Targeting a novel domain in podoplanin for inhibiting plateletmediated tumor metastasis.

Targeting a novel domain in podoplanin for inhibiting plateletmediated tumor metastasis.

Oncotarget. 2015 Dec 14;

Authors: Sekiguchi T, Takemoto A, Takagi S, Takatori K, Sato S, Takami M, Fujita N

Abstract
Podoplanin/Aggrus is a sialoglycoprotein expressed in various cancers. We previously identified podoplanin as a key factor in tumor-induced platelet aggregation. Podoplanin-mediated platelet aggregation enhances tumor growth and metastasis by secreting growth factors and by forming tumor emboli in the microvasculature. Thus, precise analysis of the mechanisms of podoplanin-mediated platelet aggregation is critical for developing anti-tumor therapies. Here we report the discovery of a novel platelet aggregation-inducing domain, PLAG4 (81-EDLPT-85). PLAG4 has high homology to the previously reported PLAG3 and contributes to the binding of its platelet receptor CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant platelet-aggregating function relative to PLAG3 and that conserved Glu81/Asp82/Thr85 residues in PLAG4 are indispensable for CLEC-2 binding. By establishing anti-PLAG4-neutralizing monoclonal antibodies, we confirmed its role in CLEC-2 binding, platelet aggregation, and tumor emboli formation. Our results suggest the requirement of simultaneous inhibition of PLAG3/4 for complete suppression of podoplanin-mediated tumor growth and metastasis.

PMID: 26684030 [PubMed - as supplied by publisher]

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1URgdTh
via IFTTT