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.

Metastasis: new functional implications of platelets and megakaryocytes

“…precisely, a new area may be opened in the development of drugs that specifically target the prometastatic activity of platelets such as CLEC-2/podoplanin, 45 TLR-4/HMGB1, 49 or ATX activity 39 without affecting their physiologic functions in hemostasis.…”

“…41 In addition, such incubation of tumor cells with washed thrombin-activated platelet membranes prior to injection in the mouse lateral tail vein lead to a significant increase in lung metastasis formation, confirming that priming tumor cells with platelet membranes 41 and interaction of C-type lectin-like receptor (CLEC)-2 with tumor-derived podoplanin. 45 Tumor cells secrete ADP that interacts with P2Y12, high-mobility group box1 protein 1 (HMGB1) that interacts with TLR-4 and express the tissue factor that activates the coagulation factors (VIIa/Xa) leading to thrombin production. All these factors mediate platelet activation and secretion of TGF-b.…”

“…43 Intriguingly, interaction of podoplanin with CLEC-2 controls tumor cell-induced platelet aggregation and metastasis. 44,45 Recent development of specific blockers of the binding domain of CLEC-2 that interacts with podoplanin revealed a promising therapeutic potential for blocking platelet-induced metastasis 46,47 ( Figure 1).…”

Elevated Platelets Enhance Cancer Cell Migration, Promote Hematogenous Metastasis and Associate with a Poor Prognosis in Advanced Non-small Cell Lung Cancer Cases

“…Such platelet-derived factors reportedly induce tumor vascular angiogenesis, growth, and epithelial-tomesenchymal transition (Italiano et al, 2008;Ho-Tin-Noé et al, 2009). Takagi et al showed the platelet aggregationinducing factor Aggrus, also known as podoplanin, was frequently upregulated in several types of tumors and enhanced hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2 (Takagi et al, 2013). The development of platelet inhibitors that influence malignancy metastasis represents a promising area of targeted cancer therapy.…”

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

“…Concerning platelets, specific surface receptors, such as C-type lectin-like receptor 2 (CLEC-2) (17), and the integrin αIIbβ3 (18)(19)(20) mediate interactions between platelets and tumor cells. Platelets also express other integrins, such as αvβ3 and 3 β1-containing integrins, namely α2β1, α5β1, and α6β1.…”