Studies of the Tumor Microenvironment in Pathogenesis of Neuroblastoma
Annual rept. 1 Jul 2012-30 Jun 2013
CHILDREN'S HOSPITAL LOS ANGELES CA
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Neuroblastoma is the most common extra cranial solid tumor of childhood, and 45 of patients have high-risk tumors, nearly all of which are metastatic stage 4 when diagnosed. Seventyone percent of metastatic stage 4 neuroblastomas mNBL lack amplification of the MYCN oncogene. An intriguing observation about survival of patients with MYCN non-amplified mNBL mNBL MNA is the extreme variation based on age at diagnosis. Children diagnosed less than 18 months of age have greater than 90 overall survival O.S., while those diagnosed after 18 months of age have only 45 O.S. even with improvements in therapy during the past 20 years. Recently, our group has identified several inflammation-related genes correlating with age at diagnosis and outcome in this group of tumors. Our characterization of a recently described 100 penetrant transgenic murine neuroblastoma model NBL-Tag established lack of MYCN amplification using comparative genomic hybridization aCGH. Remarkably, tumors are not detected by MRI until 13 weeks of life, but they then grow rapidly with liver and bone marrow metastasis by 20 weeks and demise by 28 weeks. Tumor growth coincides with IL6 becoming detectable and increasing in blood, and tumors exhibit high expression of IL-4, IL-6, and IL-10 and are infiltrated by TAMs CD11b, F480 and B lymphocytes B220,CD19IgM. Immunofluorescence analyses demonstrate immunoglobulin deposition within the tumors. These data identify the NBL-Tag mice as the only known transgenic murine model for aggressive human mNBL MNA. Importantly, the pro-inflammatory microenvironment of the NBLTag tumors mimics that observed in human neuroblastoma. Our specific aims will allow us to identify the significance of a pro-inflammatory tumor microenvironment on neuroblastoma pathogenesis.
- Medicine and Medical Research