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

Abstract

TGFβ 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 TGFβ 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 TGFβ increase their capacity to adhere and transmigrate through the lymphatic endothelium. These increments were abrogated when cells were treated with TGFβ inhibitors or β3 integrin blocking antibodies or if β3 integrin expression was reduced by specific expression of a shRNA. We have also observed that blockade of β3 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 TGFβ exposure, such as: collagen I and IV, fibronectin, versican, several MMPs (MMP 2, 3, 10, 11 and 14), ADAMTS (1 and 13) and integrins α2, αv, β1 and β3. 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 TGFβ effects and its inhibition in vivo and characterized the role of integrin β3 in tumor progression and in the metastatic process.