RESUMO
Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV-polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT+ glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMP-deficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process.
Assuntos
Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 14 da Matriz/fisiologia , Metástase Neoplásica , Animais , Proliferação de Células , Colágeno/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Modelos Biológicos , Invasividade Neoplásica , Processamento de Proteína Pós-Traducional , Células Estromais/metabolismo , Células Tumorais Cultivadas , Regulação para CimaRESUMO
This study was designed to determine particular changes in the renin gene expression and activity in renal cortex and medulla after AT(1) receptor blockade. It was found that two-week-treatment with AT(1) blocker losartan induced an increase in tissue renin activity in both parts of kidney causing subsequent elevation of plasma renin activity. Renin mRNA in losartan-treated rats was increased only in cortex, suggesting cortex origin of elevated renin activity in medulla. Medullary renin mRNA indicated local synthesis of renin within the whole kidney and supported the idea of the presence of tissue renin-angiotensin system. Our results show that gene expression of renin in kidney medulla is insensitive to AT(1) receptor blockade and this points out that the regulation of kidney renin-angiotensin system probably differs from that in cortex.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Regulação da Expressão Gênica , Medula Renal/efeitos dos fármacos , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/genética , Animais , Pressão Sanguínea , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Medula Renal/metabolismo , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Endogâmicos WKY , Renina/sangueRESUMO
In vertebrates, both nuclear all-trans and 9-cis retinoic acid receptors (RAR and RXR) belonging to the steroid/thyroid/retinoid nuclear receptor superfamily play a crucial role in the vitamin A action. Qualitative analysis of all known RAR or RXR subtypes in both pooled and non-pooled peripheral blood mononuclear cells (PBMC) from healthy human subjects has been performed by reverse transcription and polymerase chain reaction (RT-PCR). Our data, based on qualitative RT-PCR analysis has shown that human PBMC are capable to express RAR alpha, RAR gamma, RXR alpha, and RXR beta.
Assuntos
Núcleo Celular/metabolismo , Leucócitos Mononucleares/metabolismo , Receptores do Ácido Retinoico/metabolismo , Núcleo Celular/genética , Primers do DNA/química , Eletroforese em Gel de Ágar , Humanos , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/classificação , Receptores do Ácido Retinoico/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In order to better understand the mechanisms leading to insulin resistance, the number of fat tissue insulin receptors, their affinity and insulin receptor protein in rats with monosodium glutamate-induced obesity were studied. Obese rats displayed significantly lower number of insulin receptors with high affinity. Surprisingly, the amount of insulin receptor protein was significantly elevated in these animals. The same relations have been already reported for angiotensin II binding and AT1 receptor protein in the same model of obesity. Therefore we suggest an existence of general defect of adipocyte cell membrane in monosodium glutamate-induced obesity characterized by the presence of high quantity of impaired receptor protein.
