The unique angiogenic and vasculogenic properties of renal cell carcinoma in a xenograft model of bone metastasis are associated with high levels of vegf-a and decreased ang-1 expression

摘要

Management of various tumor metastases to bone has dramatically improved, but this is not so for renal cell carcinoma (RCC), which is a difficult surgical problem due to its great vascularity. Furthermore, the unique mechanisms that mediate RCC vasculogenesis in bone remain unknown. To understand this process we developed a xenograft model that recapitulates highly vascular RCC vs. less vascular tumors that metastasize to bone. Human tumor cell lines of RCC (786-O), prostate cancer (PC3), lung cancer (A549), breast cancer (MDA-MB231) and melanoma (A375) were transfected with firefly luciferase (Luc), injected into the tibiae of nude mice, and differences in growth, osteolysis and vascularity were assessed by longitudinal bioluminescent imaging (BLI), micro-CT for measurement of calcified tissues and vascularity and histology. The results showed that while RCC-Luc has reduced growth and osteolytic potential vs. the other tumor lines, it displayed a significant increase in vascular volume (p<0.05). This expansion was due to 3- and 5-fold increases in small and large vessel numbers respectively. In vitro gene expression profiling revealed that RCC-Luc expresses significantly (p<0.05) more vegf-a (10-fold) and 20-30-fold less ang-1 vs. the other lines. These data demonstrate the utility of this model to study the unique vasculogenic properties of RCC bone metastases.