Podoplanin promotes malignancy through a diversity of strategies

Podoplanin (PDPN) is a small mucin-like glycoprotein upregulated in a variety of cancers where it can be expressed in tumor as well as in stromal cells, such as cancer associated fibroblasts (CAFs). In most cancers, especially in squamous cell carcinomas (SCC) and glioblastomas, PDPN expression is associated with increased risk of metastasis to lymph nodes and reduced overall survival, although the opposite has been found in other tumor types. Studies from different laboratories, including our own, suggest that PDPN is involved in different steps of the metastatic cascade. Thus, PDPN, which is connected to the actin cytoskeleton through the binding to ezrin and/or moesin, stimulates collective tumor cell migration/invasion, and induces an epithelial-mesenchymal transition allowing a directional migration of individual cells through its interaction with the hyaluronan receptor CD44. PDPN is a component of the invadopodium contributing to its stability and promoting an efficient invasion through the extracellular matrix. In addition, PDPN favors the survival of cancer cells in the bloodstream aiding to their metastatic dissemination by inducing platelet aggregation/activation through its binding to the platelet receptor CLEC-2. More recently, we have reported that PDPN is a component of microvesicles and exosomes released by tumor cells and that PDPN-containing exosomes enhance in vitro lymphangiogenesis. In this short review, we discuss the role of PDPN in all these processes that foster malignant progression.