Novel Ways to Target Podoplanin to Combat Cancer
Cancer kills almost 8 million people per year worldwide (about 13 people every minute). Clearly, current cancer treatments are not completely effective. In addition, many chemotherapeutic reagents attack rapidly dividing cells, which renders them toxic to a wide array of normal cells in addition to cancer cells. This lack of specificity can cause collateral damage and significant side effects in patients. More targeted therapies are needed to successfully combat cancer. Tumor cell motility leads to invasion and metastasis that cause the vast majority of cancer deaths. We and others have found that the podoplanin (PDPN) receptor promotes tumor cell motility that contributes to many types of cancer. PDPN has a short intracellular domain of 9 amino acids which include two conserved serine residues. PDPN also has a large extracellular domain that is extensively O-glycosylated with α2,3-sialic acid linked to galactose. We are developing reagents to target the intracellular and extracellular domains of PDPN to inhibit cancer progression. For example, we have found that some activators of protein kinase A can induce phosphorylation of the intracellular serine residues of PDPN to inhibit tumor cell motility. In addition, we have found that Maackia amurensis seed lectin (MASL) can target the extracellular domain of PDPN to inhibit transformed cell growth and motility. The biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular circulatory system to inhibit tumor vascularization and progression. Furthermore, we utilized live cell imaging to find that PDPN expression in cancer associated fibroblasts can promote neighboring tumor cell migration and survival. Thus, reagents can be used to target PDPN from inside of the cell and outside of the cell to inhibit tumor cell migration and combat cancer progression. This work illuminates strategies designed to exploit PDPN as a functionally relevant biomarker and chemotherapeutic target.