RESUMEN
Rearrangements involving the mixed lineage leukemia gene (MLL) are found in the majority of leukemias that develop within the first year of age, known as infant leukemias, and likely originate during prenatal life. MLL rearrangements are also present in about 10% of other pediatric and adult acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). These translocations and others occurring in early life are associated with a dismal prognosis compared with adult leukemias carrying the same translocations. This observation suggests that infant and adult leukemias are biologically distinct but the underlying molecular mechanisms for these differences are not understood. In this work, we induced the same MLL chromosomal translocation in the embryo at the time of fetal liver hematopoiesis and in the adult hematopoietic tissues to develop disease models in mice that recapitulate human infant and adult leukemias, respectively. We successfully obtained myeloid leukemia in adult mice after MLL-ENL recombination induction using the interferon inducible Mx1-Cre line. Using this same Cre line, we generated embryonic MLL-ENL leukemias, which were more aggressive than the corresponding adult leukemias. In conclusion, we have developed a novel MLL-ENL embryonic leukemia model in mice that can be used to study some aspects of infant leukemia ontogeny.
Asunto(s)
Proteínas de Unión al ADN , Embrión de Mamíferos , N-Metiltransferasa de Histona-Lisina , Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Neoplasias Experimentales , Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Factores de Transcripción , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos/embriología , Embrión de Mamíferos/patología , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Leucemia Mieloide Aguda/embriología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Transgénicos , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Neoplasias Experimentales/embriología , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/embriología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: Uveal melanoma (UM) is fatal in up to 50% of patients because of liver metastases that are refractory to therapies currently available. While murine xenograft models for human uveal melanoma are available, they have limited utility for screening large compound libraries in drug discovery studies. Therefore, new robust preclinical models are needed that can efficiently evaluate drug efficacy for treatment of this malignancy. METHODS: Uveal melanoma cell lines generated from primary tumors (92.1, Mel270) and metastases (OMM2.3, OMM2.5, OMM1) were injected into the yolk of 2-day-old zebrafish embryos. After 6 days, proliferation and active migration was quantified via automated confocal image analysis. To determine the suitability of this xenotransplantation model for drug testing, drugs with three different activities (dasatinib, quisinostat, and MLN-4924) were added to the water of uveal melanoma-engrafted embryos. RESULTS: All tested UM cell lines proliferated and migrated in the embryos; significant differences could be discerned between cell lines: Cells derived from metastases showed more migration and proliferation than cells derived from the primary tumors, and provided preclinical models for drug testing. Addition of the Src-inhibitor dasatinib in the water of engrafted embryos reduced proliferation and migration of high Src-expressing 92.1 cells, but did not affect low Src-expressing metastatic OMM2.3 cells. Two experimental anticancer drugs, quisinostat (a histone deacetylase inhibitor) and MLN-4924 (neddylation pathway inhibitor), blocked migration and proliferation of 92.1 and OMM2.3. CONCLUSIONS: We established a zebrafish xenograft model of human uveal melanoma with demonstrated applicability for screening large libraries of compounds in drug discovery studies.
Asunto(s)
Antineoplásicos/uso terapéutico , Melanoma/embriología , Neoplasias Experimentales/embriología , Neoplasias de la Úvea/embriología , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Xenoinjertos , Humanos , Melanoma/tratamiento farmacológico , Células Tumorales Cultivadas , Neoplasias de la Úvea/tratamiento farmacológico , Pez Cebra/embriologíaRESUMEN
In vivo studies represent an essential step in drug development and currently rely largely on mice, yet limitations of mammalian models motivated the search for complementary vertebrate model systems. This review focuses on zebrafish, Danio rerio, as a facile model system to study human disease and drug responses. Zebrafish are particularly suited for this purpose because they represent a vertebrate species, their genome is sequenced, and a large number of synchronously developing, transparent embryos can be produced. Zebrafish embryos are permeable to drugs and can easily be manipulated using well-established genetic and molecular approaches. Here, we summarize recent work on drug discovery and toxicity in zebrafish embryos. In addition, we provide a synopsis of current efforts to establish disease models in zebrafish focusing on neoplasia. The results of these studies highlight the potential of zebrafish as a viable addition to established animal models by offering medium and, potentially, high throughput capabilities.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Modelos Animales , Pruebas de Toxicidad/métodos , Pez Cebra/embriología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Transformación Celular Neoplásica/efectos de los fármacos , Daño del ADN , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/patología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/embriología , Reproducibilidad de los Resultados , Pez Cebra/genéticaRESUMEN
The Oct-4 gene encodes a transcription factor that is essential for maintaining the mouse germline. It is expressed during the earliest stages of embryogenesis, is downregulated during gastrulation, and is thereafter constrained to the germ cell lineage. Retinoic acid induced differentiation of embryonal carcinoma cells is also accompanied by a decrease in Oct-4 expression. We have previously shown that downregulation of Oct-4 expression is mediated by a hormone regulatory element (HRE). This element is located within the basal promoter and overlaps with a GC box that is crucial for Oct-4 promoter activity. The HRE is composed of three direct repeats with 1 and 0 spacing. In this study, we demonstrate that the doublet of direct repeats with 0 spacing (DR0) is bound by two novel factors. The initial repression of Oct-4 by retinoic acid coincides with the disappearance of the first factor (named UCF for undifferentiated cellular factor) and the appearance of a transiently induced factor (TRIF) which forms a larger complex with DR0 in electrophoretic mobility shift assays. These observations support the hypothesis that downregulation of the Oct-4 gene during early mouse embryogenesis involves the repression of its promoter by TRIF.
Asunto(s)
Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Animales , Secuencia de Bases , Factor de Transcripción COUP I , Factores de Transcripción COUP , Diferenciación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Ratones , Datos de Secuencia Molecular , Neoplasias Experimentales/embriología , Factor 3 de Transcripción de Unión a Octámeros , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Células Madre/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tretinoina/farmacologíaRESUMEN
Numerous experimental protocols for short- and intermediate-term carcinogenicity assays have been available for many years. This paper surveys various of these test systems in rodents, fish species, non-vertebrates and avian embryos in ovo. The mouse skin tumour assay and the rat liver foci assay were used to introduce the basic concepts of short- and intermediate-term carcinogenicity testing in the previous part of the review. The focus of this second part of the review is on rodent assays for carcinogenicity testing in the lung, kidney, urinary bladder, pancreas, stomach, oral cavity, small intestine, colon, and on the possibility to combine several target organs in multi-organ models. The potential use of various fish species, non-vertebrates and hatching eggs for carcinogenicity testing is outlined and the advantages and limitations are discussed. This review also presents the problem of validation of any carcinogenicity test system and proposes a strategy for contemporary safety assessment of chemicals with regard to the detection and evaluation of carcinogenicity.
Asunto(s)
Pruebas de Carcinogenicidad , Carcinógenos/toxicidad , Neoplasias Experimentales/inducido químicamente , Animales , Animales Modificados Genéticamente , Carcinógenos/efectos adversos , Embrión de Pollo , Relación Dosis-Respuesta a Droga , Peces , Humanos , Ratones , Neoplasias Experimentales/embriología , Ratas , Reproducibilidad de los Resultados , Especificidad de la EspecieRESUMEN
Perinatal exposure to carcinogens may contribute to the determination of susceptibility to cancer in two situations: a) exposure in utero of embryonal or fetal somatic cells to carcinogens, and b) prezygotic exposure of the germ cells of one or both parents to carcinogens. Epidemiological as well as experimental studies demonstrate that exposure to carcinogens in utero increases the occurrence of cancer postnatally. Studies with experimental animals suggest that prezygotic exposure of germ cells to carcinogens can result in an increased incidence of cancer not only in immediate but also in subsequent generations. Although several studies suggest a transgeneration effect of carcinogens in human populations, the evidence cannot yet be considered conclusive. In particular, while some hypotheses can be advanced, the mechanism(s) by which increased susceptibility or predisposition to cancer may be transmitted via the germ cells has not yet been clarified. In conjunction with exposure both in utero and prezygotically, it is important to consider postnatal exposure to possible tumor-promoting agents. Results from experimental animals suggest that oncogenes can be activated transplacentally, and human studies indicate that tumor-suppressor gene inactivation may be involved in the transgenerational effect of carcinogens.
Asunto(s)
Carcinógenos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Intercambio Materno-Fetal , Neoplasias/inducido químicamente , Proto-Oncogenes/efectos de los fármacos , Animales , Susceptibilidad a Enfermedades , Familia , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Haplorrinos , Humanos , Ratones , Mutagénesis , Neoplasias/genética , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/embriología , Neoplasias Experimentales/genética , Embarazo , Proto-Oncogenes/genética , RatasRESUMEN
Lethal (1) discs-large-1 [l(1)dlg-1] is a non-epithelial overgrowth or neoplastic mutant of Drosophila, which results in tumor-like imaginal discs and enlarged larvae that never pupariate. In an ultrastructural analysis we found that the wing discs develop convoluted monolayers of epithelial cells characterized by well-defined apical-basal polarity and that these layered cells secrete large amounts of basement membrane material. Immuno-EM indicates that Drosophila laminin and collagen are components of this matrix. Late in development clusters or 'rosettes' of separated cells lacking cell-cell junctions and apical-basal polarity form. In in vitro culture experiments l(1)dlg-1 wing discs did not respond to a pulse of exogenous ecdysone by secreting cuticle or losing basement membrane as normal discs do. Our observations are consistent with the hypothesis that cell-cell interaction and communication is required for termination of disc cell proliferation, which must occur prior to a cellular response to ecdysone.
Asunto(s)
Polaridad Celular/genética , Proteínas de Drosophila , Drosophila melanogaster/genética , Genes Letales , Hormonas de Insectos/fisiología , Proteínas de la Membrana/fisiología , Neoplasias Experimentales/embriología , Proteínas Supresoras de Tumor , Alas de Animales/embriología , Animales , Membrana Basal/metabolismo , Comunicación Celular/genética , Muerte Celular/genética , Diferenciación Celular/genética , División Celular/genética , Drosophila melanogaster/embriología , Ecdisona/farmacología , Epitelio/patología , Proteínas de la Matriz Extracelular/biosíntesis , Hormonas de Insectos/genética , Larva , Proteínas de la Membrana/genética , Proteínas de Neoplasias/biosíntesis , Neoplasias Experimentales/metabolismo , FenotipoRESUMEN
The method of separation of germ layers of rodent embryos by treating the embryonic shields with proteolytic enzymes and by microsurgery with the subsequent transplantation to ectopic sites has helped to gain a more detailed insight into what is going on during gastrulation in mammals. The space under the kidney capsule of adult animals seems to be the most appropriate ectopic site for transplantation of early postimplantation rat embryos or separated germ layers. After transplantation the grafts develop into teratomas whose complex histological structure reflects the initial developmental capacities of the graft. At the pre-primitive streak and the early primitive streak stages the primitive ectoderm differentiates into tissue derivatives of all three definitive germ layers, often in complex organotypic combinations. This is indirect evidence that all cells of the embryonic body originate from the primitive embryonic ectoderm. Halves of the primitive ectoderm obtained by a longitudinal or transverse cut through the egg cylinder give the same result. At the head fold stage the capacity for differentiation of the ectoderm is restricted to ectodermal and mesodermal derivatives. One day before gastrulation the isolated primitive ectoderm is not able to differentiate as renal isograft. The mesoderm isolated at the head fold stage and at later stages when its segmentation occurs, differentiates almost exclusively into the brown adipose tissue. The embryonic endoderm differentiates only in combination with the mesoderm. After transplantation the embryonic ectoderm loses its epithelial organization and breaks up into a mass of mesenchyme-like cells in which epithelial structures subsequently appear and differentiate in a way reminiscent of the reaggregation of cells in mixed cell suspension in vitro.
Asunto(s)
Estratos Germinativos , Ratas/embriología , Animales , Diferenciación Celular , Gástrula , Estratos Germinativos/trasplante , Neoplasias Renales/embriología , Morfogénesis , Neoplasias Experimentales/embriología , Teratoma/embriologíaRESUMEN
A description of the experimental approaches devised to control the growth of tumors induced by transplacental exposure to carcinogens is given. Due to the massive cell proliferation and differentiation taking place during embryogenesis, fetal tissues are believed to be privileged targets of neoplastic changes. As a consequence, trace amounts of environmental carcinogens capable of accumulating into the conceptuses may determine the appearance of tumors in the offspring, a possibility documented in several animal species including humans. Endogenous and exogenous factors counteracting this process have potential application as regulators of developmental carcinogenesis. Their identification is regarded as a means to chemoprevent pediatric tumors and can be instrumental in the analysis of the aetiopathogenesis of neoplastic phenotypes.
Asunto(s)
Carcinógenos , Neoplasias Experimentales/embriología , Animales , Neoplasias Encefálicas/inducido químicamente , Neoplasias Encefálicas/embriología , Etilnitrosourea , Femenino , Neoplasias Renales/inducido químicamente , Neoplasias Renales/embriología , Intercambio Materno-Fetal , Neoplasias Experimentales/inducido químicamente , Embarazo , RatasRESUMEN
Differences in cancer frequency between men and women are well known. Sexual dimorphism is also observed in the development of some experimental tumours, including those induced transplacentally. Differences in the production and binding of sex hormones by target tissues are evidently not the only cause of sexual dichotomy in the action of modifying factors on transplacental carcinogenesis. In our experiments, the average weight of newborn rats treated with glucose during intrauterine life from day 7 to 20 of gestation exceeded that of control animals, and rats exposed transplacentally to N-methyl-N-nitrosourea (MNU) on day 21 of gestation in combination with glucose (beginning from day 7 of prenatal life to 1.5 months after delivery) had a significantly increased tumour frequency. In males, there was an increased frequency of neoplasms of the nervous system and kidneys, which are typical transplacental carcinogenic effects of MNU; however, in females, neoplasms were induced in other organs and tissues, mainly the mammary gland and pituitary body. Thus, fetal macrosomia acts as a modifying factor in transplacental carcinogenesis also by determining the tumour spectrum in females and males and not only in increasing tumour frequency. The possible causes of these differences and perspectives for further research are discussed.
Asunto(s)
Macrosomía Fetal/complicaciones , Neoplasias Experimentales/etiología , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Macrosomía Fetal/inducido químicamente , Glucosa , Masculino , Metilnitrosourea , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/embriología , Embarazo , Factores SexualesRESUMEN
The histogenetic and neoplastic potentials of defined regions of the 8th day mouse embryonic egg cylinder were examined following ectopic transfer to beneath the testis capsule. No differences in histogenetic potential were detected between anterior and posterior slices of the embryo, either when composed of all three germ layers or of embryonic ectoderm alone. Small anterior and distal fragments of embryonic ectoderm also produced similar histogenetic profiles, although posterior fragments failed to grow in this ectopic site. The histogenetic potential of anterior and distal fragments exceeded the developmental fate ascribed to these two regions in the embryo (Beddington, 1981). There was some evidence for regionalization with respect to neoplastic potential, anterior slices of the embryo giving rise to a higher incidence of embryonal carcinoma cells than posterior slices.
Asunto(s)
Estratos Germinativos/fisiopatología , Teratoma/embriología , Neoplasias Testiculares/embriología , Animales , Ectodermo/fisiopatología , Ectodermo/trasplante , Estratos Germinativos/trasplante , Masculino , Ratones , Trasplante de Neoplasias , Neoplasias Experimentales/embriología , Neoplasias Experimentales/patología , Teratoma/patología , Neoplasias Testiculares/patologíaRESUMEN
On the basis of the following literature observations, a hypothesis is advanced that the development of cancer is actively inhibited during embryonic life. Although the processes of cell differentiation and proliferation are--without comparison--most pronounced during embryonic life, cancer is rarely found in the newborn and is seldom a cause of neonatal death or spontaneous abortion. Attempts to induce cancer in early-stage animal embryos by irradiation or by transplacental chemical carcinogenesis have been unsuccessful, even when exposed animals have been observed throughout their life-time. After the period of major organogenesis, however, the embryos become susceptible to carcinogenesis. In humans, the most common embryonic tumors arise in tissues which have an unusually late ongoing development and are still partly immature at or shortly before birth. For many human embryonic tumors the survival rates are higher, and spontaneous regression more frequent, in younger children, i.e. prognosis is age-dependent. Thus, although cancer generally appears in tissues capable of proliferation and differentiation, induction of malignancy in the developmentally most active tissues seems to be beset with difficulty. One possible explanation for this paradox could be that cancer is controlled by the regulators influencing development, regulators that are most active during embryonic life.
Asunto(s)
Neoplasias/embriología , Animales , Diferenciación Celular , División Celular , Preescolar , Inducción Embrionaria , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Ratones , Modelos Biológicos , Neoplasias/congénito , Neoplasias/etiología , Neoplasias Experimentales/embriología , Neoplasias Experimentales/etiología , Neoplasias de Células Germinales y Embrionarias/embriología , Embarazo , RatasRESUMEN
The maternal organism plays a highly important role in transplacental carcinogenesis, since for carcinogens in the bloodstream of the mother to reach the fetus, they must cross several barriers, the first of which is the placenta. Some types of compounds require metabolic activation in the maternal organism, in the fetus and even sometimes in the placenta. Thus, four main pathways can be hypothesized by which substances exert a carcinogenic effect on the fetus. Most carcinogens can cross the placenta; data confirm that this process consists of simple diffusion or - in the case of high doses - facilitated diffusion. That carcinogens may be detoxified in the maternal organism is confirmed by experiments on activation of enzyme systems and on caesarean deliveries. Species and strain specificities are characteristic of transplacental carcinogenesis and are manifested in organotropism. Organotropism in transplacental carcinogenesis is determined by genetic predisposition, cell differentiation and proliferative activity in the target tissues. For indirect carcinogens, the level of metabolizing enzymes is also important.
Asunto(s)
Carcinógenos/toxicidad , Intercambio Materno-Fetal , Neoplasias Experimentales/inducido químicamente , Animales , Carcinógenos/metabolismo , Diferenciación Celular , Interacciones Farmacológicas , Femenino , Feto/metabolismo , Edad Gestacional , Ratones , Neoplasias Experimentales/embriología , Neoplasias Experimentales/metabolismo , Preparaciones Farmacéuticas/metabolismo , Placenta/metabolismo , Embarazo , Ratas , Especificidad de la EspecieRESUMEN
A sequential morphological study of the initial cellular events in teratoma induction by displaced visceral yolk sac after foetectomy in rats was undertaken. This study led to the observation that apart from proliferation of cells displaying definite endodermal or mesodermal characteristics, a population of poorly differentiated cells appeared some days after the surgical procedure. It is very likely that these poorly differentiated cell are stem cells from which differentiated structures originate afterwards by a process of redifferentiation. The development of granulation tissue rich in capillaries seems to enhance this process. Similarities and differences with blastema formation are discussed.
Asunto(s)
Teratoma/embriología , Animales , Recuento de Células , Diferenciación Celular , División Celular , Endodermo/ultraestructura , Mesodermo/ultraestructura , Microscopía Electrónica , Neoplasias Experimentales/embriología , Ratas , Ratas Endogámicas , Teratoma/ultraestructura , Factores de Tiempo , Saco Vitelino/ultraestructuraRESUMEN
The ability of cultured tumor cell lines to invade across epithelia was studied by placing 10(4) to 10(6) dispersed cells on the chorionic epithelium (CE) of the chorioallantoic membrane of the 10-day chick embryo. Tumor lines included Walker carcinosarcoma, F87 cl 6T2 and B16-BL6 melanomas, and KiSV-NIH, 3B77SC4, and HT 1080 sarcomas. The CE is a bilayer of cells with a superficial periderm overlying a basal layer. Invasion across an intact CE was very weak (limited to the formation of "microtumors" by a small fraction of the inoculated cells in 5 to 50% of the embryos) but was massive (most or all of the inoculated cells invaded in over 99% of the embryos) if the chorioallantoic membrane was traumatized in a fashion which disrupted the periderm but left the basal layer intact. Normal fibroblasts also invaded across the traumatized CE. The histological picture of invasion suggests that cells inoculated on the traumatized CE induced large-scale active retraction of the basal layer, resulting in the formation of large gaps in its continuity. Migration into the subjacent mesoderm occurred through these gaps. The nodules formed by both tumorigenic and normal cells became extensively vascularized within 3 days.
Asunto(s)
Alantoides/patología , Membranas Extraembrionarias/patología , Neoplasias Experimentales/embriología , Animales , Línea Celular , Movimiento Celular , Embrión de Pollo , Epitelio/patología , Mesodermo/patología , Trasplante de Neoplasias , Neoplasias Experimentales/genéticaRESUMEN
For the purpose of observing the cytotoxic effect of N-ethyl, N-nitrosourea (ENU), a potent carcinogen on the central nervous system (CNS) at the late period of organogenesis, the embryonal telencephalic wall was hourly examined under the light and electron microscopes. Pregnant rats on the 13th day and 15th day of gestation were given either a single intravenous injection of 40 or 80 mg/kg, of ENU. The cytotoxic effect on the embryo treated on the 15th day of gestation was severer than that treated on the 13th day of gestation. The common pathological changes in both treated groups are; (1) mitotic arrest 1 hour after administration in the most inner zone of the ventricular layer, (2) degeneration and necrosis accurred predominantly in the so-called DNA synthetic zone and resulting in cell loss of the ventricular layer, (3) elimination of degenerating products; and (4) tissue repair. The findings mentioned may indicate a cytotoxic effect inducing microencephalia, and furthermore, the teratogenic and carcinogenic mechanisms are discussed.
Asunto(s)
Anomalías Inducidas por Medicamentos/patología , Neoplasias Encefálicas/inducido químicamente , Etilnitrosourea/toxicidad , Microcefalia/inducido químicamente , Compuestos de Nitrosourea/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Animales , Encéfalo/metabolismo , Neoplasias Encefálicas/embriología , Neoplasias Encefálicas/patología , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/ultraestructura , ADN/biosíntesis , Embrión de Mamíferos/efectos de los fármacos , Etilnitrosourea/metabolismo , Femenino , Microcefalia/embriología , Mitosis/efectos de los fármacos , Necrosis , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/embriología , Neoplasias Experimentales/patología , Ratas , Formación de Roseta , Telencéfalo/efectos de los fármacos , Telencéfalo/patologíaRESUMEN
N-Nitrosomethylurea (NMU) (20 mg/kg) was i.p. administered to rats on the 21st day of pregnancy. A decrease of glucose utilisation in the oral glucose tolerance test was found in 3 month old female progeny of NMU-treated rats. The serum insulin level did not differ from control, but serum cholesterol level was higher in offspring of NMU-treated rats. The ability of diethylstilboestrol to inhibit compensatory ovarian hypertrophy was decreased in female hemicastrated 3 month old rats whose mothers were treated with NMU. Postnatal administration of the antidiabetic drug buformin decreased the malignant neurogenic tumor incidence 3.5 times (to rats transplacentally treated with NMU).
Asunto(s)
Buformina/uso terapéutico , Dietilestilbestrol/análogos & derivados , Hipoglucemiantes/uso terapéutico , Metilnitrosourea/toxicidad , Neoplasias Experimentales/prevención & control , Animales , Buformina/administración & dosificación , Buformina/farmacología , Colesterol/sangre , Carbohidratos de la Dieta/farmacocinética , Dietilestilbestrol/farmacología , Metabolismo Energético/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Hipertrofia , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Sistema Hipotálamo-Hipofisario/fisiopatología , Insulina/sangre , Neoplasias Renales/inducido químicamente , Neoplasias Renales/embriología , Neoplasias Renales/prevención & control , Masculino , Intercambio Materno-Fetal , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/embriología , Neoplasias de Tejido Nervioso/inducido químicamente , Neoplasias de Tejido Nervioso/embriología , Neoplasias de Tejido Nervioso/prevención & control , Neoplasias del Sistema Nervioso/inducido químicamente , Neoplasias del Sistema Nervioso/embriología , Neoplasias del Sistema Nervioso/prevención & control , Ovariectomía , Ovario/efectos de los fármacos , Ovario/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Somatomedinas/deficienciaRESUMEN
A survey of the behaviour of a variety of normal and malignant tumours and cells has been carried out to gain insights into the mechanisms of tumour invasiveness. The tumours and cells were implanted into the developing chick wing bud, which is a loose mesenchyme bounded by ectoderm. The distribution of the grafted cells was examined histologically after one or two days. The special feature of this assay is that the behaviour of cells is tested in a 3-dimensional tissue. Cells from 3 different carcinomas, mouse lung tumour, rat bladder tumour and human breast tumour did not invade the mesenchyme, whereas trophoblast, sarcoma 180, cultured hamster fibroblasts (BHK, PyBHK, Nil 8, HSV Nil 8) and neuroblastoma cells did. Cells from embryonic pigmented retina and heart ventricle were non-invasive. These results suggest that cell movement may not be a common feature of all invasive tumours. The cells that did move into the mesenchyme appeared to do so by various mechanisms. Lack of contact inhibition of movement, although probably involved in the invasiveness of sarcoma 180 cells, does not appear to be necessary for invasion: cells that have been shown to exhibit contact inhibition of movement (BHK and PyBHK) also invade. Both normal and transformed cells (BHK and PyBHK; Nil 8 and HSV Nil 8) moved into the mesenchyme. Other invading cells, such as trophoblast, neuroblastoma and to a small extent, HSV Nil 8 cells, destroy the adjacent host tissue and this may be important in the invasiveness of these cells. The patterns of invasion and interactions with the host tissue were varied. Trophoblast and the fibroblasts were often elongated along the basement membrane at the ectoderm/mesenchyme border and also closely apposed to the endothelial linings of blood vessels. Sarcoma 180 and neuroblastoma cells clustered around nerves. The embryonic tissues and neuroblastoma cells were often associated with blood vessels. These results are discussed in relation to tumour invasion. A striking finding was that the carcinoma cells were frequently found positioned within the wing ectoderm on the basement membrane. This affinity of carcinoma cells for the epithelium rather than the mesenchyme leads to a reappraisal of the mechanisms involved in the invasiveness of carcinomas.
Asunto(s)
Movimiento Celular , Invasividad Neoplásica , Animales , Embrión de Pollo , Microscopía Electrónica , Trasplante de Neoplasias , Neoplasias Experimentales/embriología , Neoplasias Experimentales/ultraestructura , Trasplante Heterólogo , Trasplante Homólogo , Trofoblastos/trasplanteRESUMEN
Malignant teratocarcinomas arise from developmentally totipotent normal stem cells. Whether the targets are embryonal somatic cells or germinal cells has long been a matter of controversy. Past experiments on teratocarcinoma induction by ectopic grafting of early rodent embryos or fetal germinal ridges have remained ambiguous because embryos ordinarily soon form germ cells, and parthenogenetic germ cells form "embryos." In order to interrupt the developmental cycle at its most telling point, day 6 (egg-cylinder stage) mouse embryos of genetically sterile types were grafted; in such grafts, only a terminal residue of totipotent embryonal somatic ("ectoderm") cells is available, and subsequent germ cell development is severely impaired. One graft series, from S1(J)/+ matings, comprised 25% S1(J)/S1(J) presumptive sterile embryos; these grafts formed tumors containing embryonal carcinoma cells as often (47%) as did control +/+ grafts (41%) on the same genetic background. In another series, from W/+ matings, tumors of the sterile W/W genotype were individually identified by means of a closely linked marker, phosphoglucomutase (PGM, EC 2.7.5.1; Pgm-1 locus), coding for electrophoretic enzyme variants and incorporated into the stock. Four tumors were obtained (out of 16) that had the PGM-1D phenotype diagnostic for W/W, and that also contained embryonal carcinoma cells. Therefore, the malignancy arises here in susceptible somatic embryonal stem cells at the terminal stage of their capacity for totipotency. Other teratocarcinomas-whether induced or spontaneous-of ostensible germ-cell origin by parthenogenesis may also depend upon development of the same somatic target cells before neoplastic conversion can occur. A general model based on these experiments is proposed for all malignancies: Malignant transformation of a particular kind of normal stem cell may be possible only when that stem cell has progressed to the threshold of further differentiation.