Induction of metastatic and angiogenic neuroendocrine tumors in the immunosuppressed newborn rat

Abstract

The neuroendocrine tumors of the gut are poorly understood as a result of their low frequency and their indolent growth, together with the few available animal models. In this study, we proposed an easy model of endocrine tumors by implanting STC-1 cells (a murine endocrine cell line derived from tumors of the small intestine, which expresses most of the gastrointestinal peptides) in the immunosuppressed newborn rat. STC-1 Cells were injected S.C. in the ventral area of newborn rats maintained in immunodepression by injections of antithymocytes serum. Animals were killed on post-natal day 21. Tumors were excised and processed for histological characterization. All the newborn rats injected with STC-1 cells developed small tumors (4-7 mm). Furthermore, all 18 rats injected presented visible metastases at the surface of the lung. The histology of the tumors revealed a morphology characteristic of poorly differentiated neuroendocrine carcinoma. Immunohistochemical staining with polyclonal anti-chromogranin A antibody showed endocrine phenotype of both tumors and metastases. Primary tumors exhibited substantial amounts of hormonal peptides also expressed in STC-1 cell line. Electron microscopy confirmed the endocrine phenotype through the presence of electron-dense endocrine granules inside tumors and metastases. Furthermore, a basement membrane immunostained with anticollagen IV and anti-laminin antibodies lined the tumoral islets at the interface with the stroma. In addition, histological and ultrastructural observations demonstrated a large number of vessels inside the tumoral islets. The S.C. injection of STC-1 in the immunosuppressed newborn rats induced the formation of tumors characterized by their small size, their metastatic potential and their intense neovascularization, thus bearing a clear resemblance to neuroendocrine tumors observed in humans. This model seems particularly attractive for the study of angiogenesis in neuroendocrine tumors.