CHARACTERIZATION OF THE ROLE OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 7 (IGFBP7) USING A GENETIC KNOCKOUT MOUSE MODEL
Abstract
In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.