PDPN

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, adult brain, thyroid gland, 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.{{cite journal | vauthors = Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, Plocik A, Celniker SE, Graveley BR | title = Genome-wide identification of zero nucleotide recursive splicing in Drosophila | journal = Nature | volume = 521 | issue = 7552 | pages = 376–9 | date = May 2015 | pmid = 25970244 | pmc = 4529404 | doi = 10.1038/nature14475 | bibcode = 2015Natur.521..376D | url = }} Other studies have reported that PDPN is expressed by human and/or rodent: a) type I alveolar cells of the lung and kidney podocytes (podoplanin was given its name based on its expression in podocytes); b) endothelial cells lining the lymphatic system but not endothelial cells lining blood vessels,{{cite journal | vauthors = Suzuki-Inoue K, Tsukiji N | title = A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology | journal = Current Opinion in Hematology | volume = 31 | issue = 3 | pages = 130–139 | date = May 2024 | pmid = 38359177 | doi = 10.1097/MOH.0000000000000805 | url = }}; c) reticular cells (i.e., a type of fibroblast that makes extracellular reticular fibers in, e.g., the liver, bone marrow, and lymphatic system) and epithelial cells (also termed ependymocytes or ependymal cells) in the choroid plexuses of the four brain ventricles; d) the glial and microglia cells located in the central nervous system;{{cite journal | vauthors = Zimmer G, Oeffner F, Von Messling V, Tschernig T, Gröness HJ, Klenk HD, Herrler G | title = Cloning and characterization of gp36, a human mucin-type glycoprotein preferentially expressed in vascular endothelium | journal = The Biochemical Journal | volume = 341 ( Pt 2) | issue = Pt 2 | pages = 277–84 | date = July 1999 | pmid = 10393083 | pmc = 1220357 | doi = 10.1042/bj3410277| url = }}{{cite journal | vauthors = Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L | title = Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice | journal = The Journal of Clinical Investigation | volume = 118 | issue = 11 | pages = 3725–37 | date = November 2008 | pmid = 18924607 | pmc = 2567837 | doi = 10.1172/JCI36077 }}{{cite journal | vauthors = Qian S, Qian L, Yang Y, Cui J, Zhao Y | title = Transcriptome sequencing analysis revealed the molecular mechanism of podoplanin neutralization inhibiting ischemia/reperfusion-induced microglial activation | journal = Annals of Translational Medicine | volume = 10 | issue = 11 | pages = 638 | date = June 2022 | pmid = 35813319 | pmc = 9263778 | doi = 10.21037/atm-22-1952 | doi-access = free | url = }} cells in nasal polyps, mesothelial cells, e) stromal cells, macrophages, activated T helper 17 cells;{{cite journal | vauthors = Bourne JH, Smith CW, Jooss NJ, Di Y, Brown HC, Montague SJ, Thomas MR, Poulter NS, Rayes J, Watson SP | title = CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear | journal = Thrombosis and Haemostasis | volume = 122 | issue = 12 | pages = 1988–2000 | date = December 2022 | pmid = 35817083 | pmc = 9718592 | doi = 10.1055/a-1896-6992 | url = }} cells in the basal layer of sweat glands, and external layer of hair follicles; f) a wide range of cancer cells including 80% of squamous cell carcinomas of the lung, larynx, cervix, skin, and esophagus, 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 endodermal sinus tumors (also termed yoke 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, 93% of mesotheliomas;{{cite journal | vauthors = Suzuki-Inoue K, Osada M, Ozaki Y | title = Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 15 | issue = 2 | pages = 219–229 | date = February 2017 | pmid = 27960039 | doi = 10.1111/jth.13590 | url = }} and g) the cancer-associated fibroblasts in the tissues of various cancers.{{cite journal | vauthors = Takemoto A, Miyata K, Fujita N | title = Platelet-activating factor podoplanin: from discovery to drug development | journal = Cancer Metastasis Reviews | volume = 36 | issue = 2 | pages = 225–234 | date = June 2017 | pmid = 28674748 | pmc = 5557876 | doi = 10.1007/s10555-017-9672-2 | url = }}

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 their cell's surface membrane. PDPN consists of 162 amino acids with about 128 residing on the outside the cell, about 25 spanning the cell's surface membrane, and 9 residing inside the cell.{{cite journal | vauthors = Wicki A, Christofori G | title = The potential role of podoplanin in tumour invasion | journal = British Journal of Cancer | volume = 96 | issue = 1 | pages = 1–5 | date = January 2007 | pmid = 17179989 | pmc = 2360213 | doi = 10.1038/sj.bjc.6603518 | url = }}{{cite journal | vauthors = Fischer S, Stegmann F, Gnanapragassam VS, Lepenies B | title = From structure to function - Ligand recognition by myeloid C-type lectin receptors | journal = Computational and Structural Biotechnology Journal | volume = 20 | issue = | pages = 5790–5812 | date = 2022 | pmid = 36382179 | pmc = 9630629 | doi = 10.1016/j.csbj.2022.10.019 | url = }} 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 between different animal species). Human PDPN has a molecular mass of 36 to 43 kilodaltons, depending on the amount of O-linked glycosyl residues it contains.{{cite journal | vauthors = Astarita JL, Acton SE, Turley SJ | title = Podoplanin: emerging functions in development, the immune system, and cancer | journal = Frontiers in Immunology | volume = 3 | pages = 283 | date = 2012 | pmid = 22988448 | pmc = 3439854 | doi = 10.3389/fimmu.2012.00283 | doi-access = free }} Its extracellular portion consist of four amino acid tandem repeat areas termed platelet aggregation-stimulating domains 1-4, i.e., PLAG 1-4. In addition, PDPN can be released from its parent cells as a PDPN-expressing secreted vesicle or as a free intact protein, circulate in the blood, and be measured in the plasma of humans and animals.{{cite journal | vauthors = Zhao X, Pan Y, Ren W, Shen F, Xu M, Yu M, Fu J, Xia L, Ruan C, Zhao Y | title = Plasma soluble podoplanin is a novel marker for the diagnosis of tumor occurrence and metastasis | journal = Cancer Science | volume = 109 | issue = 2 | pages = 403–411 | date = February 2018 | pmid = 29266546 | pmc = 5797814 | doi = 10.1111/cas.13475 | url = }}{{cite journal | vauthors = Tawil N, Rak J | title = Blood coagulation and cancer genes | journal = Best Practice & Research. Clinical Haematology | volume = 35 | issue = 1 | pages = 101349 | date = March 2022 | pmid = 36030072 | doi = 10.1016/j.beha.2022.101349 | url = }}

The PLAGs expressed on cells or vesicles or as a free protein can interact with proteins on the surface of other cells, particularly the C-type lectin-like receptor 2, i.e., CLEC-2 (also termed CLEC1B, 1810061I13Rik, CLEC2, CLEC2B, PRO1384, QDED721, and C-type lectin domain family 1 member B). 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)). It is expressed on: onn the surface membranes of platelets, dendritic cells, follicular dendritic cells, mesothelial cells (i.e., simple squamous epithelial cells of mesodermal origin in the mesothelium), epithelial cells in lymphatic vessels, and cancer-associated fibroblasts (i.e., fibroblasts located in cancer tissues).{{cite journal | vauthors = Agrawal S, Ganguly S, Hajian P, Cao JN, Agrawal A | title = PDGF upregulates CLEC-2 to induce T regulatory cells | journal = Oncotarget | volume = 6 | issue = 30 | pages = 28621–32 | date = October 2015 | pmid = 26416420 | pmc = 4745681 | doi = 10.18632/oncotarget.5765 | url = }} The binding of PLAG-3/PLAG-4 to the extracellular portion of CLEC-2 causes it to be phosphorylated on the tyrosine and lysine amino acids in its intracellular single cytoplasmic tyrosine-XX-lysine sequence (known as a hemi-Immunoreceptor Tyrosine-based Activation Motif, i.e., hemITAM, a key structural motif in a protein that is critical for the protein's actions (hemITAM is related to the Immunoreceptor tyrosine-based activation motif, i.e., ITAM).{{cite journal | vauthors = Kostyak JC, Mauri B, Dangelmaier C, Vari HR, Patel A, Wright M, Reddy H, Tsygankov AY, Kunapuli SP | title = Phosphorylation on Syk Y342 is important for both ITAM and hemITAM signaling in platelets | journal = The Journal of Biological Chemistry | volume = 298 | issue = 8 | pages = 102189 | date = August 2022 | pmid = 35753354 | pmc = 9287148 | doi = 10.1016/j.jbc.2022.102189 | url = }} The phosphorylated CLEC-2 then activates tyrosine-protein kinase SYK, i.e., Syk, which in turn activates various pathways that trigger these cells to make certain types of responses (see Signal transduction). 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.{{cite journal | vauthors = Morán LA, Di Y, Sowa MA, Hermida-Nogueira L, Barrachina MN, Martin E, Clark JC, Mize TH, Eble JA, Moreira D, Pollitt AY, Loza MI, Domínguez E, Watson SP, García Á | title = Katacine Is a New Ligand of CLEC-2 that Acts as a Platelet Agonist | journal = Thrombosis and Haemostasis | volume = 122 | issue = 8 | pages = 1361–1368 | date = August 2022 | pmid = 35170009 | pmc = 9393086 | doi = 10.1055/a-1772-1069 | url = }}{{cite journal | vauthors = Inoue O, Hokamura K, Shirai T, Osada M, Tsukiji N, Hatakeyama K, Umemura K, Asada Y, Suzuki-Inoue K, Ozaki Y | title = Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis | journal = PLOS ONE | volume = 10 | issue = 9 | pages = e0139357 | date = 2015 | pmid = 26418160 | pmc = 4587843 | doi = 10.1371/journal.pone.0139357 | doi-access = free | bibcode = 2015PLoSO..1039357I | url = }}

The extracellular part of PDPN interacts with the CLEC-2 expressed on the surfaces of platelets and megakaryocytes to promote blood clots, inflammation, lymphangiogenesis (i.e., formation of lymphatic vessels), angiogenesis (i.e., formation of blood vessels), immune surveillance (e.g., killing cancer cells), remodeling the extracellular matrix of normal and cancerous tissues, and epithelial–mesenchymal transitions by which epithelial cells gain migratory and invasive properties to become mesenchymal stem cells that differentiate into cell types that promote cancer metastases. PDPN's interaction with CLEC-2 is generally considered to involve the binding of PDPN on the surface of cells to CLEC-2 on the surface of adjacent cells. However, studies have found that cultured mice and human PDPN-expressing glioblastoma cell lines release PDPN-positive vesicles which when injected into mice activate their platelets. The injection of PDPN-negative vesicles into mice did not activate the platelets suggesting that the PDPN-expressing vesicles activated platelets by binding to their CLEC-2 receptors.{{cite journal | vauthors = Tawil N, Bassawon R, Meehan B, Nehme A, Montermini L, Gayden T, De Jay N, Spinelli C, Chennakrishnaiah S, Choi D, Adnani L, Zeinieh M, Jabado N, Kleinman CL, Witcher M, Riazalhosseini Y, Key NS, Schiff D, Grover SP, Mackman N, Couturier CP, Petrecca K, Suvà ML, Patel A, Tirosh I, Najafabadi H, Rak J | title = Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles | journal = Blood Advances | volume = 5 | issue = 6 | pages = 1682–1694 | date = March 2021 | pmid = 33720339 | pmc = 7993100 | doi = 10.1182/bloodadvances.2020002998 | url = }} Similar platelet-activating effects were seen in cultures of mouse ovarian cancer cells and a mouse model of ovarian cancer. These studies suggest that the release of PDPN-expressing vesicles into the circulation activate blood platelets to cause intravascular blood clots.{{cite journal | vauthors = Sasano T, Gonzalez-Delgado R, Muñoz NM, Carlos-Alcade W, Cho MS, Sheth RA, Sood AK, Afshar-Kharghan V | title = Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 20 | issue = 1 | pages = 104–114 | date = January 2022 | pmid = 34608736 | pmc = 8712373 | doi = 10.1111/jth.15544 | url = }}

PDPN activates platelets by binding to their CLEC-2 receptors and thereby causing them to 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.

Studies in mice have shown that the PDPN expressed on reticular cells in the bone marrow stimulates megakaryocytes (i.e., cells that produce platelets) to proliferate, form platelets, and thereby increase the levels of platelets that circulate in the blood.{{cite journal | vauthors = Suzuki-Inoue K, Osada M, Ozaki Y | title = Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 15 | issue = 2 | pages = 219–229 | date = February 2017 | pmid = 27960039 | doi = 10.1111/jth.13590 | url = }}

The hair follicle is an organ that resides in the dermal layer of the skin in mammals. The follicle continuously cycles through an anagen phase of growth, catagen phase of apoptosis-driven regression, and telogen phase of relative quiescence. Stem cells in the hair follicle's bulge promote repetitive regeneration of its follicle along with the follicle's hair. Studies in mice showed that PDPN was expressed in the stem cells and keratinocyte-rich regions of the hair follicle during the late anagen but not telogen phase of the hair growth cycle. The application of wax to the skin of female C57BL/6 mice caused hair removal and hair regeneration at days 1 (early-anagen phase) and 5 (mid-anagen phase) after hair removal. PDPN was expressed in lymphatic vessels but not the hair follicles' keratinocytes. At days 8 and 12 (late-anagen phase), however, PDPN was expressed in hair follicle keratinocytes and stem cells. At day 18 (catagen phase), PDPN expression was still present in the keratinocytes; and at day 22 (telogen phase) PDPN was detected in the lymphatic vessel but not hair follicles. Mice that were made to lack PDPN in the keratinocytes of their hair follicles showed increased hair follicle growth during the anagen phase of hair growth compared to mice that had normal levels of PDPN in their keratinocytes. These findings suggest that DPDN deletion promotes hair follicle cycling and growth and that inhibiting DPDN may prove useful for treating hair loss in animals and humans.{{cite journal | vauthors = Yoon SY, Dieterich LC, Tacconi C, Sesartic M, He Y, Brunner L, Kwon O, Detmar M | title = An important role of podoplanin in hair follicle growth | journal = PLOS ONE | volume = 14 | issue = 7 | pages = e0219938 | date = 2019 | pmid = 31335913 | pmc = 6650137 | doi = 10.1371/journal.pone.0219938 | doi-access = free | bibcode = 2019PLoSO..1419938Y | url = }}

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 lymphatic-venous vascular 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. Other studies suggested that the activation of CLEC-2 by the PDPN on lymphatic endothelial cells causes the release of one or more TGF-β proteins that inhibit the migration and proliferation of the lymphatic endothelial cells which otherwise would facilitate blood–lymphatic vessel separation. Studies on these vascular deficiencies in 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. Pericytes 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.{{cite journal | vauthors = Longden TA, Zhao G, Hariharan A, Lederer WJ | title = Pericytes and the Control of Blood Flow in Brain and Heart | journal = Annual Review of Physiology | volume = 85 | issue = | pages = 137–164 | date = February 2023 | pmid = 36763972 | pmc = 10280497 | doi = 10.1146/annurev-physiol-031522-034807 | url = }}{{cite journal | vauthors = Lowe KL, Finney BA, Deppermann C, Hägerling R, Gazit SL, Frampton J, Buckley C, Camerer E, Nieswandt B, Kiefer F, Watson SP | title = Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development | journal = Blood | volume = 125 | issue = 24 | pages = 3769–77 | date = June 2015 | pmid = 25908104 | pmc = 4463737 | doi = 10.1182/blood-2014-09-603803 | url = }} 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.{{cite journal | vauthors = Hoover C, Kondo Y, Shao B, McDaniel MJ, Lee R, McGee S, Whiteheart S, Bergmeier W, McEver RP, Xia L | title = Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin | journal = Blood | volume = 137 | issue = 20 | pages = 2756–2769 | date = May 2021 | pmid = 33619517 | pmc = 8138551 | doi = 10.1182/blood.2020010310 | url = }} 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.

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). 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) 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 Pdpn gene in AEV cells 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.{{cite journal | vauthors = Tsukiji N, Inoue O, Morimoto M, Tatsumi N, Nagatomo H, Ueta K, Shirai T, Sasaki T, Otake S, Tamura S, Tachibana T, Okabe M, Hirashima M, Ozaki Y, Suzuki-Inoue K | title = Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction | journal = Blood | volume = 132 | issue = 11 | pages = 1167–1179 | date = September 2018 | pmid = 29853539 | doi = 10.1182/blood-2017-12-823369 | url = }}

Two classes of rats, Munich-Wistar-Frömter (i.e., MWF){{cite journal | vauthors = Ijpelaar DH, Schulz A, Koop K, Schlesener M, Bruijn JA, Kerjaschki D, Kreutz R, de Heer E | title = Glomerular hypertrophy precedes albuminuria and segmental loss of podoplanin in podocytes in Munich-Wistar-Frömter rats | journal = American Journal of Physiology. Renal Physiology | volume = 294 | issue = 4 | pages = F758–67 | date = April 2008 | pmid = 18199599 | doi = 10.1152/ajprenal.00457.2007 | url = }} and Dahl salt-sensitive (i.e., Dahl/SS){{cite journal | vauthors = Koop K, Eikmans M, Wehland M, Baelde H, Ijpelaar D, Kreutz R, Kawachi H, Kerjaschki D, de Heer E, Bruijn JA | title = Selective loss of podoplanin protein expression accompanies proteinuria and precedes alterations in podocyte morphology in a spontaneous proteinuric rat model | journal = The American Journal of Pathology | volume = 173 | issue = 2 | pages = 315–26 | date = August 2008 | pmid = 18599604 | pmc = 2475770 | doi = 10.2353/ajpath.2008.080063 | url = }} rats, spontaneously developed pathological increases in their kidneys' glomerular permeability as defined by their development of proteinuria, i.e., large increases in the levels of the blood 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 had lost a) the expression of PDPN and b) 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 the cited kidney damage.

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.{{cite journal | vauthors = Kono H, Fujii H, Suzuki-Inoue K, Inoue O, Furuya S, Hirayama K, Akazawa Y, Nakata Y, Sun C, Tsukiji N, Shirai T, Ozaki Y | title = The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 15 | issue = 5 | pages = 998–1008 | date = May 2017 | pmid = 28294559 | doi = 10.1111/jth.13672 | url = }}

=== Repair myocardial infarction ===

Less than 5% of the myocardial cells in the hearts of adult mice express PDPN. However, following experimentally induced myocardial infarctions, i.e., heart attacks, adult mice develop greater than six-fold increases in the number of DPDN-expressing cells in the infarct's border zone, areas of developing fibrosis, and nearby 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.{{cite journal | vauthors = Cimini M, Cannatá A, Pasquinelli G, Rota M, Goichberg P | title = Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium | journal = PLOS ONE | volume = 12 | issue = 3 | pages = e0173927 | date = 2017 | pmid = 28333941 | pmc = 5363820 | doi = 10.1371/journal.pone.0173927 | doi-access = free | bibcode = 2017PLoSO..1273927C | url = }}

However, more recent studies of myocardial infarctions in mice suggest that

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 atherosclerosis and 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 the animal models. 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 thereby stimulating blood platelets.{{cite journal | vauthors = Furukoji E, Yamashita A, Nakamura K, Hirai T, Asada Y | title = Podoplanin expression on endothelial cells promotes superficial erosive injury and thrombus formation in rat carotid artery: Implications for plaque erosion | journal = Thrombosis Research | volume = 183 | issue = | pages = 76–79 | date = November 2019 | pmid = 31670230 | doi = 10.1016/j.thromres.2019.10.015 | url = }}

Ischemia/reperfusion injury is tissue damage that is worsened rather than improved by restoring the blood flow (i.e., reperfusion) to a tissue that had undergone a period of ischemia (lack of blood flow). In a model of ischemia/reperfusion injury of the brain's cerebral cortex, mice that had their middle cerebral artery occluded developed increased levels of PDPN and CLEC-2 mainly in the neurons and microglia of the 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.{{cite journal | vauthors = Meng D, Ma X, Li H, Wu X, Cao Y, Miao Z, Zhang X | title = A Role of the Podoplanin-CLEC-2 Axis in Promoting Inflammatory Response After Ischemic Stroke in Mice | journal = Neurotoxicity Research | volume = 39 | issue = 2 | pages = 477–488 | date = April 2021 | pmid = 33165736 | doi = 10.1007/s12640-020-00295-w | url = }} 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.{{cite journal | vauthors = Wu X, Zhang W, Li H, You S, Shi J, Zhang C, Shi R, Huang Z, Cao Y, Zhang X | title = Plasma C-type lectin-like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke | journal = European Journal of Neurology | volume = 26 | issue = 10 | pages = 1334–1340 | date = October 2019 | pmid = 31081579 | doi = 10.1111/ene.13984 | url = }} 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.

Ischemia/reperfusion also causes severe kidney injury and malfunction. A study of kidney function in a mouse model of ischemia/reperfusion in the kidney found that it caused PDPN to fall in the kidney's glomeruli and interstitium of the kidney's 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 to the urine and internalized by the proximal tubule epithelium cells and nearby reticular cells which in turn promoted further injuries to the kidneys.{{cite journal | vauthors = Nørgård MØ, Svenningsen P | title = Acute Kidney Injury by Ischemia/Reperfusion and Extracellular Vesicles | journal = International Journal of Molecular Sciences | volume = 24 | issue = 20 | date = October 2023 | page = 15312 | pmid = 37894994 | pmc = 10607034 | doi = 10.3390/ijms242015312 | doi-access = free | url = }}

Deep vein thrombosis (i.e., DVT) is a form of venous thrombosis in which blood clots form in deep rather than superficial veins and has 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.{{cite journal | vauthors = Payne H, Ponomaryov T, Watson SP, Brill A | title = Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis | journal = Blood | volume = 129 | issue = 14 | pages = 2013–2020 | date = April 2017 | pmid = 28104688 | pmc = 5408561 | doi = 10.1182/blood-2016-09-742999 | url = }}

Caner-associated venous thromboembolisms (cVTEs) are cancer-associated blood clots in the veins of the systemic circulation with or without involvement of the pulmonary circulation (the latter are termed pulmonary emboli).{{cite journal | vauthors = Mahani S, DiCaro MV, Tak N, Hartnett S, Cyrus T, Tak T | title = Venous Thromboembolism: Current Insights and Future Directions | journal = The International Journal of Angiology : Official Publication of the International College of Angiology, Inc | volume = 33 | issue = 4 | pages = 250–261 | date = December 2024 | pmid = 39502354 | doi = 10.1055/s-0044-1787652 | pmc = 11534468 | pmc-embargo-date = July 8, 2025 | url = }} Preclinical studies in rodent models of cancer-associated cVTEs indicate that the activation CLEC-2 by PDPN causes cVTEs in certain types of cancer. For example: a) mice injected with B16F10 cells (i.e., a highly aggressive form of mouse B16 melanoma 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 greatly reduced the extent of their pulmonary vein thromboses;{{cite journal | vauthors = Suzuki-Inoue K | title = Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin | journal = Hematology. American Society of Hematology. Education Program | volume = 2019 | issue = 1 | pages = 175–181 | date = December 2019 | pmid = 31808911 | pmc = 6913448 | doi = 10.1182/hematology.2019001388 | url = }} 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 cVTEs 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 cVTEs; and c) nude mice inoculated with PDPN-expressing human oral squamous carcinoma cells developed extensive cVTEs and suffered shorter survival times than nude mice similarly inoculated with human oral squamous carcinoma cells that had greatly reduced levels of PDPN.{{cite journal | vauthors = Suzuki-Inoue K | title = Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin | journal = Blood | volume = 134 | issue = 22 | pages = 1912–1918 | date = November 2019 | pmid = 31778548 | doi = 10.1182/blood.2019001388 | url = }} These and several other studies in rodents indicate that the activation of CLEC-2 by PDPN promotes the formation of cVTEs in these cancer models.

As first recognized in 1865 by Armand Trousseau (see Trousseau syndrome), cVTEs often occur in humans with cancer. A study published in 2007 of 1,015,598 cancer patient hospitalizations found that: a) 4.1% of the patients developed cVTEs; b) patients with the highest rates of developing a cVTE had pancreas (8.1% of cases), kidney (5.6%), ovary (5.6%), lung (5.1%), or stomach (4.9%) cancer; and c) patients with cancers of the lung or upper gastrointestinal tract had the highest rates of developing lethal cVTEs.{{cite journal | vauthors = Rao R, Lin P, Xu J, Wang C, Chen Y, Ito S, Mutoh T, Yu Z | title = Chordoma combined with Trousseau syndrome: a case report and literature review | journal = Journal of Thoracic Disease | volume = 16 | issue = 9 | pages = 6249–6262 | date = September 2024 | pmid = 39444889 | pmc = 11494589 | doi = 10.21037/jtd-24-1232 | doi-access = free | url = }}{{cite journal | vauthors = Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH | title = Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients | journal = Cancer | volume = 110 | issue = 10 | pages = 2339–46 | date = November 2007 | pmid = 17918266 | doi = 10.1002/cncr.23062 | url = }} (Gioioso et al., 2024{{cite journal | vauthors = Rao R, Lin P, Xu J, Wang C, Chen Y, Ito S, Mutoh T, Yu Z | title = Chordoma combined with Trousseau syndrome: a case report and literature review | journal = Journal of Thoracic Disease | volume = 16 | issue = 9 | pages = 6249–6262 | date = September 2024 | pmid = 39444889 | pmc = 11494589 | doi = 10.21037/jtd-24-1232 | doi-access = free | url = }} gave a more extensive list on the rates of cVTEs in different cancers.) Other studies have reported that patients with: a) breast cancer, prostate cancer, or melanoma skin cancer had low rates of developing cVTEs. Cancers that have spread locally or metastasized to other tissues were associated with a higher risk of developing cVTEs. For example, about 50% of patients presenting with cVTEs have metastatic cancers at the time of diagnosis. Furthermore, patients were at the highest risk of developing cVTEs during the first 3 months after cancer diagnosis but thereafter had a decreasing incidence of developing cVTEs although this risk remained higher than the general population for up to 15 years after their cancers first presentation.{{cite journal | vauthors = Gervaso L, Dave H, Khorana AA | title = Venous and Arterial Thromboembolism in Patients With Cancer: JACC: CardioOncology State-of-the-Art Review | journal = JACC. CardioOncology | volume = 3 | issue = 2 | pages = 173–190 | date = June 2021 | pmid = 34396323 | pmc = 8352228 | doi = 10.1016/j.jaccao.2021.03.001 | url = }}

Three types of cancers in humans, i.e., aggressive brain tumor, squamous cell carcinoma of the lung, and adenosquamous lung carcinoma have been associated with PDPN-related cVTEs. A study was conducted for a median of 24 months on 213 patients with an aggressive brain tumor: 150 had a glioblastoma, 2 had a gliosarcoma, 30 had an anaplastic astrocytoma, 7 had an anaplastic oligodendroglioma, 1 had an anaplastic ependymoma, 8 had a diffuse astrocytoma (i.e., an astrocytoma with ill-defined boundaries), and 15 had other types of aggressive brain tumors. Twenty-nine of these patients (13.6%) developed cVTEs with 15 of the cVTEs being in the leg (51.7%), 13 in the lung (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). PDPN levels were higher in patients who had more extensive cVTEs. i.e., higher tumor levels of intravascular aggregated platelet clusters, lower platelet levels in their blood, and a higher incidence of deep vein cVTEs. Patients with low, medium, and high PDPN tumor tissue levels had respectively 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 aggressive brain cancers promotes cVTEs and that measuring the levels of PDPN in these cancers may be useful for identifying patients with high risks of developing cVTEs and therefore might benefit from thromboprophylaxis measures (i.e., therapy to prevent blood clots) such as treatment with low-molecular-weight heparin.{{cite journal | vauthors = Riedl J, Preusser M, Nazari PM, Posch F, Panzer S, Marosi C, Birner P, Thaler J, Brostjan C, Lötsch D, Berger W, Hainfellner JA, Pabinger I, Ay C | title = Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism | journal = Blood | volume = 129 | issue = 13 | pages = 1831–1839 | date = March 2017 | pmid = 28073783 | pmc = 5823234 | doi = 10.1182/blood-2016-06-720714 | url = }} Another study reported that patients with brain tumors that expressed a normal IDH1 gene (the gene for isocitrate dehydrogenase) and high levels of PDPN had a significantly greater risk of developing cVTEs compared to patients with a mutated IDH1 gene and no PDPN expression (the 6‐month risks of developing cVTEs 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 result in decreased PDPN expression.{{cite journal | vauthors = Mir Seyed Nazari P, Riedl J, Preusser M, Posch F, Thaler J, Marosi C, Birner P, Ricken G, Hainfellner JA, Pabinger I, Ay C | title = Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 16 | issue = 6 | pages = 1121–1127 | date = June 2018 | pmid = 29676036 | pmc = 6099350 | doi = 10.1111/jth.14129 | url = }} Finally, 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 lymphatic vessels of 105 of these patients. The median time to a 50% mortality rate for PDPN-negative patients was 18.5 months but for PDPN-positive patients was only 9.8 months. Over a 5-year follow-up period, 20 (12.05%) patients developed a cVTE. 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 the intensities of PDPN expression in patients expressing or not expressing cVTEs were significantly different. This study concluded that high PDPN expression levels are associated with an increased risk of developing cVTEs and that higher levels of PDPN expression in these lung carcinomas are associated with poorer prognoses regardless of the patient's age, sex, or tumor grade.

=== Cancer ===

PDPN is overly expressed or expressed for the first time on the tumor cells in a proportion of individuals with: a) varying types of breast cancer; b) epithelial cell carcinomas such as those of the cervix, larynx, oral cavity, tongue, skin and lung; c) angiosarcomas (i.e., cancers of blood or lymphatic vessel endothelial cells), chondrosarcomas (i.e., cancer of bone cartilage cells), osteosarcomas, (i.e., cancer of bone cells), germ cell tumors (i.e., cancers arising from the germ cells in 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, bladder, head, neck, and mouth; and d) melanomas, extramammary Paget's disease (i.e., cancer of large epithelial carcinoma cells termed Paget's cells that develop in the dermoepidermal junction of the skin in areas outside of the breast such as the vulva, perineum, torso, belly button, inguinal canal, and axilla{{cite journal | vauthors = Shah RR, Shah K, Wilson BN, Tchack M, Busam KJ, Moy A, Leitao MM, Cordova M, Neumann NM, Smogorzewski J, Nguyen KA, Hosein S, Dafinone M, Schwartz RA, Rossi A | title = Extramammary Paget disease. Part I. epidemiology, pathogenesis, clinical features, and diagnosis | journal = Journal of the American Academy of Dermatology | volume = 91 | issue = 3 | pages = 409–418 | date = September 2024 | pmid = 38704032 | doi = 10.1016/j.jaad.2023.07.1051 | url = }}), mycosis fungoides, (i.e., the most common form of cutaneous T-cell lymphomas), and Sézary disease (another form of cutaneous T-cell lymphoma). PDPN is also abnormally expressed by the cancer-associated fibroblasts (i.e., CAFs) in adenocarcinoma of the lung, squamous-cell carcinoma of the lung, adenocarcinoma of the breast, adenocarcinoma of the pancreas, cholangiocarcinoma (i.e., cancer of the bile duct), adenocarcinoma of the esophagus, and melanomas.{{cite journal | vauthors = Yamaguchi K, Hara Y, Kitano I, Hamamoto T, Kiyomatsu K, Yamasaki F, Yamaguchi R, Nakazono T, Egashira R, Imaizumi T, Irie H | title = Relationship between MRI findings and invasive breast cancer with podoplanin-positive cancer-associated fibroblasts | journal = Breast Cancer (Tokyo, Japan) | volume = 28 | issue = 3 | pages = 572–580 | date = May 2021 | pmid = 33389554 | doi = 10.1007/s12282-020-01198-6 | url = }} The expression of PDPN, particularly at high levels, in the cancer cells and/or CAFs has been associated with increased incidences of developing metastasis and shorter survival times in patients with most of these cancers. However, other studies have reported that the absence of PDPN in squamous cell cancer of the cervix and the mixed, glandular-epithelial form of cervical cancer, as well as the expression of relatively low PDPN levels in the CAFs of colon cancers were associated with more aggressive diseases and poorer survival times. These and other contradictory findings on the effects of PDPN on severity and survival times of the cancers indicate that further studies are needed to clarify the associations of PDPN levels with the severity of these cancers. Some of these needed studies have been conducted on breast cancer patients presenting with PDPN-expressing CAFs. A 2024 review of 27 studies on a total of 6,830 patients with breast cancer reported that the high expression of PDPN on the CAFs of this cancer was associated with significantly reduced recurrence-free survival times, disease-free survival times, metastasis-free survival times, and event-free survival (i.e., cancer recurrence, cancer progression that cannot be treated surgically, or death due to any cause).

Various antibodies have been developed that inhibit the activities of PDPN. These include antibodies that: a) bind to and block PDPN's binding to CLEC-2 such as the monoclonal antibodies NZ-1 (also termed podoplanin monoclonal antibody NZ-1.3), SZ-168, and chLpMab-2, and the polyclonal antibody, sc-134483 (also known as glycoprotein 38 and gp38);{{cite journal | vauthors = Cimini M, Garikipati VN, de Lucia C, Cheng Z, Wang C, Truongcao MM, Lucchese AM, Roy R, Benedict C, Goukassian DA, Koch WJ, Kishore R | title = Podoplanin neutralization improves cardiac remodeling and function after acute myocardial infarction | journal = JCI Insight | volume = 5 | issue = 15 | pages = | date = July 2019 | pmid = 31287805 | doi = 10.1172/jci.insight.126967 | pmc = 6693826 | url = }} and b) the antibodies 2CP and 2A2B10 which bind to CLEC-2 thereby blocking its binding of DPDN.{{cite journal | vauthors = Chang YW, Hsieh PW, Chang YT, Lu MH, Huang TF, Chong KY, Liao HR, Cheng JC, Tseng CP | title = Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis | journal = Oncotarget | volume = 6 | issue = 40 | pages = 42733–48 | date = December 2015 | pmid = 26528756 | doi = 10.18632/oncotarget.5811 | pmc = 4767466 | url = }}{{cite journal | vauthors = Shirai T, Inoue O, Tamura S, Tsukiji N, Sasaki T, Endo H, Satoh K, Osada M, Sato-Uchida H, Fujii H, Ozaki Y, Suzuki-Inoue K | title = C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 15 | issue = 3 | pages = 513–525 | date = March 2017 | pmid = 28028907 | doi = 10.1111/jth.13604 | url = }} These antibodies may prove useful for treating PDPN-promoted disorders in humans but need further studies to determine if they can be used safely when injected into humans. Three compounds, cobalt hematoporphyrin (i.e., cobalt complexed with hematoporphyrin), protoporphyrin IX, and protoporphyrin IX complexed with cobalt (termed cobalt hematoporphyrin) bind to CLEC-2 thereby inhibiting its activation by PDPN. These three compounds suppress PDPN-induced platelet aggregation and cancer metastasis in animal models.{{cite journal | vauthors = Tsukiji N, Osada M, Sasaki T, Shirai T, Satoh K, Inoue O, Umetani N, Mochizuki C, Saito T, Kojima S, Shinmori H, Ozaki Y, Suzuki-Inoue K | title = Cobalt hematoporphyrin inhibits CLEC-2-podoplanin interaction, tumor metastasis, and arterial/venous thrombosis in mice | journal = Blood Advances | volume = 2 | issue = 17 | pages = 2214–2225 | date = September 2018 | pmid = 30190281 | pmc = 6134222 | doi = 10.1182/bloodadvances.2018016261 | url = }}

NIR-PIT (i.e., near-infrared photoimmunotherapy) is a recently developed method to treat cancers. It uses an antibody-IRDye700DX complex (i.e., a monoclonal antibody conjugated to the phthalocyanine dye, IRdye700DX). The conjugated antibody is made to bind a target protein expressed on cancer cells. Following this binding, the antibody-IRDye700DX complex kills these cells when exposed to a beam of near-infrared light.{{cite journal | vauthors = Kobayashi H, Choyke PL | title = Near-Infrared Photoimmunotherapy of Cancer | journal = Accounts of Chemical Research | volume = 52 | issue = 8 | pages = 2332–2339 | date = August 2019 | pmid = 31335117 | pmc = 6704485 | doi = 10.1021/acs.accounts.9b00273 | url = }} A study has used antibody-IRDye700DX in which IRDye700DX was conjugated to a commercial antibody termed 8.1.1 that binds to mouse PDPN. This conjugate was injected into mice that had been injected with mouse oral squamous cell carcinoma cancer cells (i.e., MOC cells) and had developed large MOC tumors. This PDPN-targeted NIR-PIT procedure: a) killed PDPN-expressing MOC cancer cells and PDPN-expressing cancer-associated fibroblast (i.e., CAFs) with little or no injury to other cells, b) suppressed the progression of these tumors, c) prolonged the survival of these mice; d) caused minimal damage to PDPN-expressing lymphatic vessel, and e) exerted a lesser but statistically significant therapeutic effect by killing the PDPN-expressing CAFs in MOC tumors that did not have PDPN-positive cancer cells. The authors suggested that further studies may show that this NIR-PIT method will prove useful for treating patients with tumors that express PDPN in their cancer cells and/or CAFs.{{cite journal | vauthors = Kato T, Furusawa A, Okada R, Inagaki F, Wakiyama H, Furumoto H, Fukushima H, Okuyama S, Choyke PL, Kobayashi H | title = Near-Infrared Photoimmunotherapy Targeting Podoplanin-Expressing Cancer Cells and Cancer-Associated Fibroblasts | journal = Molecular Cancer Therapeutics | volume = 22 | issue = 1 | pages = 75–88 | date = January 2023 | pmid = 36223542 | pmc = 9812859 | doi = 10.1158/1535-7163.MCT-22-0313 | url = }}

Working within the same cell, the transmembrane part of PDPN interacts with tetraspanin 9 and the CD44 cell surface glycoprotein. The intracellular portion of PDPN interacts with intracellular ezrin and radixin and the surface membrane protein moesin.{{cite journal | vauthors = Asai J | title = The Role of Podoplanin in Skin Diseases | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | date = January 2022 | page = 1310 | pmid = 35163233 | pmc = 8836045 | doi = 10.3390/ijms23031310 | doi-access = free | url = }} Further studies on these interactions may lead to the development of agents that interrupt these interactions and thereby be useful for inhibiting the deleterious actions of PDPN.

{{reflist}}

• {{PDBe-KB2|Q86YL7|Human Podoplanin}}
• {{PDBe-KB2|Q62011|Mouse Podoplanin}}

Category:Mucins