Inhibition of tumor cell-induced platelet aggregation and tumor metastasis using a novel anti-podoplanin antibody Free

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Podoplanin (aggrus) is a platelet aggregation-inducing mucin-type sialoglycoprotein on cancer cells such as squamous cell carcinoma, malignant mesothelioma, angiosarcoma, testicular seminoma, and brain tumors. Podoplanin is also known as a specific lymphatic marker. We previously described up-regulated expression of podoplanin in malignant astrocytic tumors and its expression was associated with tumor malignancy. In the present study, we investigated podoplanin expression and platelet-aggregating activities of glioblastoma cell lines. First, we established a highly reactive anti-podoplanin antibody, NZ-1. NZ-1 recognized the highly conserved platelet aggregation-stimulating (PLAG) domains with O-glycosylated threonine residues, which are critical for exhibiting platelet aggregation-inducing capabilities. Using 642 tumors, NZ-1 stained astrocytic tumors, lung or esophageal squamous cell carcinomas and testicular seminomas. However, stomach adenocarcinoma, colorectal adenocarcinoma, and malignant melanoma were not stained by NZ-1. Interestingly, NZ-1 inhibits podoplanin-induced platelet aggregation completely. Furthermore, NZ-1 suppressed pulmonary metastasis of podoplanin-transfected CHO cells. Of 15 glioblastoma cell lines, LN319 highly expressed podoplanin and induced platelet aggregation. Glycan profiling using a lectin microarray showed that podoplanin on LN319 possesses sialic acid, which is important in podoplanin-induced platelet aggregation. NZ-1 also neutralized platelet aggregation by LN319. Podoplanin might become a therapeutic target of glioblastoma or other cancers for antibody-based therapy.