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(American Journal of Pathology. 1999;154:395-403.)
© 1999 American Society for Investigative Pathology

Regular Articles

Inhibition of Angiogenesis Induces Chromaffin Differentiation and Apoptosis in Neuroblastoma

Erik Wassberg* , Fredrik Hedborg§ , Erik Sköldenberg* , Mats Stridsberg¶ and Rolf Christofferson*

From the Department of Medical Cell Biology,* Biomedical Centre, Uppsala University, Uppsala; the Departments of Women and Child Health and Surgery, Children's Academic Hospital, Uppsala, and the Departments of Genetics and Pathology § and Medical Sciences,¶ University Hospital, Uppsala, Sweden

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 (L_V, V_V, S_V) 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 µm) 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.

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