Related Experiment Videos
Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma
E Wassberg1, F Hedborg, E Sköldenberg
1Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Sweden. erik.wassberg@medcellbiol.uu.se
Abstract:
Inhibition of angiogenesis has been shown to reduce tumor growth, metastasis, and tumor microvascular density in experimental models. To these effects we would now like to add induction of differentiation, based on biological analysis of xenografted human neuroblastoma (SH-SY5Y, WAG rnu/rnu) treated with the angiogenesis inhibitor TNP-470. Treatment with TNP-470 (10 mg/kg s.c., n = 15) reduced the tumor growth by 66% and stereological vascular parameters (Lv, Vv, Sv) by 36-45%. The tumor cell apoptotic fraction increased more than threefold, resulting in a decrease in viable tumor cells by 33%. In contrast, the mean vascular diameter (29 microm) and the mean tumor cell proliferative index (49%) were unaffected. TNP-470-treated tumors exhibited striking chromaffin differentiation of neuroblastoma cells, observed as increased expression of insulin-like growth factor II gene (+88%), tyrosine hydroxylase (+96%), chromogranin A, and cellular processes. Statistical analysis revealed an inverse correlation between differentiation and angiogenesis. It is suggested that by inhibiting angiogenesis, TNP-470 induces metabolic stress, resulting in chromaffin differentiation and apoptosis in neuroblastoma. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis.
Insights
The angiogenesis inhibitor TNP-470 reduces neuroblastoma tumor growth and increases cancer cell death. This treatment also promotes cancer cell differentiation, suggesting a new therapeutic link.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Inhibiting angiogenesis is a known strategy to reduce tumor growth and metastasis.
- The role of angiogenesis inhibitors in inducing cancer cell differentiation requires further investigation.
Purpose of the Study:
- To investigate the effects of the angiogenesis inhibitor TNP-470 on human neuroblastoma xenografts.
- To determine if TNP-470 can induce differentiation and apoptosis in neuroblastoma cells.
Main Methods:
- Human neuroblastoma xenografts (SH-SY5Y) were treated with TNP-470 (10 mg/kg s.c.).
- Tumor growth, vascular parameters, apoptosis, proliferation, and differentiation markers were analyzed using stereology and gene expression analysis.
Main Results:
- TNP-470 significantly reduced tumor growth (66%) and vascular parameters (36-45%).
- Apoptotic fraction increased threefold, decreasing viable tumor cells by 33%.
- Neuroblastoma cells showed significant chromaffin differentiation, with increased expression of IGF-II, tyrosine hydroxylase, and chromogranin A.
Conclusions:
- TNP-470 inhibits angiogenesis and induces chromaffin differentiation and apoptosis in neuroblastoma xenografts.
- Metabolic stress induced by angiogenesis inhibition may drive this differentiation and apoptosis.
- Agonal differentiation could be a key mechanism linking angiostatic therapy to tumor cell apoptosis.