The Molecular Biology of Soft-Tissue Sarcomas and Current Trends in Therapy

Figure 1

Several growth factor signals activate cell membrane receptor tyrosine kinases leading to activation of downstream interacting signal transduction pathways (PI3K/AKT, RAF/MAPK, and MTOR). Within the RAF/MAPK pathway, activated receptors lead to SHC-mediated activation of RAS and propagation of signalling through RAF, MEK (a.k.a. MAP2K), and MAPK (a.k.a. ERK). Activated MAPK forward signals to the nucleus that regulate proliferation, differentiation, angiogenesis, and cell survival. A second essential signalling pathway is the PI3K/AKT pathway. PI3K catalyzes triple phosphorylation of phosphatidylinositol (PI) AKT in conjunction with its PDK1. AKT is a key molecular “node” acting as a master switch, which triggers multiple downstream signaling pathways including mTOR pathway activation. A key regulatory enzyme is PTEN that modulates PI3K and SHC phosphorylation. Activated AKT signals a number of mitogenic processes promoting proliferation and increased cell survival, antiapoptotic signals, and upregulation of cell-cycle proteins (cyclin D1 and CDK4).