Neuroblastoma is a malignant solid
tumor of childhood with a poor prognosis. The growth of solid
tumors has been shown to be dependent on new blood vessel formation, i.e. angiogenesis. Several steps in the metastatic process have also been found to be angiogenesis-dependent.
Neuroblastomas grow quickly, are highly vascularized, and metastasize early, and hence inhibition of angiogenesis--angiostatic
therapy--may be indicated in this disease. In order to investigate the effects of
angiostatic agents in this disease, a new animal experimental model for human
neuroblastoma was developed. Three
angiostatic agents were tested in the model:
TNP-470, the synthetic analogue of
fumagillin, given subcutaneously, and the endogenous
steroid 2-methoxyestradiol and its derivative 2-propynylestradiol, given orally.
TNP-470 administration resulted in a significant reduction of the
tumor growth rate and microvascular counts, and of the fraction of viable
tumor cells, compared to controls. The fraction of apoptotic
tumor cells increased threefold, while that of proliferative cells remained unaltered. This can explain the reduced net growth. Treatment with the angiostatic and chemotherapeutic
steroids 2-methoxyestradiol and 2-propynylestradiol yielded similar results. However, the mechanism of action of these
steroids was bimodal; the effect occurring both through inhibition of
tumor angiogenesis and through induction of
tumor cell apoptosis. It was shown for the first time that inhibition of angiogenesis regardless of agent induces striking chromaffin differentiation, observed as increased expression of
insulin-like growth factor II gene,
tyrosine hydroxylase, and
chromogranin A, and increased formation of cellular processes. It is suggested that inhibition of angiogenesis induces metabolic stress, resulting in chromaffin differentiation and apoptosis. Such agonal differentiation may be the link between angiostatic
therapy and
tumor cell apoptosis.
Angiostatic agents administered as single
therapy have an objective tumoristatic effect in our
neuroblastoma model. Angiostatic treatment of
neuroblastoma is a new and promising treatment modality that merits clinical investigation.