ABSTRACT
BACKGROUND/PURPOSE: Neuroblastoma is the most common tumor of the abdomen in children. Consistently effective treatments are lacking for aggressive disease. The authors previously reported that therapy with anti-vascular endothelial growth factor (VEGF) antibodies suppresses both growth and metastasis in an experimental model of Wilms' tumor. The authors hypothesized that, in a parallel model of neuroblastoma, anti-VEGF treatment would inhibit (1) growth and (2) metastasis. METHODS: Primary tumors were established in the kidneys of nude mice. In cohort 1 (n = 42), mice were killed at 3 time-points, and tissues were evaluated histologically. Tumors were assayed for VEGF. In cohort 2 (n = 28), anti-VEGF antibody or vehicle was administered. Tumor weights and the incidence of metastases in the 2 groups were compared. VEGF deposition was evaluated by immunohistochemistry. RESULTS: Mice displayed large tumors with liver and lung metastases. VEGF levels in tumors increased over time. Antibody-treated animals displayed significantly smaller tumors, but incidence and size of metastases were unaffected. VEGF was localized to tumor stroma immunohistochemically, with no difference in pattern observed in control and antibody-treated tumors. CONCLUSIONS: Anti-VEGF antibodies inhibit primary tumor growth in experimental neuroblastoma, but not metastasis. This may contrast with the effect of the same antibody in a parallel model of Wilms' tumor.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Endothelial Growth Factors/immunology , Kidney Neoplasms/therapy , Lymphokines/immunology , Neuroblastoma/therapy , Animals , Endothelial Growth Factors/analysis , Female , Humans , Immunohistochemistry , Kidney Neoplasms/chemistry , Kidney Neoplasms/pathology , Lymphokines/analysis , Mice , Mice, Nude , Neoplasm Transplantation , Neuroblastoma/chemistry , Neuroblastoma/pathology , Neuroblastoma/secondary , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
BACKGROUND/PURPOSE: Vascular endothelial growth factor (VEGF) has been shown previously to correlate with tumor growth and metastasis in an experimental model of anaplastic Wilms' tumor. The authors hypothesized that treatment with anti-VEGF antibodies would suppress both primary tumor growth and metastasis in this model. METHODS: Tumors were induced in the right kidneys of nude mice by the injection of cultured Wilms' tumor cells. After 1 week, anti-VEGF treatment was begun with injection of either vehicle or an anti-VEGF antibody intraperitoneally. Mice were killed after 4.5 weeks of treatment and tumor weights and the incidence of metastases evaluated. RESULTS: Anti-VEGF treatment resulted in a greater than 95% reduction in tumor weight (P < .0001). Anti-VEGF treatment also abolished the establishment of lung metastases (40% in control animals, P < .003). Cessation of treatment resulted in rebound tumor growth. CONCLUSION: Anti-VEGF therapy can suppress both primary tumor growth and the establishment of metastases in experimental anaplastic Wilms' tumor.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Endothelial Growth Factors/immunology , Kidney Neoplasms/therapy , Lymphokines/immunology , Wilms Tumor/therapy , Animals , Endothelial Growth Factors/physiology , Female , Kidney Neoplasms/pathology , Lung Neoplasms/secondary , Lymphokines/physiology , Mice , Mice, Nude , Neoplasm Transplantation , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Wilms Tumor/pathology , Wilms Tumor/secondaryABSTRACT
BACKGROUND/PURPOSE: Pathological vascular architecture is a feature of neoangiogenic processes such as diseases of the retina and tumor growth. The authors hypothesized that experimental human Wilms' tumors would display a vascular architecture similar to retinal diseases that are driven by vascular endothelial growth factor (VEGF). METHODS: Human Wilms' tumors were established in the right kidneys of nude mice. After 4.5 weeks of tumor growth, fluorescein angiograms were performed before death. Representative sections of tumors and contralateral, control kidneys were evaluated by fluorescent microscopy. RESULTS: Fluorescein angiograms demonstrated a characteristic pathological architecture. Vascular tortuosity, capillary tufting, and hemorrhage were noted. These features were not present in normal kidneys. CONCLUSIONS: Vascular architecture of Wilms' tumor displays the specific features previously described in diseases of the retina, which have been shown to be driven by VEGF, suggesting that neoangiogenesis in this model is also VEGF driven.
Subject(s)
Endothelial Growth Factors/physiology , Kidney Neoplasms/blood supply , Lymphokines/physiology , Neovascularization, Pathologic , Wilms Tumor/blood supply , Animals , Disease Models, Animal , Kidney Neoplasms/pathology , Mice , Mice, Inbred Strains , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Wilms Tumor/pathologyABSTRACT
BACKGROUND/PURPOSE: The growth and spread of solid tumors are critically dependent on the induction of angiogenesis. We hypothesized that vascular endothelial growth factor (VEGF) would be detected in Wilms' tumors, and that both growth and metastasis would parallel VEGF levels in a murine model. METHODS: Primary tumors were established in the right kidneys of nude mice (n = 21). Mice were killed at 3, 4.5, or 6 weeks. Tumor-bearing and control kidneys were subjected to enzyme-linked immunosorbent assay (ELISA) for VEGF. Representative sections were assessed by histology and immunohistochemistry. Lungs were examined for metastases. Clinical specimens of Wilms' tumor (n = 12) also were assayed for VEGF. RESULTS: The authors detected VEGF by ELISA with increasing frequency, and in increasing quantity, as experimental Wilms' tumors were grown over time. Immunohistochemistry demonstrated accumulation of VEGF in areas of viable tumor. Lung metastases occurred in 8 of 10 animals with VEGF-positive tumors, but in only 3 of 11 animals with VEGF-negative tumors, an association that was statistically significant. VEGF was found in 10 of 12 clinical Wilms' tumor specimens tested. CONCLUSIONS: VEGF is present in both clinical and experimental Wilms' tumors. In a murine model, absolute VEGF levels increase as primary tumors grow, and VEGF production is significantly associated with tumor metastasis.
Subject(s)
Endothelial Growth Factors/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Lung Neoplasms/secondary , Lymphokines/metabolism , Wilms Tumor/metabolism , Wilms Tumor/secondary , Animals , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Mice , Mice, Nude , Neovascularization, Pathologic , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
Reproducible animal models of Wilms tumor have been difficult to establish. We describe a model in which cells, banked from a patient with metastatic Wilms tumor, were implanted into nude mice, resulting in the development of primary renal and metastatic pulmonary lesions. Pathologically, the lesions resembled the blastemal component of anaplastic Wilms tumor. Primary tumors showed a significant propensity for growth in the kidney as opposed to other organs. Pulmonary metastases, histologically similar to the primary lesions, were regularly observed. This represents the first reproducible model of anaplastic, metastasizing human Wilms tumor. This system may prove effective for the study of factors influencing growth and angiogenesis in aggressive variants of Wilms tumor.