Insulin-Like Growth Factor-I Receptor Expression Regulates Neuroblastoma Metastasis to Bone

Abstract

Neuroblastoma is a pediatric tumor that preferentially metastasizes to bone. Patients with bone metastases have a mortality rate >93%, indicating a need for novel treatment targets. Our laboratory has shown that type I insulin-like growth factor receptor (IGF-IR) expression and activation regulate neuroblastoma cell proliferation, motility, invasion, and survival, and that expression of the IGF-IR correlates with neuroblastoma tumorigenicity. Bone expresses large amounts of IGF ligands, and the IGF system is required for normal bone physiology. The current study addresses the role of the IGF system in neuroblastoma metastasis to bone. Upon reaching the bone marrow through the circulation, neuroblastoma cells must dock at the bone marrow endothelium, extravasate into the bone microenvironment, and destroy bone tissue to allow for tumor growth. This report examines the effects of high IGF-IR expression on neuroblastoma cell interaction with bone. The current data show that neuroblastoma cells with high IGF-IR expression, either endogenously or through transfection, adhere to human bone marrow endothelial cells and subsequently migrate toward both IGF-I and human bone stromal cells. High IGF-IR-expressing neuroblastoma cells adhere tightly to bone stromal cells, flatten, and extend processes. When neuroblastoma cells are injected directly into the tibiae of mice, those cells with increased IGF-IR form both osteolytic lesions within the tibiae and secondary tumors within other sites. These results support the hypothesis that IGF-IR expression in neuroblastoma cells increases tumor cell interaction with the bone microenvironment, resulting in greater formation of metastases. (Cancer Res 2006; 66(13): 6570-8)

Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis

“…Circulating level of insulin-like growth factor-1 (IGF-1) has been shown to be associated with development of various cancers and metastasis (Dunn et al, 1998;Wu et al, 2002;van Golen et al, 2006). In this study, we provide evidence that IGF-1-dependent activation of Akt1, but not Akt2, is mediated by molecular interaction with mTORC2.…”

Molecular Biology of Bone Metastasis

“…In biopsies from prostate cancer patients with bone metastases, IGF-IR was frequently increased, as was the receptor substrate IRS-1 (47). Stable overexpression of IGF-IR in neuroblastoma cells increased tumor growth and osteolysis when the cells were directly injected in the tibia of mice (48). Similar results were obtained using MDA-MB-231 cells expressing of a dominant-negative IGF-IR, which decreased bone metastases (49).…”

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

“…Increased expression of IGF-IR in rhabdomyosarcomas has also been linked to chimeric transcription factor PAX3-FKHR (20). Highly metastatic neuroblastoma and osteosarcoma cells possess higher expression of IGF-IR than tumor cells that are less prone to metastasize (21). Furthermore, IGF-IR activation has been shown to generate strong antiapoptotic signals in various cancer cells including sarcoma and neuroblastoma cells, conferring resistance to the cytotoxic effects of chemotherapies (6,21,22).…”

“…Highly metastatic neuroblastoma and osteosarcoma cells possess higher expression of IGF-IR than tumor cells that are less prone to metastasize (21). Furthermore, IGF-IR activation has been shown to generate strong antiapoptotic signals in various cancer cells including sarcoma and neuroblastoma cells, conferring resistance to the cytotoxic effects of chemotherapies (6,21,22). Epidemiologic data have linked elevated plasma levels of IGF-I and IGF-II with increased risk for major cancers such as breast, colon, lung, and prostate cancers, although no such data are currently available for pediatric cancers (6,(23)(24)(25).…”