RESUMO
Phorbol ester tumor promoters activate protein kinase C (PKC) isozymes and novel non-kinase receptors, suggesting a high degree of complexity in the signaling mechanisms of tumorigenesis. Many studies have shown that PKC isozymes contribute to the progression of malignant phenotype. We review the emerging understanding of the roles of PKC isozymes in the three sequential cellular processes of tumor invasion and metastasis: attachment to extracellular matrix or basement membrane components, matrix degradation by proteolytic enzymes, and migration through the digested matrix. In addition, we discuss the potential role of chimaerins, novel non-kinase phorbol ester receptors, in carcinogenesis.
Assuntos
Proteínas de Caenorhabditis elegans , Invasividade Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Proteína Quinase C/metabolismo , Receptores de Droga/metabolismo , Animais , Proteínas de Transporte , Humanos , Metástase Neoplásica , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Forbóis/metabolismoRESUMO
We have investigated the effects of desmopressin (DDAVP), a synthetic analog of the natural hormone vasopressin, on experimental lung colonization of mammary tumor cells using a syngeneic BALB/c mouse model. Coinjection of DDAVP (1-2 microg/kg body weight) at the time of i.v. inoculation of F3II carcinoma cells or LM3 adenocarcinoma cells significantly inhibited the formation of experimental lung metastases. In both cases, the number of pulmonary nodules was reduced about 70%. Inhibition of metastasis was also obtained with i.v. administration of DDAVP 24 h after tumor cell inoculation. Interestingly, the inhibition of lung metastasis was not due to direct cytotoxic effects of DDAVP on mammary tumor cells. The in vitro formation of multicellular aggregates in the presence of citrated plasma from control and DDAVP-treated mice was also examined. Control plasma rapidly induced a significant tumor cell aggregation. In contrast, in the presence of plasma from DDAVP-treated mice, tumor cells remained as a single cell suspension. DDAVP may help to dissolve the protective fibrin shield of circulating tumor cells. Our data suggest, for the first time, that adjuvant DDAVP therapy may impair successful implantation of circulating mammary tumor cells.
Assuntos
Desamino Arginina Vasopressina/farmacologia , Hemostáticos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Animais , Agregação Celular/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Lovastatin, a fungal antibiotic used in the treatment of hypercholesterolemia, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the key regulatory enzyme in the mevalonate pathway of cholesterol synthesis. We examined the antitumor properties of lovastatin on the F3II sarcomatoid mammary carcinoma, a highly invasive and metastatic murine tumor model. Female BALB/c inbred mice were inoculated subcutaneously with F3II tumor cells and injected i.p. daily with 10 mg/kg body weight of lovastatin or administered p.o. at a level corresponding to the human dosage of 1-2 mg/kg/day. Treatment significantly prolonged tumor latency and reduced tumor formation and metastatic dissemination to the lungs from established mammary tumors. In vitro, antitumor properties of lovastatin were strongly associated with inhibition of tumor cell attachment and migration. These actions were prevented by addition of mevalonate but not by equivalent concentrations of farnesyl pyrophosphate. In accordance, Western blot assays showed that lovastatin effects did not appear to be related to modifications in Ras oncoproteins in our model. The present data indicate that lovastatin could be an antitumor agent with potentially useful clinical applications in breast cancer.
Assuntos
Anticolesterolemiantes/farmacologia , Antineoplásicos/farmacologia , Lovastatina/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Ácido Mevalônico/metabolismo , Animais , Feminino , Concentração Inibidora 50 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Células Tumorais CultivadasRESUMO
We have transfected a full-lenght cDNA-encoding human tissue inhibitor of metalloproteinases-1 (TIMP-1) by lipofection in highly invasive F3II mouse mammary sarcomatoid carcinoma cells. In vitro, overexpression of TIMP-1 was associated with abrogation of metalloproteinase activity, extended doubling time, and a more flattened, epithelioid polyhedric morphology. Female Balb/c mice inoculated subcutaneously with TIMP-1 transfectant exhibited a prolonged tumor latency and tumor burden was significantly lower in early stages of tumor growth. Control F3II cells grew by invading the muscular and adipose layers of the subcutis, dermis, and dermal papillae. On the contrary, mammary carcinoma cells transfected with TIMP-1 grew without signs of active invasion of dermis. Tumors also revealed a decreased amount of necrosis and host inflammatory cell infiltrates. However, histological analysis did not demonstrate any change in vascular density. Animals bearing F3II tumors overexpressing TIMP-1 showed a significant reduction in the size of metastatic lung nodules. These data suggested that TIMP-1 overexpression may reduce local invasion and delay the progression of the metastatic disease in the present mammary tumor model.