KeywordsLymphatic Vessel Lymphatic Endothelial Cell Lymphatic Endothelium Podoplanin Expression Epithelial Canine Kidney Cell
Human podoplanin is a type-1 transmembrane glycoprotein consisting of 162 amino acids, nine of which form the intracellular domain. The extracellular domain is extensively O-glycosylated. Depending on glycosylation, the molecular mass is between 36 and 45 kDa. Podoplanin is physiologically expressed in kidney podocytes, skeletal muscle, placenta, lung, heart, myofibroblasts of the breast and salivary glands, osteoblasts and mesothelial cells, and on the apical surface of alveolar type I cells. Occasionally, focal expression of podoplanin can be found in circumscribed areas of the basal layer of the human epidermis. Podoplanin is also expressed in lymphatic endothelium, but not in blood vessels. Pathological expression of podoplanin is observed in many human cancers, in particular squamous cell carcinomas.
In tumors, podoplanin is expressed by the cancer cells themselves, where it is involved in tumor progression. In addition, it is expressed in lymphatic endothelial cells and serves as an immunohistochemical marker for lymphatic vessels.
Podoplanin Expression in Human Tumors
The physiological role of podoplanin remains in great parts unknown. Podoplanin-deficient mice die at birth owing to respiratory failure and exhibit a phenotype of alveolar hypoplasia, dilated malfunctioning lymphatic vessels, and lymphoedema. In addition, podoplanin has an extracellular platelet aggregation-stimulating domain and is therefore able to promote hemostasis.
The podoplanin gene promoter is characterized by the absence of a consensus TATA and CAAT box, the presence of multiple Sp1 binding sites, and a high GC-content. This promoter structure is mostly found in ubiquitously expressed or growth-related genes. In human sarcoma cell lines, the basal transcription of podoplanin is regulated by the transcription factors Sp1 and Sp3 and presumably by other not yet identified factors. In lymphatic endothelium, podoplanin is an early responder to Prox-1, a master regulator of lymphatic vessel formation. In human carcinoma cells, upregulated expression of podoplanin is observed upon treatment of cells with EGF, FGF-2, TNF-α, or bradykinin. The expression of podoplanin is increased in mouse skin during tissue regeneration after wounding or by treatment with the carcinogen phorbol-12-myristate-13-acetate. Podoplanin expression is also induced by 12-O-tetradecanoylphorbol-13-acetate in mouse osteoblastic cells, and it is constitutively expressed in oncogenic Ras-transformed cells.
Podoplanin and Tumor Invasion
Podoplanin induces tumor invasion in vitro and in vivo. Transfection of podoplanin into human cancer cells usually results in increased spreading of the cells on fibronectin, a component of the extracellular matrix. Podoplanin also enhances cell migration and invasion through a collagen IV containing basal membrane-like substrate. The enhanced migration is accompanied by a strong polarization of the cells. Depending on the cell of origin, podoplanin promotes collective or single cell invasion. During collective cell invasion, epithelial cancer cells remain attached to each other, since they continue to express E-cadherin, a cell adhesion molecule required for the formation of epithelial adherens junctions. In a transgenic mouse model of insulinoma, podoplanin was shown to shift the invasion pattern from single to collective cell invasion. Podoplanin also mediates single cell invasion upon loss of E-cadherin (e.g., in MDCK cells, an epithelial canine kidney cell line). Single cell invasion and loss of E-cadherin are often associated with epithelial-mesenchymal transition (EMT), a phenomenon that also occurs during embryogenesis, for example, during neurulation or gastrulation. During both collective and single cell invasion, podoplanin promotes phosphorylation of ERM-proteins, in particular ezrin. Upon phosphorylation, ezrin associates with the cell membrane and reorganizes the actin cytoskeleton.
The expression of podoplanin also affects cell morphology. Stress fibers, which are often found in quiescent cells, are lost and filopodia are formed. Both cell migration and membrane motility are increased, and the formation of multiple microspikes of the cell membrane is induced.
Podoplanin modulates the activity of the family of Rho GTPases, in particular RhoA, Cdc42, and Rac. The modulation of RhoA signaling can directly translate into an increased cell movement. However, depending on the cell type, migration and invasion are induced by either up- or downregulation of distinct Rho GTPases.
Podoplanin and Metastasis
The extracellular portion of podoplanin contains a platelet aggregation domain. Indeed, the expression of podoplanin on circulating tumor cells increases the formation of thrombotic cancer cell emboli, thereby increasing the efficiency of metastasis formation. In a mouse model, acetylsalicylic acid inhibits platelet aggregation and reduces the incidence of metastasis after intravenous injection of podoplanin-expressing Chinese hamster ovary (CHO) cells. Thus, podoplanin may be involved in the transport of tumor cell-platelet clusters in the bloodstream.
Podoplanin as a Marker for Tumor-Associated Lymphatic Vessels
Podoplanin is expressed in lymphatic endothelial cells, but not in blood endothelium. Therefore, podoplanin is frequently used as a selective marker for lymphatic vessels. Together with Lyve-1, another lymphatic endothelium specific marker, it is employed to visualize and quantify lymphatic vessels. Tumor-associated lymphatic endothelial cells are thought to be involved in intralymphatic transport of cancer cells, and the lymphatic microvessel density is important for prognosis. For example, the density of lymphatic vessels is an independent prognostic factor for the prediction of melanoma metastasis and patient survival.
Podoplanin promotes tumor invasion and metastasis formation in both carcinoma and sarcoma. However, in carcinoma in situ and in regenerating epithelium, its role has remained elusive. Alone or together with Lyve-1, podoplanin is an important marker for the assessment of lymphatic microvessel density in tumors.
- (2012) Carcinoma. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 657. doi:10.1007/978-3-642-16483-5_848Google Scholar
- (2012) Collective Cell Invasion. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 896. doi:10.1007/978-3-642-16483-5_1262Google Scholar
- (2012) Lyve-1. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2128. doi:10.1007/978-3-642-16483-5_3473Google Scholar
- (2012) Microspikes. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2308. doi:10.1007/978-3-642-16483-5_3733Google Scholar
- (2012) Outer Edge of the Tumor Mass. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2670. doi:10.1007/978-3-642-16483-5_4292Google Scholar
- (2012) Rho. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3302. doi:10.1007/978-3-642-16483-5_5099Google Scholar
- (2012) Sarcoma. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3335. doi:10.1007/978-3-642-16483-5_5161Google Scholar
- (2012) Single Cell Invasion. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3412. doi:10.1007/978-3-642-16483-5_5311Google Scholar
- (2012) Thrombotic Cancer Cell Emboli. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3682. doi:10.1007/978-3-642-16483-5_5797Google Scholar
- (2012) Tumor Progression. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3800. doi:10.1007/978-3-642-16483-5_6046Google Scholar