The impact of Aggrus/podoplanin on platelet aggregation and tumour metastasis

Abstract

Platelets are small blood components that play indispensable roles in the initial stages of coagulation. In addition to their role in haemostasis, platelets participate in inflammation and tissue regeneration under physiological conditions. Recent studies also revealed the role of platelets under pathological conditions, including the oncogenic process. Platelets enhance tumour growth and metastasis by secreting many growth factors and angiogenic factors or by forming a coat around tumour cells in the blood stream. We previously discovered Aggrus (also known as podoplanin, gp36, gp38P, T1alpha and OTS-8) expressed on tumour cell surfaces as a key molecule for tumour-induced platelet aggregation. Aggrus expression is increased in various malignant tumours such as squamous cell carcinomas, mesotheliomas, glioblastomas and osteosarcomas. Detailed analysis revealed that Aggrus contains three tandem repeats of platelet aggregation-stimulating (PLAG) domains that are associated with its platelet aggregation-inducing ability. PLAG domains of Aggrus are involved in binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). Neutralizing monoclonal antibodies that interfere with Aggrus-CLEC-2 binding attenuate Aggrus-induced platelet aggregation, tumour cell growth and metastasis formation. Aggrus is also expressed in advanced atherosclerotic lesions, suggesting that Aggrus is associated with thrombus formation on disrupted atherosclerotic lesions. These data suggest that Aggrus is a promising cell surface target for developing new therapies against cancer and thrombosis.