Visit our Expo - Redox and Inflammation signaling 2012

Session XII : Cell death and neurodegenerative diseases Poster XII, 23
Targeting the IGF-IR for Therapy in Metastatic Human Neuroblastoma
Cynthia M. van Golen, Ph.D. 1, Tracy S. Schwab, Ph.D. 1, Bhumsoo Kim, Ph.D.1, Mary
Soules1, Sang Su Oh1, Kevin Fung, M.D. 2, Kenneth L van Golen, Ph.D. 3 and Eva L
Feldman, M.D., Ph.D. 1.
1Neurology, University of Michigan, Ann Arbor, MI, 48109, 2Otorhinolaryngology,
University of Michigan, Ann Arbor, MI, 48109, and 3Internal Medicine, Hematology
and Oncology Division, University of Michigan, Ann Arbor, MI, 48109.
Neuroblastoma (NBL), the second most common pediatric extracranial tumor, produces
metastases in bone resulting in a survival rate of less than 7%. Therefore, understanding how
bony metastases form is critical for improving patient survival. Our laboratory has shown
that Type I insulin-like growth factor receptor (IGF-IR) expression and activation are present
in advanced stage NBL tumors and regulate NBL cell proliferation, motility, invasion, and
survival. Bone expresses large amounts of IGF ligands, and the IGF system is required for
normal bone physiology. Therefore, we addressed in the current study the role of the IGF
system in NBL metastasis to bone. Upon reaching the bone marrow through the circulation,
NBL cells must adhere to the bone marrow endothelium, extravasate into the bone
microenvironment, and destroy bone tissue to allow for tumor growth. We show high-IGF-
IR-expressing NBL cells migrate across a human bone marrow endothelial cell layer toward
bone stromal cells, which produce IGF-I, and then adhere tightly to these stromal cells.
Transendothelial migration is blocked by both a small molecule inhibitor and a monoclonal
neutralizing antibody against the IGF-IR. Intratibial injection of human NBL cells expressing
high levels of the IGF-IR, either endogenously or through transfection of an IGF-IR
expression construct, leads to tumor formation, osteolytic lesions, and additional secondary
tumors in other organs. Intraventricular injection of high-IGF-IR-expressing NBL cells also
leads to tumor formation within bone and osteolysis. Osteolytic lesions form when
osteoclasts differentiate and become activated in response to tumor cells. When high IGF-IR
expressing NBL cells are injected intratibially, increased numbers of multinucleated tartrateresistant
acid phosphatase (TRAP) positive cells are detected, suggesting an increase in
osteoclast differentiation. In vivo, micro-CT analysis of the bone demonstrates that high-IGF-
IR expressing NBL cells promote osteolysis of 81% of trabecular bone by 3 weeks and over
97% of trabecular bone by 4 weeks, with resorption pits also evident within the cortical bone.
Conditioned media from high IGF-IR-expressing NBL cells are also capable of supporting
osteoclast differentiation in vitro within 10 d. These data suggest that IGF-IR expression in
NBL cells in part determines their ability to form osteolytic metastatic tumors within bone;
therefore, targeted treatment against the receptor may prove efficacious in treating advanced
stage NBL. Targeting the IGF-IR for therapy has recently gained attention in numerous
tumors, leading to pharmaceutical production of a number of inhibitors. We are currently
testing several of these inhibitors for both in vitro and in vivo efficacy. This work was
supported by the Program for Understanding Neurological Diseases (PFUND), the Juvenile
Diabetes Research Foundation Center for the Study of Complications in Diabetes, NIH RO1
NS36778, and NIH RO1 NS38849.
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