Loss of syndecan-1 and increased expression of heparanase in invasive esophageal carcinomas

Heparan sulfate proteoglycans play important biological roles in cell-cell and cell-matrix adhesion, and are closely associated with growth factor actions. Loss of syndecan-1, a cell surface-bound heparan sulfate proteoglycan, has been reported for advanced head and neck carcinomas, and expression of endoglycosidic heparanase, which cleaves heparan sulfate glycosaminoglycans (HS-GAGs), is associated with invasion and metastatic potential of malignant tumors. Paraffin sections of 103 primary esophageal squamous cell carcinomas were immunohistochemically examined for the expression of syndecan-1 core protein, HS-GAGs and heparanase protein, and the results were compared with various clinicopathological parameters, such as invasion depth. For 16 cases, fresh tumor samples were quantitatively analyzed for heparanase and syndecan-1 mRNA expression by real-time RT-PCR in addition to the immunohistochemical studies. Syndecan-1 core protein and HS-GAGs expression was significantly decreased in pT2 and pT3 cases compared with their pTis and pT1 counterparts. Decreased expression of core protein and HS-GAGs was correlated with the incidence of lymphatic invasion, and venous involvement. Furthermore, decreased expression of HS-GAGs was correlated positively with the incidence of nodal metastasis and distant organ metastasis, and negatively with the grade of tumor cell differentiation. The percentage of cytoplasmic heparanase protein-positive cases increased significantly in pT2 and pT3 cases compared to that in pTis and pT1 cases, and this was associated with lymphatic invasion, and venous and lymph nodal involvement. The level of heparanase mRNA was inversely correlated with the degree of HS-GAGs expression rather than core protein. In conclusion, loss of syndecan-1 and heparanase overexpression in esophageal squamous cell carcinomas are closely associated with malignant potential. Regarding the mechanism of loss of HS-GAGs, heparanase upregulation appears to play an important role.