RESUMO
Concomitant resistance (CR) is the phenomenon according to which a tumor-bearing host inhibits the growth of a secondary implant of the same tumor at a distant site. Confirming and extending previous results of our laboratory, histological studies have revealed that two temporally separate peaks of CR can be detected throughout tumor evolution. The first peak induced by immunogenic small tumors, in euthymic but not in nude mice, is associated with extensive necrosis of the secondary tumor implant and a profuse infiltration of polymorphonuclear granulocytes and mononuclear cells resulting in its final destruction; these features correspond to a typical immunological rejection. The second peak of CR induced by both immunogenic and non-immunogenic large tumors, in euthymic as well as in nude mice, is characterized by a dormant tumor stage with scarce or null mononuclear infiltration, associated with a significant reduction of tumor mitotic index and of the number of PCNA+ cells along with an increase in apoptosis and an arrest in S phase. In previous reports we suggested that a 1000 D serum fraction from mice bearing large tumors could be responsible for the induction of this dormant tumor stage. In this study tumor cells incubated in vitro with that serum factor mimicked the inhibition and cellular alterations observed in vivo in the secondary tumor inhibited by the second peak of CR. Moreover, the passive transfer of this factor by the intra-peritoneal (i.p.) route induced an in vivo inhibition of an i.p. tumor reproducing the image characteristic of the second peak of CR. This represents a direct proof that this serum factor can restrain tumor growth in vivo and that it is, most probably, the effector of the second peak of CR.
Assuntos
Fibrossarcoma/imunologia , Leucemia Linfoide/imunologia , Animais , Apoptose , Proteínas Sanguíneas/imunologia , Ciclo Celular , Divisão Celular/fisiologia , Feminino , Fibrossarcoma/sangue , Fibrossarcoma/patologia , Imunidade Inata/imunologia , Leucemia Linfoide/sangue , Leucemia Linfoide/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica/imunologia , Neovascularização Patológica/prevenção & controleRESUMO
Human polymorphonuclear neutrophils (PMN) participate in different cellular functions, including phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and release of reactive oxygen intermediates. Each of these functions can be triggered by receptors for the Fc portion of IgG molecules (Fc gamma R). Normal resting neutrophils possess Fc gamma RII and Fc gamma RIIIB receptors. They also have specific membrane receptors for formylated peptides such as the prototype N-formylmethionylleucylphenylalanine (FMLP). In this report, we present evidence that preincubation of PMN with FMLP inhibits different PMN Fc gamma R-dependent functions such as phagocytosis, ADCC, and immune complex-dependent cytotoxicity. These inhibitory effects can be explained, at least in part, by downregulation of both Fc gamma RII and Fc gamma RIII. Unexpectedly, preincubation of FMLP with PMN was not necessary for ADCC inhibition. Taking into account that the FMLP-dependent Fc gamma R downregulation is not observed before 30 min of incubation, and the onset of ADCC occurs rapidly (seconds), it is possible that FMLP can modify this function by altering early intracellular events.
Assuntos
Anti-Inflamatórios/farmacologia , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/ultraestrutura , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/efeitos dos fármacos , Adulto , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/fisiologia , Complexo Antígeno-Anticorpo/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Regulação para Baixo , Humanos , Medições Luminescentes , NADPH Oxidases/metabolismo , Neutrófilos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Receptores de IgG/fisiologia , Fatores de TempoRESUMO
Resistance of tumour-bearing mice to a second tumour challenge, that is concomitant resistance, was evaluated in euthymic and nude mice using nine tumours with widely different degrees of immunogenicity. Two temporally separate peaks of concomitant resistance were detected during tumour development. The first one was exhibited only by small immunogenic tumours; it was tumour specific and mediated by classical immunological T-cell-dependent mechanisms. The second peak was shared by both immunogenic and non-immunogenic large tumours; it was non-specific, thymus independent and correlated with the activity of a serum factor (neither antibody nor complement) that inhibited the in vitro proliferation of tumour cells. This factor was eluted from a Sephadex G-15 column at fractions corresponding to a molecular weight of approximately 1000 Da and it was recovered from a high-performance liquid chromatography column in one peak presenting maximum absorption at 215 and 266 nm. The data presented in this paper suggest for the first time, to our knowledge, that in spite of the differences between immunogenic and non-immunogenic tumours, a common serum-mediated mechanism seems to underlie the concomitant resistance induced by both types of tumours at late stages of tumour development.
Assuntos
Imunoterapia Adotiva , Neoplasias Experimentais/sangue , Neoplasias Experimentais/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/imunologia , Adenocarcinoma/terapia , Animais , Formação de Anticorpos/imunologia , Feminino , Fibrossarcoma/sangue , Fibrossarcoma/imunologia , Fibrossarcoma/terapia , Imunidade Celular/imunologia , Imunidade Inata , Leucemia Linfoide/sangue , Leucemia Linfoide/imunologia , Leucemia Linfoide/terapia , Masculino , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/terapia , Sensibilidade e EspecificidadeRESUMO
In the embryo, both differentiation and temporospatial organization are regulated by the mesoderm. Some of these functions are expressed by the connective tissue during wound or organ repair and regeneration. The normal development of the latter depends on the epithelium-mesenchyme interrelationship and the formation of an adequate amount of stroma and a certain type of collagen or proteoglycans. Our hypothesis proposes that cancer is a regenerative process which has failed as a consequence of alterations in the connective tissue. The object of this paper was to investigate whether the connective tissue and the amorphous fundamental substance (SFA) are capable of regulating the proliferation and death of normal and tumor cells and to duplicate the mechanisms involved. The results obtained in vivo, ex-vivo and in vitro experiments indicate that following: 1) SFA exerts a direct and selective cytotoxic effect on tumor cells; 2) SFA reduces the proliferative capacity of normal and tumor cells; 3) both the cytotoxic and antiproliferative effects of SFA are independent of cellular and humoral immune responses but are dependent on the chemical integrity of its component since its denaturalization reduces its antitumoral activity; 4) the tumor cells modulate the regulatory effects of SFA through endocellular enzymes liberated by cell death induced by the cytotoxic action of SFA itself. These results suggest that in the absence of the inhibitory effect of SFA, the tumor cells which remain viable con now proliferate actively due to enzyme stimulation. In conclusion, the regulatory function of the connective tissue on the proliferation and viability of tumor cells would depend on the molecular constitution of SFA.
Assuntos
Tecido Conjuntivo/fisiologia , Neoplasias/patologia , Animais , Morte Celular , Divisão Celular , Sobrevivência Celular , Camundongos , Camundongos Endogâmicos BALB C , Células Tumorais CultivadasRESUMO
Concomitant resistance of tumor-bearing mice against a second tumor challenge was evaluated in euthymic and athymic mice using 17 tumors with different degrees of immunogenicity. Two temporarily separated peaks of concomitant resistance were detected during tumor development: the first peak was only observed associated with small immunogenic tumors (< 500 m3., it was tumor-specific and mediated by T cell-dependent immunological mechanisms. The second peak was exhibited by large tumors (> 2000 mm3) independently of their immunogenicity; it was non-tumor specific, thymus-independent and correlated with a serum-activity (neither antibodies nor complement) which inhibited the in vitro proliferation of tumor cells. Out of 17 tumors studied, 15 tumors exhibited a moderate or strong concomitant resistance. The remaining two, which exhibited a weak or undetectable concomitant resistance and correlatively, a low or absent serum-inhibitory activity were the only tumors which included lung metastases. This fact suggested a correlation between concomitant resistance, absence of metastases and the existence of an inhibitory factor(s) in the serum. This inhibitory factor was partially characterized: it was resistant to boiling (5-10' at 100 degrees C) and to variations of pH; its molecular weight was estimated between 850 and 1200 D; it was recovered in only one fraction from HPLC (high power liquid chromatography) columns presenting maximum absorption at 215 and 266 nm; amino acid analysis and magnetic nuclear resonance studies suggested the presence of a molecule of thyrosine and one or two molecules of carbohydrates in its structure.