Podoplanin: Emerging functions in development, the immune system, and cancer

Frontiers in Immunology

Volumn 3, Issue SEP, 2012, Pages

  Astarita, Jillian L ^a,b   Acton, Sophie E ^a,c   Turley, Shannon J ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Cancer associated fibroblasts; CLEC 2; Lymph node stromal cells; Lymphatic endothelial cells; Platelets; Podoplanin

Indexed keywords

EID: 84873339567     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00283     Document Type: Short Survey

References (93)

1. Abtahian, F., Guerriero, A.,Sebzda, E., Lu, M.-M., Zhou, R., Mocsai, A., Myers, E. E., Huang, B., Jackson, D. G., Ferrari, V. A., Tybulewicz, V., Lowell, C. A., Lepore, J. J., Koret-zky, G. A., and Kahn, M. L. (2003). Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299, 247-251.
2. Acton, S.E., Astarita, J., Malhotra, D., Luckacs-Kornek, V., Franz, B., Hess, P., Jakus, Z., Kuligowski, M., Fletcher, A., Elpek, K., Bellemare-Pelletier, A., Sceats, L., Reynoso, E., Gonzalez, S., Graham, D., Chang, J., Peters, A., Woodruff, M., Kim, Y., Swat, W., Morita, T., Kuchroo, V., Carroll, M., Kahn, M., Wucherpfennig, K., and Turley, S. (2012). Podoplanin-rich stromal networks induce dendritic cell motility via activation of C-type lectin receptor CLEC-2. Immunity 37, 276-289.
3. Bajénoff, M., Egen, J. G., Koo, L. Y., Laugier, J. P., Brau, F., Glaichenhaus, N., and Germain, R. N. (2006). Stromal cell networks regulate lymphocyte entry, migration, and terri-toriality in lymph nodes. Immunity 25, 989-1001.
4. Barth, K., Bläsche, R., and Kasper, M. (2010). T1alpha/podoplanin shows raft-associated distribution in mouse lung alveolar epithelial E10 cells. Cell Physiol. Biochem. 25, 103-112.
5. Bekiaris, V., Withers, D., Glanville, S. H., Mcconnell, E M., Parnell, S. M., Kim, M.-Y., Gaspal, E M. C., Jenkinson, E., Sweet, C., Anderson, G., and Lane, P. J. L. (2007). Role of CD30 in B/T segregation in the spleen. J. Immunol. 179, 7535-7543.
6. Bertozzi, C. C., Schmaier, A. A., Mer-icko, P., Hess, P. R., Zou, Z., Chen, M., Chen, C.-Y., Xu, B., Lu, M.-M., Zhou, D., Sebzda, E., Santore, M. T., Merianos, D. J., Stadtfeld, M., Flake, A. W., Graf, T., Skoda, R., Maltz-man, J. S., Koretzky, G. A., and Kahn, M. L. (2010). Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 116, 661-670.
7. Breiteneder-Geleff, S., Matsui, K., Soleiman, A., Meraner, P., Poczewski, H., Kalt, R., Schaffner, G., and Kerjaschki, D. (1997). Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am. J. Pathol. 151, 1141-1152.
8. Colonna, M., Samaridis, J., and Angman, L. (2000). Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells. Eur. J. Immunol. 30, 697-704.
9. Cueni, L. N., and Detmar, M. (2009). Galectin-8 interacts with podoplanin and modulates lymphatic endothelial cell functions. Exp. Cell Res. 315, 1715-1723.
10. Douglas, Y L, Mahtab, E. A. F., Jong-bloed, M. R. M., Uhrin, P., Zaujec, J., Binder, B. R., Schalij, M. J., Poel-mann, R. E., Deruiter, M. C., and Gittenberger-De Groot, A. C. (2009). Pulmonary vein, dorsal atrial wall and atrial septum abnormalities in podoplanin knockout mice with disturbed posterior heart field contribution. Pediatr. Res. 65, 27-32.
11. Durchdewald, M., Guinea-Viniegra, J., Haag, D., Riehl, A., Lichter, P., Hahn, M., Wagner, E. F., Angel, P., and Hess, J. (2008). Podoplanin is a novel fos target gene in skin carcinogenesis. Cancer Res. 68, 6877-6883.
12. Eferl, R., and Wagner, E. E (2003). AP-1: a double-edged sword in tumorigen-esis. Nat. Rev. Cancer 3, 859-868.
13. Ekwall, A.-K. H., Eisler, T., Anderberg, C., Jin, C., Karlsson, N., Brisslert, M., and Bokarewa, M. I. (2011). The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplas-tic synovial lining layer in rheumatoid arthritis. Arthritis Res. Ther. 13, R40.
14. Farr, A., Nelson, A., and Hosier, S. (1992a). Characterization of an antigenic determinant preferentially expressed by type I epithelial cells in the murine thymus. J. Histochem. Cytochem. 40, 651-664.
15. Farr, A. G., Berry, M. L., Kim, A., Nelson, A. J., Welch, M. P., and Aruffo, A. (1992b). Characterization and cloning of a novel glyco-protein expressed by stromal cells in T-dependent areas of peripheral lymphoid tissues. J. Exp. Med. 176, 1477-1482.
16. Fehon, R. G., Mcclatchey, A. I., and Bretscher, A. (2010). Organizing the cell cortex: the role of ERM proteins. Nat. Rev. Mol. Cell Biol. 11, 276-287.
17. Fernández-Muñoz, B., Yurrita, M. M., Martín-Villar, E., Carrasco-Ramírez, P., Megías, D., Renart, J., and Quintanilla, M. (2011). The trans-membrane domain of podoplanin is required for its association with lipid rafts and the induction of epithelial-mesenchymal transition. Int. J. Biochem. Cell Biol. 43, 886-896.
18. Fu, J., Gerhardt, H., Mcdaniel, J. M., Xia, B., Liu, X., Ivanciu, L., Ny, A., Hermans, K., Silasi-Mansat, R., Mcgee, S., Nye, E., Ju, T., Ramirez, M. I., Carmeliet, P., Cummings, R. D., Lupu, F., and Xia, L. (2008). Endothelial cell O-glycan deficiency causes blood/lymphatic misconnec-tions and consequent fatty liver disease in mice. J. Clin. Invest. 118, 3725-3737.
19. Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., and Sahai, E. (2007). Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392-1400.
20. Gröger, M., Loewe, R., Holnthoner, W., Embacher, R., Pillinger, M., Herron, G. S., Wolff, K., and Pet-zelbauer, P. (2004). IL-3 induces expression of lymphatic markers Prox-1 and podoplanin in human endothelial cells. J. Immunol. 173, 7161-7169.
21. Hong, Y.-K., Harvey, N., Noh, Y.-H., Schacht, V., Hirakawa, S., Det-mar, M., and Oliver, G. (2002). Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev. Dyn. 225, 351-357.
22. Honma, M., Minami-Hori, M., Taka-hashi, H., and Iizuka, H. (2012). Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22. J. Dermatol. Sci. 65, 134-140.
23. Hoshino, A., Ishii, G., Ito, T., Aoyagi, K., Ohtaki, Y., Nagai, K., Sasaki, H., and Ochiai, A. (2011). Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res. 71, 4769-4779.
24. Hou, T. Z., Bystrom, J., Sherlock, J. P., Qureshi, O., Parnell, S. M., Anderson, G., Gilroy, D. W., and Buckley, C. D. (2010). A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis. FEBS Lett. 584, 3955-3961.
25. Huber, L. C., Distler, O., Tarner, I., Gay, R. E., Gay, S., and Pap, T. (2006). Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford) 45, 669-675.
26. Ito, S., Ishii, G., Hoshino, A., Hashimoto, H., Neri, S., Kuwata, T., Higashi, M., Nagai, K., and Ochiai, A. (2012). Tumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activity. Biochem. Biophys. Res. Commun. 422, 194-199.
27. Jäger, A., Dardalhon, V., Sobel, R. A., Bettelli, E., and Kuchroo, V. K. (2009). Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 183, 7169-7177.
28. Ji, R.-C. (2006). Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: new insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev. 25, 677-694.
29. Kaji, C., Tomooka, M., Kato, Y., Kojima, H., and Sawa, Y. (2012). The expression of podoplanin and classic cad-herins in the mouse brain. J. Anat. 220, 435-446.
30. Kalluri, R., and Zeisberg, M. (2006). Fibroblasts in cancer. Nat. Rev. Cancer 6, 392-401.
31. Kaneko, M. K., Kato, Y., Kitano, T., and Osawa, M. (2006). Conservation of a platelet activating domain of Aggrus/podoplanin as a platelet aggregation-inducing factor. Gene 378, 52-57.
32. Kato, T., Kaneko, M., Sata, M., Fujita, N., Tsuruo, T., and Osawa, M. (2005). Enhanced expression of Aggrus (T1alpha/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma. Tumour Biol. 26, 195-200.
33. Kato, Y., Fujita, N., Kunita, A., Sato, S., Kaneko, M., Osawa, M., and Tsuruo, T. (2003). Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J. Biol. Chem. 278, 51599-51605.
34. Kawase, A., Ishii, G., Nagai, K., Ito, T., Nagano, T., Murata, Y., Hishida, T., Nishimura, M., Yoshida, J., Suzuki, K., and Ochiai, A. (2008). Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int. J. Cancer 123, 1053-1059.
35. Kerjaschki, D., Regele, H. M., Moosberger, I., Nagy-Bojarski, K., Watschinger, B., Soleiman, A., Birner, P., Krieger, S., Hovorka, A., Silber-humer, G., Laakkonen, P., Petrova, T., Langer, B., and Raab, I. (2004). Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15, 603-612.
36. Kerrigan, A. M., Dennehy, K. M., Mourão-Sá, D., Faro-Trindade, I., Willment, J. A., Taylor, P. R., Eble, J. A., Reis E Sousa, C., and Brown, G. D. (2009). CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils. J. Immunol. 182, 4150-4157.
37. Kerrigan, A. M., Navarro-Nuñez, L., Pyz, E., Finney, B. A., Willment, J. A., Watson, S. P., and Brown, G. D. (2012). Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J. Thromb. Haemost. 10, 484-486.
38. Kimura, N., and Kimura, I. (2005). Podoplanin as a marker for mesothe-lioma. Pathol. Int. 55, 83-86.
39. Kitano, H., Kageyama, S.-I., Hewitt, S. M., Hayashi, R., Doki, Y., Ozaki, Y., Fujino, S., Takikita, M., Kubo, H., and Fukuoka, J. (2010). Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch. Pathol. Lab. Med. 134, 1520-1527.
40. Kunita, A., Kashima, T. G., Ohazama, A., Grigoriadis, A. E., and Fukayama, M. (2011). Podoplanin is regulated byAP-1 and promotes platelet aggregation and cell migration in osteosarcoma. Am. J. Pathol. 179, 1041-1049.
41. Link, A., Hardie, D. L., Favre, S., Britschgi, M. R., Adams, D. H., Sixt, M., Cyster, J. G., Buckley, C. D., and Luther, S. A. (2011). Association of T-zone retic-ular networks and conduits with ectopic lymphoid tissues in mice and humans. Am. J. Pathol. 178, 1662-1675.
42. Lowe, K. L., Navarro-Nunez, L., and Watson, S. P. (2012). PL-06 Platelet CLEC-2 and podoplanin in cancer metastasis. Thrombosis Res.129(Suppl. 1), S30-S37.
43. Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G., and Cyster, J. G. (2000). Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl. Acad. Sci. U.S.A. 97, 12694-12699.
44. Mahtab, E. A. F., Vicente-Steijn, R., Hahurij, N. D., Jongbloed, M. R. M., Wisse, L. J., Deruiter, M. C., Uhrin, P., Zaujec, J., Binder, B. R., Schalij, M. J., Poelmann, R. E., and Gittenberger-De Groot, A. C. (2009). Podoplanin deficient mice show a Rhoa-related hypoplasia of the sinus venosus myocardium including the sinoatrial node. Dev. Dyn. 238, 183-193.
45. Mahtab, E. A. F., Wijffels, M. C. E. F., Van Den Akker, N. M. S., Hahurij, N. D., Lie-Venema, H., Wisse, L. J., Deruiter, M. C., Uhrin, P., Zaujec, J., Binder, B. R., Schalij, M. J., Poelmann, R. E., and Gittenberger-De Groot, A. C. (2008). Cardiac malformations and myocar-dial abnormalities in podoplanin knockout mouse embryos: correlation with abnormal epicardial development. Dev. Dyn. 237, 847-857.
46. Malhotra, D., Fletcher, A. L., Astarita, J., Lukacs-Kornek, V., Tayalia, P., Gonzalez, S. F., Elpek, K. G., Chang, S. K., Knoblich, K., Hemler, M. E., Brenner, M. B., Carroll, M. C., Mooney, D. J., Turley, S. J., and Consortium, I. G. P. (2012). Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunologi-cal hallmarks. Nat. Immunol. 13, 499-510.
47. Martín-Villar, E., Fernández-Muñoz, B., Parsons, M., Yurrita, M. M., Megías, D., Pérez-Gómez, E., Jones, G. E., and Quintanilla, M. (2010). Podoplanin associates with CD44 to promote directional cell migration. Mol. Biol. Cell 21, 4387-4399.
48. Martín-Villar, E., Megías, D., Cas-tel, S., Yurrita, M. M., Vilaró, S., and Quintanilla, M. (2006). Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J. Cell Sci. 119, 4541-4553.
49. Martín-Villar, E., Scholl, F. G., Gamallo, C., Yurrita, M. M., Muñoz-Guerra, M., Cruces, J., and Quintanilla, M. (2005). Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int. J. Cancer 113, 899-910.
50. Meri, S., and Pangburn, M. K. (1990). Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proc. Natl. Acad. Sci. U.S.A. 87, 3982-3986.
51. Michalek, M. T., Bremer, E. G., and Mold, C. (1988). Effect of ganglio-sides on activation of the alternative pathway of human complement. J. Immunol. 140, 1581-1587.
52. Millien, G., Spira, A., Hinds, A., Wang, J., Williams, M. C., and Ramirez, M. I. (2006). Alterations in gene expression in T1 alpha null lung: a model of deficient alveolar sac development. BMC Dev. Biol. 6, 35. doi: 10.1186/1471-213X-6-35
53. Mishima, K., Kato, Y., Kaneko, M. K., Nishikawa, R., Hirose, T., and Matsutani, M. (2006). Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression. Acta Neuropathol. 111, 483-488.
54. Nakazawa, Y., Sato, S., Naito, M., Kato, Y., Mishima, K., Arai, H., Tsuruo, T., and Fujita, N. (2008). Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood 112, 1730-1739.
55. Navarro, A., Perez, R. E., Rezaiekha-ligh, M., Mabry, S. M., and Ekekezie, I. I. (2008). T1/podoplanin is essential for capillary morphogenesis in lymphatic endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L543-L551.
56. Navarro, A., Perez, R. E., Rezaiekhaligh, M. H., Mabry, S. M., and Ekekezie, I. I. (2010). Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42. Am. J. Physiol. Lung Cell. Mol. Physiol. 1, L32-L42.
57. Ngo, V. N., Cornall, R. J., and Cyster, J. G. (2001). Splenic T zone development is B cell dependent. J. Exp. Med. 194, 1649-1660.
58. Nose, K., Saito, H., and Kuroki, T. (1990). Isolation of a gene sequence induced later by tumor-promoting 12-O-tetradecanoylphorbol-13-acet-ate in mouse osteoblastic cells (MC3T3-E1) and expressed consti-tutively in ras-transformed cells. Cell Growth Differ. 1, 511-518.
59. Onder, L., Scandella, E., Chai, Q., Firner, S., Mayer, C. T., Spar-wasser, T., Thiel, V., Rülicke, T., and Ludewig, B. (2011). A novel bacterial artificial chromosome-transgenic Podoplanin-Cre mouse targets lymphoid organ stromal cells in vivo. Front. Immunol. 2:50. doi: 10.3389/fimmu.2011.00050
60. Ordóñez, N. G. (2005). D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant meso-thelioma. Hum. Pathol. 36, 372-380.
61. Osada, M., Inoue, O., Ding, G., Shirai, T., Ichise, H., Hirayama, K., Takano, K., Yatomi, Y., Hirashima, M., Fujii, H., Suzuki-Inoue, K., and Ozaki, Y. (2012). Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells. J. Biol. Chem. 287, 22241-22252.
62. Peduto, L., Dulauroy, S., Lochner, M., Spath, G. F., Morales, M. A., Cumano, A., and Eberl, G. (2009). Inflammation recapitulates the ontogeny of lymphoid stromal cells. J. Immunol. 182, 5789-5799.
63. Peters, A., Pitcher, L. A., Sullivan, J. M., Mitsdoerffer, M., Acton, S. E., Franz, B., Wucherpfennig, K., Turley, S., Carroll, M. C., Sobel, R. A., Bet-telli, E., and Kuchroo, V. K. (2011). Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986-996.
64. Peterziel, H., Müller, J., Danner, A., Bar-bus, S., Liu, H.-K., Radlwimmer, B., Pietsch, T., Lichter, P., Schütz, G., Hess, J., and Angel, P. (2012). Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation. Neuro Oncol. 14, 426-439.
65. Raica, M., Kondylis, A., Mogoanta, L., Encica, S., and Cîmpean, A. M. (2010). Diagnostic and clinical significance of D2-40 expression in the normal human thymus and thy-moma. Rom. J. Morphol Embryol. 51, 229-234.
66. Ramirez, M. I., Millien, G., Hinds, A., Cao, Y., Seldin, D. C., and Williams, M. C. (2003). T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev. Biol. 256, 61-72.
67. Rishi, A. K., Joyce-Brady, M., Fisher, J., Dobbs, L. G., Floros, J., Vander-spek, J., Brody, J. S., and Williams, M. C. (1995). Cloning, characterization, and development expression of a rat lung alveolar type I cell gene in embryonic endodermal and neural derivatives. Dev. Biol. 167, 294-306.
68. Schacht, V., Dadras, S. S., Johnson, L. A., Jackson, D. G., Hong, Y.-K., and Detmar, M. (2005). Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am. J. Pathol. 166, 913-921.
69. Schacht, V., Ramirez, M. I., Hong, Y.-K., Hirakawa, S., Feng, D., Harvey, N., Williams, M., Dvorak, A. M., Dvorak, H. F., Oliver, G., and Detmar, M. (2003). T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22, 3546-3556.
70. Scholl, F. G., Gamallo, C., Vilaró, S., and Quintanilla, M. (1999). Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in ker-atinocytes. J. Cell Sci. 112(Pt 24), 4601-4613.
71. Sebzda, E., Hibbard, C., Sweeney, S., Abtahian, F., Bezman, N., Clemens, G., Maltzman, J. S., Cheng, L., Liu, F., Turner, M., Tybulewicz, V., Koretzky, G. A., and Kahn, M. L. (2006). Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev. Cell 11, 349-361.
72. Shibahara, J., Kashima, T., Kikuchi, Y., Kunita, A., and Fukayama, M. (2006). Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch 448, 493-499.
73. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M., and Swartz, M. A. (2010). Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749-752.
74. Shivdasani, R. A., Rosenblatt, M. F., Zucker-Franklin, D., Jackson, C. W., Hunt, P., Saris, C. J., and Orkin, S. H. (1995). Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81, 695-704.
75. Sobanov, Y., Bernreiter, A., Derdak, S., Mechtcheriakova, D., Schweighofer, B., Düchler, M., Kalthoff, F., and Hofer, E. (2001). A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex. Eur. J. Immunol. 31, 3493-3503.
76. Suzuki-Inoue, K., Inoue, O., Ding, G., Nishimura, S., Hokamura, K., Eto, K., Kashiwagi, H., Tomiyama, Y., Yatomi, Y., Umemura, K., Shin, Y., Hirashima, M., and Ozaki, Y (2010). Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnec-tions and impaired thrombus formation of CLEC-2-deficient platelets. J. Biol. Chem. 285, 24494-24507.
77. Suzuki-Inoue, K., Inoue, O., and Ozaki, Y (2011). Novel platelet activation receptor CLEC-2: from discovery to prospects. J. Thromb. Haemost. 9(Suppl. 1), 44-55.
78. Swartz, M. A., and Lund, A. W. (2012). Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12, 210-219.
79. Taylor, M. E., and Drickamer, K. (2007). Paradigms for glycan-binding receptors in cell adhesion. Curr. Opin. Cell Biol. 19, 572-577.
80. Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442-454.
81. Turley, S. J., Fletcher, A. L., and Elpek, K. G. (2010). The stromal and haematopoietic antigen-presenting cells that reside in secondary lymphoid organs. Nat. Rev. Immunol. 10, 813-825.
82. Uhrin, P., Zaujec, J., Breuss, J. M., Olcaydu, D., Chrenek, P., Stockinger, H., Fuertbauer, E., Moser, M., Haiko, P., Fässler, R., Alitalo, K., Binder, B. R., and Kerjaschki, D. (2010). Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 115, 3997-4005.
83. Wetterwald, A., Hoffstetter, W., Cec-chini, M. G., Lanske, B., Wagner, C., Fleisch, H., and Atkinson, M. (1996). Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes. Bone 18, 125-132.
84. Weyand, C. M., Kurtin, P. J., and Goronzy, J. J. (2001). Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am. J. Pathol. 159, 787-793.
85. Wicki, A., and Christofori, G. (2007). The potential role of podoplanin in tumour invasion. Br. J. Cancer 96, 1-5.
86. Wicki, A., Lehembre, F., Wick, N., Hantusch, B., Kerjaschki, D., and Christofori, G. (2006). Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9, 261-272.
87. Williams, M. C. (2003). Aleveolar type I cells: molecular phenotype and development. Annu. Rev. Physiol. 65, 669-695.
88. Williams, M. C., Cao, Y., Hinds, A., Rishi, A. K., and Wetterwald, A. (1996). T1 alpha protein is develop-mentally regulated and expressed by alveolar type I cells, choroid plexus, and ciliary epithelia of adult rats. Am. J. Respir. Cell Mol. Biol. 14, 577-585.
89. Yamanashi, T., Nakanishi, Y., Fujii, G., Akishima-Fukasawa, Y., Moriya, Y., Kanai, Y., Watanabe, M., and Hirohashi, S. (2009). Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma. Oncology 77, 53-62.
90. Yu, H., Gibson, J. A., Pinkus, G. S., and Hornick, J. L. (2007). Podoplanin (D2-40) is a novel marker for follicu-lar dendritic cell tumors. Am. J. Clin. Pathol. 128, 776-782.
91. Zick, Y., Eisenstein, M., Goren, R. A., Hadari, Y R., Levy, Y., and Ronen, D. (2004). Role of galectin-8 as a modulator of cell adhesion and cell growth. Glycoconj.J. 19, 517-526.
92. Zimmer, G., Oeffner, F., Von Messling, V., Tschernig, T., Gröness, H. J., Klenk, H. D., and Herrler, G. (1999). Cloning and characterization of gp36, a human mucin-type gly-coprotein preferentially expressed in vascular endothelium. Biochem. J. 341(Pt 2), 277-284.
93. Zöller, M. (2009). Tetraspanins: push and pull in suppressing and promoting metastasis. Nat. Rev. Cancer 9, 40-55.