{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPodoplanin (PDPN) is a small, mucin‐type transmembrane glycoprotein that is normally expressed on lymphatic endothelial cells and select specialized cell types—including osteocytes, keratinocytes, and certain mesothelial cells—where its proper glycosylation (notably at Thr52) is critical for function. In normal physiology, PDPN plays important roles in lymphatic development, blood–lymphatic vessel separation, and in mediating cell–matrix interactions through binding partners such as galectin‑8. Moreover, its interaction with the platelet receptor CLEC‑2 enables PDPN‐expressing cells to induce platelet aggregation, which is essential not only for normal developmental processes but also for the pathogenesis of thrombosis in diverse settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cancer context, PDPN expression is frequently upregulated in a wide array of tumors—including squamous cell carcinomas (oral, head and neck, lung), astrocytic neoplasms, glioblastomas, osteosarcomas, and germ cell tumors—and its elevated expression is often correlated with increased cell motility, invasion, and metastasis. PDPN enhances tumor cell invasion by promoting collective cell migration (via filopodia and invadopodia formation) without necessarily triggering a full epithelial–mesenchymal transition. A key mechanism is its ability to bind CLEC‑2 on platelets, which triggers platelet aggregation; this in turn facilitates tumor embolus formation, protects circulating tumor cells, and induces the release of growth factors such as TGF‑β that further potentiate tumor progression. In addition, PDPN is expressed by cancer‐associated fibroblasts (CAFs) in several tumor microenvironments, where its presence is associated with enhanced local invasion and poorer clinical outcome. Regulatory factors such as specific microRNAs (e.g., miR‑29b, miR‑125a, and miR‑363) have been shown to modulate PDPN expression, thereby affecting the invasive and metastatic potential of tumor cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in tumor cell behavior, PDPN serves as a valuable diagnostic and prognostic biomarker in numerous neoplasms. Its expression is leveraged to distinguish between tumor types (e.g. follicular dendritic cell tumors, chondrosarcoma, and osteosarcoma) and to identify tumor-initiating cell populations within squamous cell carcinomas. Furthermore, PDPN’s interactions with other cell surface proteins such as CD44 and tetraspanin CD9—as well as the functional importance of its PLAG domains—underscore its multifaceted contributions to tumor biology. In inflammatory and other non‐malignant contexts, including rheumatoid arthritis and wound-healing responses, PDPN expression in stromal cells underscores its broader role in modulating cell adhesion and migration, suggesting that targeted inhibition of PDPN–mediated pathways may offer therapeutic benefit across a range of diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "38"}, {"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "26"}, {"type": "fg_f", "ref": "39"}, {"type": "fg_f", "ref": "28"}, {"type": "fg_fs", "start_ref": "40", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yukinari Kato, Naoya Fujita, Akiko Kunita, et al. 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