Abstract
Patient-derived (PDX) and cell-derived (CDX) xenograft models are widely used in preclinical studies of human neuroblastoma. In this study, we constructed orthotopic and subcutaneous neuroblastoma CDX models by injecting human neuroblastoma cells into the adrenal gland and the flanks of immunodeficient mice, respectively. The tumorigenesis, metastasis and response to chemotherapy for the two models were also compared. Our results indicated that orthotopic tumor mice showed significantly faster tumor growth than that of subcutaneous mice. Importantly, the expression of PHOX2B and GAB2 was dramatically increased in the tumors of orthotopic CDX mice. Furthermore, orthotopic CDX mice developed multiple organ metastasis resembling that of neuroblastoma patients, while metastasis occurred predominantly in lung in subcutaneous CDX mice. Moreover, the two CDX models showed comparable response to cyclophosphamide treatment. Our results suggest that orthotopic CDX mice are superior to subcutaneous CDX mice as a preclinical model to study human neuroblastoma.
Highlights
Neuroblastoma (NB), which arises from the neural crest cells of the peripheral sympathetic nervous system, is frequently observed in adrenal glands [1]
The expression of GAB2, PHOX2B, GRB2, PTPN11 and TP53 in tumors was detected by RT-PCR and the mRNA level of GAB2 and PHOX2B was significantly higher in orthotopic CDX mice tumors than that in subcutaneous CDX mice tumors (Figure 1I, 1J)
Secondary Subq→Subq CDX mice showed significantly faster tumor growth than Orth→Subq CDX mice, while both groups were comparably responsive to CTX treatment (Figure 3E), and the CTX treatment dramatically extended the survival time of Subq→Subq and Orth→Subq CDX mice (Figure 3F). These results indicate that, orthotopic and subcutaneous CDX mice were highly different in tumorigenesis and metastasis, both models were comparably responsive to CTX treatment
Summary
Neuroblastoma (NB), which arises from the neural crest cells of the peripheral sympathetic nervous system, is frequently observed in adrenal glands [1]. NB is the most common extracranial malignant solid tumor in children and contributes to about 15% childhood cancer mortality [2, 3]. NB is an important cause of tumor deaths in children aged 1 to 4 years [4]. Many high-risk NB patients show no response to conventional treatments. NB patients develop resistance to chemotherapy treatments that are currently used. It is of importance to fully understand the underlying mechanisms for the development, metastasis and recurrence of high-risk NB and subsequently develop new therapeutic strategies to improve the survival rate of patients with high-risk neuroblastoma
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