Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas

Endostatin inhibits angiogenesis and tumor growth in mice. The role of its endogenous precursor collagen XVIII in human cancer is unknown. In normal t issues, two variants of collagen XVIII, namely, the short and long forms re gulate tissue specificity, the long form being almost exclusively expressed by hepatocytes in the liver. We analyzed RNA arrays from 57 hepatocellular carcinomas (HCCs) with common and variant specific probes and investigated the relationships between collagen XVIII expression and angiogenesis by me asuring the CD34-positive microvessel density. Low collagen XVIII expressio n by tumor hepatocytes was associated with large tumor size (r, -0.63; P < 0.001) and replacement of trabeculae with pseudoglandular-solid architectur e (<chi>(2), 28; P < 0.001), which indicate tumor progression. Tumors expre ssing the highest collagen XVIII levels were smaller and had lower microves sel density (P = 0.01) than those expressing moderate levels; and HCCs with the lowest collagen XVIII levels approached a plateau of microvessel densi ty, which indicated that a decrease in collagen XVIII expression is associa ted with angiogenesis in primary liver cancer. HCCs recurring within 2 year s of resection showed 2.2-fold lower collagen XVIII mRNA than nonrecurring ones (P = 0.02). The findings relied on the hepatocyte-specific long form. Thus, the endogenous expression of the endostatin precursor decreases along with tumor progression in HCCs.