Roles of Podoplanin in Malignant Progression of Tumor

Abstract

Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial-to-mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is upregulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating its involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in the malignant progression of tumors and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

Keywords: CasMab; PDPN; antibody therapy; cancer-specific monoclonal antibody; podoplanin; tumor malignancy; tumor marker.

Figure 1

Schematic representation of podoplanin (PDPN) structure and functions. PDPN is a type I transmembrane glycoprotein consisting of an extracellular domain, a transmembrane portion, and a short cytoplasmic tail. The PDPN extracellular domain contains PLAG1-3 (PL1, PL2, and PL3) domains and PLAG-like domain (PLD). C-type lectin-like receptor 2 (CLEC-2), a platelet receptor, recognizes both the sialylated PLAG3 domain and PLD with the adjacent PDPN peptides, inducing CLEC-2 tyrosine phosphorylation and platelet aggregation. The intracellular domain of PDPN contains basic residues (RK), which function as binding sites for ezrin, radixin, and moesin (ERM) family proteins that modulate RHO GTPase activity and promote actin cytoskeleton reorganization to promote cell migration, motility, and EMT. PDPN interacts with hyaluronan receptor CD44 and matrix metalloproteinase 14 (MMP14), promoting hyaluronan-binding and extracellular matrix (ECM) degradation, respectively. Anti-PDPN mAb NZ-1 recognizes the PLAG2/3 domain, exhibits a neutralizing activity for PDPN–CLEC-2 interaction, and inhibits PDPN-induced platelet aggregation and metastasis. Anti-PDPN mAb D2-40 identifies the PLAG1/2 domain and is widely employed for immunohistochemistry. A cancer-specific mAb (CasMab) to PDPN, LpMab-2, recognizes a glycopeptide (Thr55-Leu64) of human PDPN. A CasMab to PDPN, LpMab-23 recognizes a naked peptide of human PDPN (Gly54–Leu64), especially Gly54, Thr55, Ser56, Glu57, Asp58, Arg59, Tyr60, and Leu64 of PDPN, and is a critical epitope of LpMab-23. A CasMab to PDPN, chPMab-117 recognizes the glycopeptide of PDPN (Ile78-Thr85), which includes O-glycosylated Thr85.

Figure 2

Roles of PDPN in the tumor-metastatic cascade. Tumor metastasis is a multistep biological process termed the invasion-metastasis cascade. PDPN-mediated induction of epithelial to mesenchymal transition (EMT) reduces E-cadherin levels and promotes the dissemination of cancer cells from primary sites. PDPN recruits CD44 and MMP14 at filopodia, lamellipodia, and invadopodia and stimulates hyaluronan-binding and extracellular matrix (ECM) degradation, respectively. The intracellular actin cytoskeleton reorganization by PDPN also promotes cell motility. These events confer the migration/invasion phenotype and stimulate the intravasation. Note that PDPN expression is observed at the invasive front of the tumor’s collective invasion, which implies the importance of tumor–stroma interaction. PDPN-mediated platelet aggregation promotes survival of shear stress and immune attacks in the circulation. Furthermore, platelet-derived factors (PDGFs and TGF-β) also promote the tumor cell survival and plasticity. PDPN confers stemness, probably through the Rho-ROCK pathway, and promotes colonization in a distant organ. Furthermore, PDPN-positive CAFs construct the immunosuppressive TME by producing TGF-β, a potent immunosuppressive cytokine. Furthermore, PDPN is expressed in both CD4⁺ and CD8⁺ T cells and acts as a co-inhibitory receptor, which could control tumor immunity. Thus, PDPN is involved in multiple steps of the invasion-metastasis cascade.