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Caveolin and Thrombospondin Expression During Hepatocellular Carcinogenesis

Macroregenerative and dysplastic nodules (MDNs) are hepatocellular carcinoma (HCC) precursor lesions and exhibit distinct vascular profiles relative to adjacent cirrhotic liver. Recent microarray analysis of MDN identified aberrant expression of caveolin-1 and thrombospondin-1, genes suspected to play a role in tumorigenesis at other sites. We used immunohistochemistry to localize caveolin and thrombospondin expression in 14 MDNs from livers with hepatitis C cirrhosis and in tissue arrays that included samples of MDNs, HCC, and nonneoplastic liver. Hepatocytes were uniformly negative for caveolin. Sinusoidal endothelial cells exhibited increased caveolin expression in MDNs relative to adjacent cirrhotic liver in most (28 of 36, 78%) MDNs evaluated. However, few HCCs showed increased caveolin expression as compared with nonneoplastic liver (5 of 19, 26%). Unpaired arteries showed strong positive endothelial cell staining. Thrombospondin staining was weak or negative in hepatocytes in nearly all (77 of 92, 84%) MDNs and in 46 of 49 HCCs evaluated (94%). Sinusoidal endothelial cells were negative for thrombospondin, but hepatic arteries and MDNs showed positive mural staining; portal veins were positive both in vessel walls and in endothelial cells. The altered expression profiles of these genes identified in microarray analysis are not likely related directly to malignant transformation of hepatocytes but rather to an alteration in the vascular supply to these lesions. The results illustrate the critical role of histologic techniques in interpretation of microarray data.