Gastro-Enteropancreatic Neuroendocrine Tumor Cell Dynamics in Liver Microvasculature

Abstract For many cancers, liver metastasis is common and usually indicates poor prognosis. Gastro-enteropancreatic neuroendocrine tumors (GEPNETs) of the midgut are a heterogeneous group of cancers that typically remain asymptomatic until they metastasize to the liver. However, the mechanisms by which these usually indolent cancers establish distal metastasis remain unclear. To begin to elucidate this process, we performed standard in vitro assays to assess cell motility, transendothelial migration, and invasion using BON cells, a widely used model GEPNET cell line. In addition, transmission electron microscopy was used in combination with a novel ex vivo organ slice xenograft model to reveal ultrastructural details of the initial events of BON cell extravasation and re-distribution within the liver. The ultrastructural resolution of the extravasation process revealed the route, sequence, and time course by which tumor cells migrated from the sinusoidal lumen into the hepatic parenchyma in this organ slice model. Both standard in vitro assays and our organ slice model indicated that tumor cells migrated through the discontinuous sinusoidal endothelium to invade the liver parenchyma.