Preclinical Models of Pediatric Solid Tumors (Neuroblastoma) and Their Use in Drug Discovery

Abstract

Neuroblastoma is the most common pediatric abdominal solid tumor. This aggressive embryonal malignancy of neural crest origin has a peak age of onset of 22 months, and accounts for ~11% of all pediatric cancers and 15% of all pediatric cancer deaths. With current treatment protocols, including high-dose chemotherapy with autologous stem cell transplantation, radiation, and surgery, ~80% of high-risk patients go into remission, although the majority relapse and succumb to therapy-resistant tumors. Long-term survival rates (>5 years) are <50%. Mouse models of neuroblastoma provide clinically relevant tools for studying the growth and metastasis of this aggressive malignancy, and for testing the efficacy of potentially novel therapeutics in vivo. This unit describes an orthotopic murine model of neuroblastoma using cultured human cells that closely mimics the clinical condition in terms of the bulky intra-abdominal tumors and other aspects of metastatic disease. Also described are methods for in vivo imaging and monitoring of tumor growth, and procedures for necropsy and tumor preservation for pathological analysis.

G-CSF Receptor Positive Neuroblastoma Subpopulations Are Enriched in Chemotherapy-Resistant or Relapsed Tumors and Are Highly Tumorigenic

“…An orthotopic xenograft model was used to compare the in vivo tumorigenicity of FACS-sorted CD114+ and CD114− subpopulations (26). In vivo limiting dilution analysis was performed using binomial generalized linear modeling with the complementary log-log link (Fig.…”

“…Utilizing our previously described orthotopic kidney capsule model (orthotopic model) of neuroblastoma, an inoculum of sorted CD114 positive or CD114 negative NGP cells in 0.1 ml of PBS was injected under the renal capsule (26). Three experiments were performed with decreasing numbers of implanted neuroblastoma cells: 1000 cells per mouse (CD114+ n=5; CD114− n=5), 100 cells per mouse (CD114+ n=10; CD114− n=10), 10 cells per mouse (CD114+ n=10; CD114− n=10).…”

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

“…However, other preclinical models are more suitable to investigate how AZA+RA treatment could affect additional key properties of tumor biology, such as metastasis, angiogenesis, and tumor microenvironment. Orthotopic xenografts wherein human NB cells are transplanted beneath the renal capsule (47) and transgenic mouse models of NB (48,49) would provide more appropriate experimental settings for future investigation of such parameters.…”

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation

“…Mice were inbred and genotyped for colony maintenance. Mice were implanted using our previously described orthotopic xenograft model of neuroblastoma (12). Briefly, 1×10 6 NB cells were surgically implanted in the sub-renal capsule of mice and tumor growth was monitored bi-weekly by bioluminescent imaging (IVIS Lumina XR System, Caliper Life Sciences, Hopkinton, MA).…”