Abstract No. 172: Angiogenesis and cell death after liver embolization with bland vs doxorubicin-loaded microspheres: Gene expression and histology in pig

Embolization has been shown to promote angiogenesis (Jensen RL, J Neurosurg 2002) (Sure U, J Neurosurg 2004) and doxorubicin is known to repress pro-angiogenic genes (Duyndam MC, Biochem Pharmacol 2007). By combining DNA-microarray to histology, we investigated the effects of embolization with bland vs doxorubicin-eluting beads, including angiogenesis and lesions. Hepatic arteries of two pigs were embolized with 1mL of 100–500μm non-loaded beads (BlandMS) or doxorubicin-eluting beads (25mg) (DoxMS) (Sacrifice at 1W). Histopathological effects of the embolization were evaluated. RNAs were extracted from embolized areas (n=3/pig) and from non embolized liver control areas (n=1/pig), and hybridized onto porcine microarrays. Genes showing significantly different expression were listed and classified by biological process. BlandMS limited embolization caused no tissue damage in histology and had low impact on gene expression in liver tissues vs Control (2 up- and 18 down-regulated genes) whereas embolization with DoxMS caused important tissue damages (vascular necrosis in 51% of the embolized vessels, and parenchymal necrosis in 38%) and drastic gene expression changes vs Control (469 up- and 103 down-regulated genes), which related massively to cell death. By comparing DoxMS vs BlandMS, 353 genes were up-regulated and 119 genes were down-regulated. The activated genes related to cell proliferation (growth factors, transcription regulators), and to tissue remodeling (matrix metalloproteases, several types of collagen). Thirty-two activated genes related to angiogenesis, but neither HIF1A nor VEGF were included in this list. DoxMS down-regulated genes related to hepatic functions (enzymes of lipid and carbohydrate metabolisms), which was consistent with the necrosis observed in histology. The effects of a limited bland embolization of the liver were not visible 1W after embolization. DoxMS induced vascular and parenchymal necrosis, and cell death. A repair process was being organized at 1W after DoxMS embolization, through cell proliferation, tissue remodeling and angiogenesis mechanisms, excluding HIF1A and VEGF, which might be muted at this date.