Role of the IGF-axis in liver metastasis: Experimental and clinical evidence

The insulin-like growth factors (IGF)-I and -II and their receptor IGF-IR play a major role during embryogenesis, development and pre-pubertal growth and in the maintenance of tissue homeostasis. A large and compelling body of evidence that accumulated over the past 2 decades has implicated this axis in tumorigenesis and the progression of malignant diseases. Here we summarize the evidence, based on experimental and clinical data that collectively identify the IGF-I receptor/ligand system as an important mediator of tumor metastasis in general, and liver metastasis in particular. We show that the IGF axis can be involved in each of the critical steps of the metastatic process by regulating cell-cell connectivity, tumor cell migration and invasion, angiogenesis and lymphangiogenesis and tumor cell survival and growth in distant sites, particularly the liver. We summarize clinical data based on genomic/proteomic analyses of clinical specimens that identify the IGF axis proteins as potential tumor biomarkers and indicators of advanced disease and review the pharmacological strategies that have been developed to target the IGF axis for anti-cancer therapy and their translational status. Taken together, the data provide a compelling rationale for the use of IGF - targeting strategies as a single modality or in combination with other drugs for prevention and treatment of metastatic disease.