Endostatin-mediated concomitant resistance in neuroblastoma

Abstract

Purpose Concomitant resistance, the phenomenon whereby a primary malignancy inhibits the growth of metastatic lesions, is likely caused by the production of endogenous anti-angiogenic factors. The purpose of this study was to evaluate the influence of the angiogenesis inhibitor, endostatin, expressed by primary sites of neuroblastoma, on synchronous disease. Methods Two neuroblastoma models were used. In one, the growth of a second primary tumor in mice with an already established primary tumor was compared with tumor growth in naı̈ve mice. In the other, the growth of liver metastases arising spontaneously from a subcutaneous tumor was compared in mice in which the primary tumor was either excised or left in place. Systemic endostatin levels and endothelial cell density, vascularity, and degree of apoptosis in the secondary tumors and liver metastasis were evaluated. Results Subcutaneous tumors in mice with preexisting neuroblastoma were significantly smaller than in mice without an established primary tumor; systemic endostatin levels at the time of tumor implantation in mice with preexisting tumors were nearly 3 times that of naı̈ve mice. Decreased angiogenesis and increased apoptosis were seen in the secondary tumors of mice with preexisting tumors. Similarly, the weight of liver metastases was significantly less in mice in which the primary tumor was left in place as compared with those in which the primary tumor had been excised. Systemic endostatin levels in this model paralleled the status of the primary tumor; levels decreased with primary tumor excision but increased when the primary tumor was retained and allowed to grow. Although no difference in microvessel density was seen between groups in the liver metastasis, more tumor cell apoptosis was seen in liver metastasis when the primary tumor was retained. Thus, the presence of an established primary neuroblastoma had a significant inhibitory effect on the growth of secondary disease in both models and was associated with elevated systemic endostatin levels. Conclusions Concomitant antitumoral resistance occurred in these experimental murine models of neuroblastoma and appears to be caused, at least in part, by angiogenesis inhibition mediated by endostatin elaborated from primary tumors.