Valoración del papel de las células cebadas en la carcinogenesis pulmonar

Laburpena

Titulo: Valoración del papel de las células cebadas en la carcinogenesis pulmonar Resumen: Role OF MAST cells IN lung carcinogenesis Carcinogenesis in vivo implies not only tumor cells and the deregulated genes in them, but al so the heterotypic interactions that these tumor cells estabfish with the neighboring cells of the stroma: endothelial cells, fibroblasts, and inflammatory cells. Our study has focused on the role of one of the most frequent type of inflammatory cells found in tumors, the mast cell. The implication of this cellular type in neoplastic development is not clear. Mast cells are cytotoxic for some tumors, and therefore they could be considered as part of the immune response against them. Nevertheless, many other studies support that some mast cell products promote tumor growth and metástasis. Our working hypothesis was that mast cells may actively participate in lung carcinogenesis and to test this, we proposed different objectives: (i) to analyze the presence of mast cells and its relation with a greater microvascular density in both biopsies of human lung tumors and in a rat model of lung carcinogenesis induced by intratracheal instillation of silica particles; (ii) to identify by microarray analysis mediators produced by a mast cell line (HMC-1) after activation, whicn might influence tumor development; (iii) to study the effect of some of these mediators on different lung tumor cell Tines using proliferation, migration and invasión assays. Our results show that the presence of mast cells positively correlates with the capillary density in human lung tumors and tumors in trie rat lung carcinogenesis model, which might be indicative of mast cells participating in angiogenesis processes. In preneoplastic lesions of the rat model, however, this correlation does not exist; this suggests that in this type of lesions mast cells could produce factors influencinq the migration or proliferation of the niperplastic/displastic cells in a paracrine fashion. On the other hand, the conditioned médium produced by the activated HMC-1 cell line increases the proliferation of some non-small cell lung cáncer cell unes, whereas it inhibits the growth of others. This fact might be related to the different receptor set expressed by these cell lines. After microarray expression analysis of the HMC-1 cell line after activation, three genes encoding with a putative role in carcinogenesis [macrophage inflammatory protein (MlP)-lfÓ, 1309 and cathepsin L] were selected for further studies. We have observed that chemokines MiP-lfó and 1309 secreted by HMC-1 cells induce the migration of different lung cáncer cell lines in vitro. Moreover, tumors and endothelial cells in lung biopsies express the specific receptors for these chemokines. These data indicate that chemokines MlP-lfó and 1309 produced by mast cells might have a role at the first stages of tumor invasión and metástasis, as well as in the angiogenesis process. We have observed expression of cathepsin L by tumor cells and macrophages in human lung tumors. No evidence was found that this protease might promote invasion of lung tumor cell lines in vitro