiopatologiaRESUMO
A differential effect of pregnancy on the growth of subcutaneous implants of four murine tumors has been observed. Two tumors lacking receptors for progesterone and estrogen [methylcholanthrene-induced fibrosarcoma (MC-C) and spontaneous lymphoid leukemia (LB)] exhibited slow kinetics throughout the course of pregnancy, although inhibition was stronger beyond day 10. On the other hand, one of two tumors bearing receptors for progesterone and estrogen [medroxyprogesterone (MPA)-induced mammary adenocarcinoma (C7HI)] exhibited three phases: up to days 8-10 of gestation the tumor grew faster than in virgins, between days 8-10 and 15 it reached a plateau, and beyond day 15 a sharp reduction in tumor mass was observed. The other tumor [mouse mammary tumor virus (MMTV)-induced mammary carcinoma(T2280)] behaved as a typical pregnancy-dependent tumor (i.e., it grew in pregnant but not in virgin mice, regressed soon after delivery, and reassumed its growth at the middle of a second round of pregnancy). Neither MPA nor estrogen affected MC-C and LB tumor growth. On the other hand, MPA-treated mice enhanced C7HI tumor and reciprocally C7HI tumor-bearing mice treated with estrogen strongly inhibited tumor growth. As for T2280, neither MPA nor estrogen alone could promote tumor growth and, in consequence, no tumor developed. However, when MPA plus estrogen was administered in a schedule simulating the successive appearance of these hormones in pregnancy, T2280 grew even faster than in pregnant mice. When the four tumors were implanted in mice bearing grafts of embryonal tissues (teratomas), all of them were inhibited. This antitumor effect was similar to that observed in pregnancy when tumors unresponsive to progesterone and estrogen were tested. On the other hand, with tumors bearing progesterone and estrogen receptors, differences in tumor growth were detected in pregnant and teratoma-bearing mice. This suggested the existence during pregnancy of two factors potentially acting on tumor growth. First, a progesterone and estrogen-mediated hormonal component, which would exert either inhibitory or stimulatory effects only evidenced with tumors bearing hormonal receptors. Secondly, an antitumor effect proportional to the growing embryonal mass, inhibiting all tumors independently of their origin or hormone responsiveness. This antitumor effect could be attributed to a beat-resistant serum factor (1,000-1,200 Da molecular weight) presumably associated with the pathway of the arachidonic acid metabolism. The interplay between the hormonal component and the serum factor associated with embryonal mass could account for some of the largely heterogeneous and otherwise unexplained effects of pregnancy on tumor growth reported in the literature and illustrated by the four tumors studied here.
Assuntos
Hormônios/fisiologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/fisiopatologia , Complicações Neoplásicas na Gravidez/fisiopatologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Estrogênios/farmacologia , Feminino , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/patologia , Fibrossarcoma/fisiopatologia , Hormônios/farmacologia , Indometacina/farmacologia , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/patologia , Leucemia Linfoide/fisiopatologia , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Neovascularização Patológica , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Progesterona/metabolismo , Progesterona/farmacologia , Receptores de Progesterona/metabolismo , Teratoma/patologia , Teratoma/fisiopatologiaRESUMO
The authors studied the effect of either extracts from liver (LE) or the malignant tumour ES2 (TE) or plasma from intact mice (PI) or tumour-bearing animals (PT) on the mitotic activity of the hepatocytes and tongue keratinocytes in young, growing C3H/s male mice (28+/-1 days old). Animals standardized for periodicity analysis were injected intraperitoneally with either TE, LE, PI, PT, or saline (S) at 16:00 h with 0.01 ml of sample/g of body weight and were then killed at (time of day/h post-injection) 20:00/04, 00:00/08, and 04:00/12. Colchicine (2 microg/g) was injected 4 h before death. Samples of the liver and tongue from each animal were processed for histology and assessment of mitotic index. The results were expressed as colchicine-arrested metaphases/1000 nuclei. The TE and LE stimulated the mitotic activity of hepatocytes and tongue keratinocytes. Taking into account the time elapsed between the injections and the measurements made in these light-dark synchronized animals, we conclude that the increase in mitotic index observed in those tissues stemmed from a reinitiation of cell-cycle traverse in a subpopulation of G2-arrested, noncycling cells.