Angiogenesis of liver metastases - Role of sinusoidal endothelial cells

PURPOSE: Tumor-induced angiogenesis requires migration and remodeling of en dothelial cells derived from preexisting blood vessels. Vascular endothelia l growth factor is the growth factor most closely implicated in the develop ment of neovessels in colon cancer. However, vascular endothelial growth fa ctor-specific receptors flt-1 and KDR mRNA expression are absent in normal sinusoid vessels surrounding vascular endothelial growth factor-producing s econdary hepatic tumors. Thus, the potential role of sinusoidal endothelial cells in the mechanism of neovessel formation within liver metastatic carc inomas remains unclear. The purpose of this study was to determine whether sinusoidal endothelial cells ate involved in tumor angiogenesis in a syngen eic model of liver metastases from colorectal cancer. METHODS: Sinusoidal e ndothelial cells were identified by fluorescence microscopy after uptake of acetylated low density lipoprotein labeled with a fluorescent probe (dioct adecyl-lindocarbocyanine). One hundred microliters of dioctadecyl-indocarbo cyanine acetylated low density lipoprotein were injected intraportally at t he start of experiment in ED IS rats. Two days later, intraportal injection of 10(7) DHD K12, a chemically induced colon carcinoma cell line, was perf ormed in syngeneic ED IX rats. Animals were killed one week later and the l ivers were processed for routine histologic examination and immunohistochem istry using the mt endothelial cell antigen-I monoclonal antibody RESULTS: In normal parenchyma fluorescence was associated with sinusoidal cells but not with endothelium of large blood vessels. Thus, specific acetylated low density lipoprotein uptake allowed histologic;ll differentiation of sinusoi dal endothelial cells from other large-vessel endothelial cells present in the hepatic parenchyma. In tumor-bearing liver a spatial gradient of fluore scence was generated. Labeled cells accumulated at the periphery of the met astases. When tumors grow beyond 200 mu m, neovessel formation was observed ; there was an invasion of fluorescent-labeled cells from the periphery, wh ich were arranged in a tubular formation within neoplasia. CONCLUSION: In l iver metastases tumor vessels are lined with sinusoidal endothelial cells. Identification of a specific cell type involved in the formation of the str omal compartment of tumors has important implications. Sinusoidal endotheli al cells express well-characterized surface receptors and differ morphologi cally and metabolically from large-vessel endothelia. They should be consid ered as attractive targets for future and existing antiangiogenic strategie s directed against the stromal compartment of liver metastases.