Estudio de los mecanismos celulares y moleculares implicados en la adhesión y migración de células de carcinoma pulmonar no microcítico inducidas por TGFß

Resumen

TGF? plays a dual role in tumorigenesis, acting as a tumor suppressor early in the process, but turning into tumor promoter in late-stage disease. Cancer metastasis is linked to the ability of the tumor cell to degrade its pre-existing extracellular milieu while assembling a tumor specific niche. The main purpose of this study is to determine how TGF? modifies non-small cell lung carcinoma (NSCLC) cell adhesion and migration through the lymphatic endothelium and to what extent this influences the occurrence of metastasis into the lymph nodes. We have observed that human squamous cell carcinoma (H157) cells treated with TGF? increase their capacity to adhere and transmigrate through the lymphatic endothelium. These increments were abrogated when cells were treated with TGF? inhibitors or ?3 integrin blocking antibodies or if ?3 integrin expression was reduced by specific expression of a shRNA. We have also observed that blockade of ?3 integrin ligands: L1-CAM and CD31 on the LEC side partially impedes H157 cell transmigration through endothelial cell monolayers. In addition, our findings showed profound changes in the expression of genes related to ECM deposition and metabolism after TGF? exposure, such as: collagen I and IV, fibronectin, versican, several MMPs (MMP 2, 3, 10, 11 and 14), ADAMTS (1 and 13) and integrins ?2, ?v, ?1 and ?3. In order to provide an in vivo model to translate these results, we have established an H157 cell carcinoma orthotopic mouse model and studied the TGF? effects and its inhibition in vivo and characterized the role of integrin ?3 in tumor progression and in the metastatic process.