Inhibition of cancer invasion and metastasis targeting heparanase

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Heparanase (HPA) is thought to play critical roles in invasion and metastasis of esophageal carcinomas. Cyclooxygenase-2 (COX-2) is a potent carcinogenic and angiogenic molecule that promotes tumor angiogenesis by prostaglandin E2 synthesis. We analyzed HPA and COX-2 expression in esophageal carcinoma, and found that HPA and COX-2 exhibited a similar expression pattern in esophageal tumor tissues. Moreover, expression of these molecules showed a significant correlation with high intratumoral microvessel density. In esophageal cancer cell lines transfected with the HPA-cDNA, upregulation of COX-2 mRNA and protein was detected by RT-PCR and western blotting. A COX-2 promoter assay showed that cyclic AMP responsible element (CRE), NFκB and NF-IL-6 sites in the COX-2 promoter were essential for the transcriptional activation induced by HPA. Next, we studied the relation of HPA and COX-2 using breast cancer and gastric cancer. Our results suggest that HPA and COX-2, both of which are thought to play independently critical roles in tumor progression and metastasis, are closely related.