Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma - Evidence for its role in colonic tumorigenesis

The human heparanase gene, an endo-P-glucuronidase that cleaves heparan sul fate at specific intrachain sites, has recently been cloned and shown to fu nction in tumor progression and metastatic spread. Antisense digoxigenin-la beled heparanase RNA probe and monoclonal anti-human heparanase antibodies were used to examine the expression of the heparanase gene and protein in n ormal, dysplastic, and neoplastic human colonic mucosa, To our knowledge, t his is the first systematic study of heparanase expression in human colon c ancer. Both the heparanase gene and protein were expressed at early stages of neoplasia, already at the stage of adenoma, but were practically not det ected in the adjacent normal-looking colon epithelium. Gradually increasing expression of heparanase was evident as the cells progressed from severe d ysplasia through well-differentiated to poorly differentiated colon carcino ma Deeply invading colon carcinoma cells showed the highest levels of the h eparanase mRNA and protein associated with expression of both the gene and enzyme by adjacent desmoplastic stromal fibroblasts, A high expression was also found in colon carcinoma metastases to lung, liver, and lymph nodes, a s well as in the accompanying stromal fibroblasts. Moreover, extracts deriv ed from tumor tissue expressed much higher levels of the heparanase protein and activity as compared to the normal colon tissue. In all specimens, the heparanase gene and protein exhibited the same pattern of expression. Thes e results suggest a role of heparanase in colon cancer progression and may have both prognostic and therapeutic applications.