title: Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.
abstract: The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus-CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus-CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet-tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma.
authors.affiliation: Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takagi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Tomoko
authors.initials: T
authors.lastname: Oh-hara
authors.forename: Miho
authors.initials: M
authors.lastname: Takami
authors.forename: Sumie
authors.initials: S
authors.lastname: Koike
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujita
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D037181:Lectins, C-Type / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding; D000098853:Podoplanin
chemical_list: D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C104778:CLEC2B protein, human; C117468:PDPN protein, human; D000098853:Podoplanin