LAM/TSC CELLS BEARING A TSC2 MUTATION SECRETE CHEMOKINES AND MATRIXMETHALLOPROTEINASES

LAM/TSC cells bear a TSC2 germline mutation and do not express tuberin for an epigenetic modification. These cells survive in adherent and nonadherent status. A metastatic process has been proposed in dissemination of LAM cells by chemokines, cytokines and MMPs. LAM/TSC cells secreted high amount of IL-6 and IL-8 which were not affected by rapamycin or anti-EGFR antibody exposure. These cells also secreted monocyte chemotactic protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Secretion and mRNA expression of IL-6, IL-8, GM-CSF and MCP-1 were regulated by tuberin since their levels were reduced by 5-azacytidine. In adherent status LAM/TSC cells expressed much higher levels of MMP-2 than in nonadherent condition. In LAM lesions MMP-2 high levels likely degrade extracellular matrix. In LAM/TSC cells MMP-2 mRna expression was related to tuberin because it was significantly reduced by 5-azacytidine. Anti-EGFR and rapamycin incubation significantly decreased MMP-2 mRna expression. MMP-7 contributes to tumor progression, invasion and metastasis. In nonadherent LAM/TSC cells MMP-7 mRNA expression was higher than in nonadherent LAM/TSC cells suggesting that in nonadherent status LAM/TSC cells acquired invasive features. These data suggest that IL-6, IL-8, GM-CSF and MCP-1 might be the driven and regulatory factors to induce migration and chemotactic modulation in LAM/TSC cells lacking tuberin. MMP-e and MMP-7 appear to be related to the adherent and nonadherent status.