IGFBP7 Deletion Promotes Hepatocellular Carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 15; pp. 4014 - 4025
• Main Authors: Akiel, Maaged, Guo, Chunqing, Li, Xia, Rajasekaran, Devaraja, Mendoza, Rachel G., Robertson, Chadia L., Jariwala, Nidhi, Yuan, Fang, Subler, Mark A., Windle, Jolene, Garcia, Dawn K., Lai, Zhao, Chen, Hung-I Harry, Chen, Yidong, Giashuddin, Shah, Fisher, Paul B., Wang, Xiang-Yang, Sarkar, Devanand
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.08.2017
• Subjects: Angiogenesis; Animals; Antigen presentation; Antitumor activity; Apoptosis; Blotting, Western; Carcinogens; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; CD4 antigen; CD8 antigen; Clonal deletion; Dendritic cells; Disease Models, Animal; Embryo fibroblasts; Embryos; Flow Cytometry; Fluorescent Antibody Technique; Gene deletion; Hepatocellular carcinoma; Hepatocytes; Immunohistochemistry; Immunosuppression; Immunosurveillance; Inflammation; Insulin; Insulin-Like Growth Factor Binding Proteins - deficiency; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - immunology; Insulin-like growth factor I; Insulin-like growth factors; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Lung cancer; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Microenvironments; Real-Time Polymerase Chain Reaction; Rodents; Senescence; Tumor suppressor genes; Tumors
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2885

Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF1 receptor (IGF1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here, we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with proinflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7−/− murine livers, which was associated with a marked inhibition in antigen cross-presentation by Igfbp7−/− dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC. Cancer Res; 77(15); 4014–25. ©2017 AACR.