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PDPN, i.e., podoplanin (also termed PA2.26, gp36, gp38, T1α, aggrus, OTS-8, E11 antigen, and RANDAM-2[1][2][3][4]) is a mucin-containing glycoprotein located on the surface membrane of various cell types. The extracellular component of PDPN interacts with a wide range of other cells to regulate their function.[2] Human PDPN is encoded by the PDPN gene located on the "p", i.e., short, arm of chromosome 1, region 3, band 1 (location notated as 1p36.21; see Gene nomenclature).[5] This gene directs the formation of PDPN messenger RNA (i.e., mRNA) which in turn directs formation of the PDPN. PDPN is expressed in animals but has most often been termed: a) OTS-8, gp38, aggrus, antigen PA2.26, or RANDAM-2 (i.e., retinoic acid-induced neuronal differentiated-associated molecule-2) in mice; b) T1α protein, E11 antigen, or podoplanin in rats; c) gp40 or aggrus in canines; and d) aggrus in hamsters and cows.[4] Here, the term PDPN is used for the non-human as well as human protein, PDPN for the human PDPN gene, and Pdpn for the animal PDPN gene.

PDPN structure and activation of CLEC-2

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Human PDPN is a mucin-containing, O-linked glycosyl, type I transmembrane glycoprotein. Type 1 glycoproteins pass through a cell's surface membrane once and have their N-terminal and C-terminal ends located respectively on the extracellular and intracellular sides of the cell's surface membrane.[2] PDPN consists of 162 amino acids with its major portion residing on the cell's exterior, about 25 amino acids spanning the cell's surface membrane, and 9 residing inside the cell.[2][6][7] Human PDPN's structure is similar to that of animal PDPNs in its transmembrane and cytoplasmic portions but has a somewhat different structure in its extracellular portions than that of animals which vary in different animal species.[3] Human PDPN has a molecular mass of 36 to 43 kilodaltons, depending on the amount of O-linked glycosyl residues it contains.[8] Its extracellular portion consist of four amino acid tandem repeats termed platelet aggregation-stimulating domains, i.e., PLAG 1-4. PLAGs interact with proteins on the surface of other cells, particularly the C-type lectin-like receptor 2, i.e., CLEC-2 (also termed CLEC2, CLEC1B, C-type lectin domain family 1 member B, and CLEC1B). CLEC-2 is a member of the C-type lectin receptors in the superfamily of pattern recognition receptors (see C-type lectin section on Classification).[7][9] It is located on the surface membranes of platelets, dendritic cells,[10] Follicular dendritic cells, mesothelial cells (i.e., simple squamous epithelial cells of mesodermal origin in the mesothelium), epithelium cells in blood and lymphatic vessels, fibroblasts, and various types of cancerous tumor cells.[11] The binding of PDPN's PLAGs to CLEC-2 causes CLEC-2 bearing cells to phosphorylate tyrosine and lysine in its single cytoplasmic tyrosine-XX-lysine sequence (known as a hem-immunoreceptor tyrosine-based activation motif, i.e., hemITAM). The phosphorylated CLEC-2 activates tyrosine-protein kinase SYK,i.e., Syk, which in turn activates various pathways which elicit cell function (see Signal transduction).[9][10][11] CLEC-2 is also activated by the human immunodeficiency virus (i.e., HIV), rhodocytin (a platelet-activating snake venom also termed aggretin), hemin, galectin-9, dextran sulfate, sulfated polysaccharides, fucoidan, ketacine (i.e., an extract of the Polygonaceae family of flowering plants), S100A13 (i.e., S100 calcium-binding protein A13), CLEC7A (also termed C-type lectin domain family 7 member A or dectin-1), and the soot, carbon, and other particles in the exhaust gas of diesel engines.[9][12][13]

Cells and tissues that express PDPN

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A study on the levels of PDPN in 20 human tissues reported that it was: most highly expressed on the cells in the lung, placenta, heart, trachea, uterus, cerebellum, fetal brain, stomach, thymus, and prostate; less strongly expressed in skeletal muscle and cells in the brain, thyroid, adrenal gland, kidney, salivary gland, and small intestine; and minimally expressed or not detected in cells of the fetal liver, non-fetal liver, and spleen.[5][14] Other studies reported that PDPN is also expressed in human and/or rodent type I alveolar cells of the lung, kidney podocytes (podoplanin was given its name based on its expression in podocytes[2]), endothelial cells lining the lymphatic system but not endothelial cells lining blood vessels,[15]) reticular cells (i.e., a type of fibroblast that makes extracellular reticular fibers in, e.g., the liver, bone marrow, and tissues of the lymphatic system), epithelial cells (also termed ependymocytes[4]) in the choroid plexus of brain ventricles, glial cells and microglia in the central nervous system,[2][8][16][17][18] cells in nasal polyps,[16] mesothelial cells,[1] stromal cells, macrophages, and T helper 17 cells that are activated during inflammation,[19] cells in the basal layer of sweat glands, cells in the external layer of hair follicles, and a wide range of cancer cells in, e.g., 80% of squamous cell carcinomas of the lung, larynx, cervix, skin, and esophagus, in 25% of oral squamous cell carcinoma cells, 98% of seminoma cells; 69% of embryonal carcinoma cells; 29% of the cells in teratomas; 25% of the cells in yolk sac tumors; 98% of the cells in brain germinomas, 71% of the cells in immature brain teratomas, 47% of the cells in brain glioblastomas, 25% of brain anaplastic astrocytomas, 100% of lymphangiomas, 90-100% of Kaposi's sarcomas, and 93% of mesotheliomas[20][15] and the cancer-associated fibroblastd in tissues of various cancerous tissues.[4][21] Finally, PDPN can be released from the surfaces of cells to circulate and be measured in the plasma of humans and animals.[22]

Stimulators of PDPN expression

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Inhibitors of PDPN

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The ability of PDPN to activate CLEC-2 is inhibited by various monoclonal antibodies that bind to PDPN such as the NZ-1 (also known as podoplanin monoclonal antibody (NZ-1.3),[9] anti-PDPN antibody SZ-168,[23] and chLpMab-2.[24] 2CP[25] and 2A2B10[26] bind to CLEC-2 thereby inhibiting PDPN from binding to and activating CLEC-2.[24] These antibodies may prove useful for treating PDPN-promoted disorders in humans but need further studies to determine if they have deleterious side-effects.[24] Cobalt hematoporphyrin, a Protoporphyrin IX and to a greater extent protoporphyrin IX complexed with cobalt (termed cobalt hematoporphyrin) binds to CLEC-2 thereby inhibiting its activation by PDPN.[27]

Actions of PDPN

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The extracellular portion of PDPN interacts with the CLEC-2 expressed on the surfaces of [[platelets and megakaryocytes activation, thrombosis (i.e., blood clot formation), inflammation responses, lymphangiogenesis (i.e., formation of lymphatic vessels), angiogenesis (i.e., formation of blood vessels), immune surveillance (i.e., identify and eliminate cancers), remodeling the extracellular matrix including those in cancers, and epithelial–mesenchymal transitions (i.e., the processes by which epithelial cells gain migratory and invasive properties to become mesenchymal stem cells which can differentiate into cell types that, e.g., promote metastasis of cancer cells).[2] The molecules in neighboring cells that PDPN interacts with include mainly CLEC-2. This interaction is generally considered to involve the binding of PDPN on the surface of cells to CLEC-2 on the surface of target cells, e.g., blood platelets. However, studies have shown the certain cancer cells such as gliomas released PDPN-positive vesicles that leave their parent cells to bind their membrane-bound PDPN cells the CLEC-2) on e.g., platelets, leading to platelet aggregation and thrombosis formation. although it may also interact with CCL21 (i.e., Chemokine (C-C motif) ligand 21), galectin-8, and HSPA9 (i.e., heat-shock protein A9). Certain types of tumors such as glioma express podoplanin (PDPN) and the released PDPN-positive extracellular vesicles (EVs) bind to C-type lectin-like receptor 2 (CLEC-2) on platelets, leading to platelet aggregation and thrombosis formationThe transmembrane part of PDPN interacts with the CD9 (also termed tetraspanin) family of transmembrane proteins and the CD44 cell surface glycoprotein while the intracellular portion of PDPN interacts with the intracellular ezrin and radixin proteins and the surface membrane protein moesin; all of these proteins are in PDPN-expressing cells.[28] Further studies on these CLEC-2 activators may lead to the development of agents that bind to but do not activate CLEC-2 and thereby be useful to inhibit the deleterious actions of PDPN.[12]

Platelet activation

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PDPN activates platelets by binding to their CLEC-2 receptors and thereby causing them to dimerize, phosphorylate the immunoreceptor tyrosine-based activation motifs on their intercellular portions, and activate cell signaling pathways that cause the platelets to bind fibrinogen, aggregate with other platelets, and release various agents such as fibrinogen, adenosine diphosphate, serotonin, von Willebrand factor, platelet-derived growth factor, and transforming growth factor-β which act to further increase platelet activation.[15]

Platelet formation

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Studies in mice have shown that the PDPN expressed on reticular cells in the bone marrow stimulates megakaryocytes (i.e., cells that that produce platelets) to proliferation, form platelets, and thereby increase the levels of platelets that circulate in the blood.[4][20]

Development of blood vessels, lymphatic vessels, and the heart

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Mouse embryos made deficient in PDPN, CLEC-2, the tyrosine-based activation residues in CLEC-2's cytoplasmic domain, or the cell signaling molecules activated by PDPN's binding to CLEC-2, i.e., Syk, SLP-76, or PLCG2 (also termed PLCγ2), did not separate blood vessels from lymphatic vessels. The lymphatic vessels were dilated, tortuous, rugged, and blood-filled. These changes appeared due to a failure of platelets at the emerging lympho-venous junctions in the lymph sacs that develop into lymphatic vessels to stimulate blood-lymphatic vessel separation because: a) the lymphatic endothelial cells did not express PDPN, b) the blood platelets did not express CLEC-2, or c) PDPN-bound CLEC-2 lacked the tyrosine residues that activate platelets or one of the cited platelet-activating pathways.[8][9][15] Other studies suggest that the activation of CLEC-2 by the PDPN on lymphatic endothelial cells causes the release of members in the TGF-β family which in turn inhibit the migration and proliferation of these lymphatic endothelial cells which facilitates the blood–lymphatic vessel separation.[15] Studies on these vascular deficiencies that focused on brain tissues reported that early in their embryonic development mice embryos deficient in PDPN or CLEC-2 developed spontaneous hemorrhages throughout their forebrains, midbrains, and hindbrains. This appeared due to a defect in the recruitment of pericytes. These cells lie adjacent to vascular endothelial cells and act to protect these cells, alter the blood flow in the developing vessels, regulate the tightness of the blood–brain barrier, and influence new blood vessel formation.[3][29][30] It has also been noted that PDPN-deficient or CLEC-2-deficient mice developed brain aneurisms and brain hemorrhages during their embryonic gestation. Treating the mothers carrying PDPN-deficient embryos with a combination of two inhibitors of platelet activation, aspirin and ticagrelor, almost completely blocked the development of these brain hemorrhages.[2][31] Finally, mouse embryos made to lack PDPN also had a small proepicardial organ (i.e., an organ that forms the heart's epicardium and other cardiac cells), reduced sizes of the cardiac muscle, and defects in their developing hearts' atrium dorsal wall and septum.[3]

Development of the lung

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Mouse embryos express PDPN in their lungs' alveolar epithelial cells (i.e., AEV), plerual cavity mesothelial cells )i.e., PCM), and lymphatic endothelial cells, i.e., LECs. Mouse embryos that: a) had their Pdpn gene deleted in their whole body. b) had their Pdpn gene deleted just in their LECs, c) had their Clec-2 gene deleted in their platelets, or d) were made thrombocytopenia (i.e., 90% reductions in the number of circulating platelets) developed severe defects in the development of their lungs that caused them to die from respiratory failure immediately after birth. Their lungs had lumpy surfaces, various other malformations, low levels of ACTA2 (i.e., actin alpha 2, also termed alpha smooth muscle actin or α-SMA) in their lung's interstitium, almost complete absence of lung myofibroblasts that contained ACTA2, abnormal expression of the Wilms tumor protein gene (i.e., Wt1 gene), and a near complete loss of alveolar elastic fibers. Mice that had their genes for AEV or LMCs deleted did not show these changes. The study concluded that the PDPN on LECs stimulates the ClEC-2 on platelets and that this is necessary for the development of the lung in mice.[4][15][32]

Kidney function

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Munich-Wistar-Frömter (i.e., MWF)[33] and Dahl salt-sensitive (i.e., Dahl/SS)[34] rats spontaneously develop pathological increases in their kidneys' glomerular permeability as defined by their development of [proteinuria]], i.e., large increases in the levels of a protein, albumin, in their urine. This proteinuria is the first sign of kidney damage that may progress to Kidney failure. Studes of these rats showed that PDPN is expressed on the foot processes of the kidney podocytes' apical surfaces that face the urinary proximal tubules. These podocytes lost the expression of PDPN and the foot process that face the urinary proximal tubules. The studies suggested that the PDPN on podocytes acts to maintain their foot processes and thereby their glomeruli's filtration function and avert further proteinuria-induce kidney damage.[33][34][35]

Atherosclerotic and thrombotic diseases

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Atherosclerosis

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Atherosclerosis is a form of vascular disease in which the walls of arteries develop progressively increasing thickening, hardening, accumulations of atheromatous plaques, and losses in elasticity that can lead to arterial occlusions such as ischemic heart diseases and strokes. Studies in human, mouse, and rat models of atherosclerosis indicated that their atheromatous plaques express CLEC-2 on vascular smooth muscle cells and PDPN on activated macrophages as well as smooth muscle cells. In a rat model of atherosclerosis, however, PDPN was overexpressed in endothelial cells but not in smooth muscle cells. The activation of CLEC-2 by PDPN appeared responsible for worsening but not initiating atherosclerosis in most of these animal models, i.e., the activation of CLEC-2 by S100A13 (i.e., S100 calcium-binding protein A13) appeared to initiate and cause the early progression of atherosclerosis while other factors in the developing atherosclerotic lesions increased the expression of PDPN to levels which promoted further progression of the atherosclerotic lesions, presumably by binding to CLEC-2 on, and stimulating blood platelets.[13][28][36]

Ischemia/reperfusion tissue damage

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In an ischemia/reperfusion injury model of cerebral injury, mice that had their middle cerebral artery occluded developed increased levels of PDPN and CLEC-2 mainly in the neurons and microglia in their afflicted cerebral cortex areas. Pretreatment of these mice with an antibody that blocks PDPN's binding to CLEC-2 reduced the cerebral infarct (i.e., dead tissue) size and attenuated the neurological deficits during the acute and recovery stages of this model.[3][28][37] A study of 352 patients with acute ischemic strokes (i.e., sudden blockage or reduction in blood flow to the brain which causes brain tissue damage) who were followed for one year found that patients with higher levels of CLEC-2 in their plasma had higher rates of further vascular events, i.e., recurrent strokes, heart attacks, angina (i.e., chest pain or pressure caused by insufficient blood flow to the heart), and/or peripheral arterial disease (i.e., reductions in arterial blood flow and damage to any tissue excluding the heart and brain) that required treatment. The study also reported that plasma CLEC-2 levels appeared to be an important prognostic factor for patients with acute ischemic strokes. It was presumed that these stokes involve PDPN activation of platelet-bound CLEC-2.[28][38] The strokes caused by atherosclerosis are commonly associated with inflammation at the sites of arterial narrowing/blockade. This inflammation contributes to the severity of atherosclerosis which in animal modes is promoted by the actions of PDPN.[28] Ischemia/reperfusion can also cause severe kidney injury and malfunction.[39] A study of kidney function in a mouse ischemia/reperfusion model found that it caused PDPN to fall in the kidney's glomeruli and the interstitium of the kidney tubules shortly after ischemia/reperfusion. The intensity of PDPN decline on the tubular interstitial compartment cells increased with the severity of the ischemia. The study suggested that PDPN was shed from the podocytes in vesicles into the urine and internalized by the proximal tubule epithelium cells and nearby reticular cells which in turn promoted further injuries to the kidneys.[28]

Deep vein thrombosis

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Deep vein thrombosis (i.e., DVT) is a form of venous thrombosis in which blood clots form in deep rather than superficial veins and have a high mortality rate. In a model of DVT caused by vascular narrowing (i.e., stenosis) of the inferior vena cava (a large deep vein that transports blood from the lower and middle body to the heart), mice: a) made to lack CLEC-2 were completely protected from forming DVT; b) made to lack CLEC-2 only in their platelets had significantly reduced venous thromboses and transfusing them with CLEC-2-expressing platelets restored full thrombus formation; c) made to have very low blood platelet levels had reduced venous thromboses; and d) treated with an anti-PDPN antibody had significant reductions in the sizes of their DVTs. The study concluded that in mice the activation of CLEC-2 in platelets by the PDPNs located in the inferior vena cava walls contributes to the formation of DVTs.[24][28][40]

Cancer-associated venous thromboembolism

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Venous thromboembolisms (i.e., VTEs) are the clotting of blood in the veins of the systemic or pulmonary circulation (the latter are termed pulmonary emboli).[41]. Preclinical studies in rodent models of cancer-associated VTEs indicate that the activation CLEC-2 by PDPN causes VTEs in certain types of cancer.[28] For example: a) mice injected with B16F10 cells (i.e., a highly aggressive form of mouse B16 melanoma cells that express PDPN) caused extensive pulmonary tumors and pulmonary vein thromboses but mice depleted of CLEC-2 by injecting them with the anti-CLEC-2 antibody 2A2B10 markedly reduced the extent of their pulmonary vein thromboses;[26][42] b) nude mice (i.e., mice with suppressed immune systems) that were injected with tumor causing PDPN-expressing C8161 melanoma or Chinese hamster ovary cells developed tumors and extensive VTEs whereas mice injected with either of these two cell types that had been pretreated with the antibody SZ-168 that inhibits PDPN binding to CLEC-2 developed far smaller VTEs;[23] and c) nude mice inoculated with PDPN-expressing human oral squamous carcinoma cells in their neck region developed extensive VTEs and had shorter survival times than nude mice similarly inoculated with human oral squamous carcinoma cells that had greatly reduced levels of PDPN.[43] These and several other studies in rodents indicate that the activation of CLEC-2 by PDPN promotes the formation of VTEs in these cancer models.[28]

As first recognized in 1865 by Armand Trousseau (see Trousseau syndrome), VTEs often occur in patients with cancer.[41] A study published in 2007 of 1,015,598 cancer patient hospitalizations found that: a) 4.1% of these patients developed VTEs; b) patients with the highest rates of developing VTEs had pancreas (8.1% of cases), kidney (5.6%), ovary (5.6%), lung (5.1%), and stomach (4.9%) cancers; and c) patients with cancers of the lung or upper gastrointestinal tract had the highest rates of developing lethal VTEs.[44][45] Other studies have reported that patients with: a) chordomas (i.e., cancer of the notochord) and cancers of the breast, prostate gland, and skin melanomas) had low rates of developing VTEs.[41] Cancers that have spread regional or metastasized are associated with a higher risk of VTE, e.g., about 50% of patients presenting with VTEs at the time of diagnosis have metastastatic cancers. Timing also appears to be important; patients are at the highest risk in the first 3 months after cancer diagnosis, followed by a declining incidence although the risk of developing cancer-related VTES remains higher than the general population for up to 15 years after their cancers first presentation.[46]

Only a few types of human cancer have been associated with PDPN. One study was conducted for a median of 24 months on 213 patients with brain tumors, i.e., 150 with a glioblastoma, 2 with a gliosarcoma, 30 with an anaplastic astrocytoma, 7 with an anaplastic oligodendroglioma, 1 with an anaplastic (i.e., highly malignant) ependymoma, 8 with a diffuse astrocytoma (i.e., an astrocytoma with ill-defined boundaries), and 15 with other types of aggressive brain tumors. Twenty-nine of these patients (13.6%) developed VTEs with 15 of these VTEs being in leg (51.7%), 13 in the lung (i.e., they had pulmonary embolisms) (44.8%), and 1 in the arm (3.4%). Overall, 151 (70.9%) of these patients had tumors that expressed PDPN (71 at low, 47 at medium, and 33 at high levels). The PDPN levels were higher in patients who had more extensive VTEs. i,e., higher tumor tissue levels of intravascular aggregated platelet clusters, lower platelet levels in their circulation, and a higher incidence of deep vein VTEs. Patients with low, medium, and high PDPN tumor tissue levels had 2.78-fold, 4.70-fold, and 4.44-fold higher death rates than individuals with undetectable levels of PDPN in their cancer tissues. These findings suggest that the PDPN in the cited forms of brain cancer promotes VTEs and that determining the levels of PDPN in these brain cancer may useful in identifying patients with very high risk of VTEs and therefore who might benefit from thromboprophylaxis measures such as low-molecular-weight heparin.[24][28][47] Another study reported that patients with brain tumors that had a normal IDH1 gene (i.e., the gene for isocitrate dehydrogenase and high levels of PDPN expression carried a significantly increased VTE risk of developing VTEs compared to patients with a mutated IDH1 gene and no PDPN expression (the 6‐month risks of developing VTEs were 18.2% vs. 0%, respectively). The mutant IDH gene caused hypermethylation of CpG islands (see CpG island hypermethylation in the PDPN gene promoter that resulted in decreased PDPN expression.[28][48]

A study of 139 patients with squamous cell carcinoma of the lung and 27 patients with adenosquamous lung carcinoma found that PDPN was detected on the membranes of tumor cells and in some cases lymphatic vessels of 105 of these 166 patients. The median time to a 50% mortality rate for PDPN-negative patients was 18.5 months and for PDPN-positive patients was 9.8 months. Over a 5-year follow-up, 20 (12.05%) patients developed a VTE. The expression of PDPN was undetected in 61, low in 35, medium in 43, and high in 27 cases with 7.2%, 8.6%, 16.9% and 21.8% of these respective cases. The differences in survival times in the PDPN-positive versus PDPN-negative patients and tlhe intensities of PDPN expression in patients expressing or not expressing VTEs were significantly different. The study concluded that high PDPN expression levels were associated with an increased risk of developing VTEs and that higher levels of PDPN expression in these cancers is associated with poorer prognoses regardless of cancer patients age, sex, or tumor grade.[23]


Cancers

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PDPN is overly expressed or expressed for the first time on the tumor cells in a proportion of individuals with: a) epithelial cell carcinoma such as those of the cervix, larynx, oral cavity, tongue, skin and lung;[4] b) angiosarcomas (i.e., cancers of the endothelial cells in blood or lymphatic vessels), chondrosarcomas, osteosarcomas, germ cell tumors (i.e., tumors of the ovaries or testicles), gliomas (i.e., cancers of the glial cells in the brain or spinal cord), glioblastomas (i.e., highly aggressive cancers of the brain), and squamous cell carcinomas of the skin, esophagus, uterus, lung, cervix, head, and neck,[49][50] and c) melanomas, extramammary Paget's disease (i.e., a cancer of Paget cells that develops in the dermoepidermal junction of the skin in areas outside the breast such as the vulva, perineum, torso, anus, belly button, inguinal canal, and axilla[51]), mycosis fungoides, and Sézary disease (the latter two disorders are classified as cutaneous T-cell lymphomas).[50]

PDPN is also expressed on cancer-associated fibroblasts in lung adenocarcinomas, breast cancers, and pancreatic cancers.

In most cancers, a high level of podoplanin expression, both in cancer cells, as well as in CAFs, is correlated with an increased incidence of metastasis to lymph nodes and shorter survival time of patients[4]


PDPN is often upregulated in cancerous cells and might therefore serve as a biomarker in detecting malignant cells in a CLEC2-specific manner.[7]

In lymphatic endothelial cells, experimentation has indicated that podoplanin plays a role in proper formation of linkages between the cardiovascular system and the lymphatic systems, typically causing fatty liver disease in these mice.[17]

Liver regeneration

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Studies in mice found that regeneration of the liver after partial hepatectomy (i.e., in this study surgical removal of 70% of the liver) was significantly slowed in mice that had their CLEC-2 gene knocked out, had the CLEC-2 only in their platelets knocked out, or had been pretreated with the inhibitor of platelet activation, clopidogrel. This regeneration of the liver was associated with a significant, short-term rise in levels of PDPN that were expressed on the sinusoids (i.e., endothelial cells in the liver's capillaries. The study concluded that this liver regeneration was promoted by PDPN's activation of CLEc-2.[9][52]

Myocardial infarction repair

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Less than 5% of the myocardial cells in the hearts of adult mice express PDPN. However, flowing experimentally induced myocardial infarctions, i.e., heart attacks, adult mice develop greater than six-fold increases in the number of cells in the infarct's border zone, areas of developing fibrosis, and near activated blood vessels during the heart muscles stages of scar formation and maturation. These findings suggest that PDPN may act to promote the repair and resolution of heart attacks in mice.[3][53]

Clinical significance

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PDPN has been studied extensively in the cancer field. It is a specific lymphatic vessel marker, and since lymphangiogenesis levels are correlated with poor prognosis in cancer patients, it can be used as a diagnostic marker.[8] It is often upregulated in certain types of cancer, including several types of squamous cell carcinomas, malignant mesothelioma and brain tumors.[8] Moreover, it can be upregulated by cancer-associated fibroblasts (CAFs) in the tumor stroma,[8][54] where it has been associated with poor prognosis.[55]

In squamous cell carcinomas, PDPN is believed to play a key role in the cancer cell invasiveness by controlling invadopodia, and thus mediating efficient ECM degradation.[56]

References

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Further reading

[edit]
[edit]
  • Overview of all the structural information available in the PDB for UniProt: Q86YL7 (Human Podoplanin) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q62011 (Mouse Podoplanin) at the PDBe-KB.
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