[Immunogical surveillance and oncogenesis: role of proliferation signal inhibitors]

The authors review the antineoplastic effect of mTOR inhibitors and their biological basis. In normal cells mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from a variety of sources as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades through PI3K-AKT-mTOR (phosphatidylinositol 3-kinase/serine-threonine kinase-mTOR), leading to protein synthesis. As a consequence, activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in a number of cellular processes, including growth, proliferation, angiogenesis, and nutrient uptake. Deregulation of mTOR-linked pathways increases the risk of developing cancer and has been identified in many human cancer types. Such deregulation includes overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways. These changes permit the survival, growth, proliferation, and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancer in transplanted patients, or making them regress once developed, has been documented in clinical trials and case reports.