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Emerging Roles of TGF-β Co-receptors in Human Disease

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TGF-β in Human Disease

Abstract

TGF-β signaling is both regulated and mediated by signaling co-receptors. Several TGF-β co-receptors have been identified including endoglin (CD105), the type III TGF-β receptor (TβRIII, betaglycan), neuropilin-1/2, syndecan-2, CD109, and LRP1. These co-receptors serve diverse functions including the regulation of ligand access to other TGF-β receptors and receptor trafficking. The TGF-β co-receptors can also signal directly. The TGF-β co-receptors are broadly expressed, have essential roles in embryonic development, and are frequently altered during disease progression. TGF-β co-receptors regulate cancer initiation and progression through effects on cell growth, migration, invasion, proliferation, and angiogenesis. In addition to their roles in cancer, these co-receptors are dysregulated during development, in vascular disease and fibrotic disorders. Collectively, the TGF-β co-receptors influence disease biology through complex mechanisms involving the regulation of growth factor-dependent and independent signaling events as well as through interactions with diverse scaffolding protein partners.

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References

  • Abdalla SA, Letarte M (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43(2):97–110. doi:10.1136/jmg.2005.030833

    PubMed  CAS  Google Scholar 

  • Ahn JY, Park S, Yun YS, Song JY (2010) Inhibition of type III TGF-β receptor aggravates lung fibrotic process. Biomed Pharmacother 64(7):472–476. doi:10.1016/j.biopha.2010.01.006

    PubMed  CAS  Google Scholar 

  • Andres JL, Ronnstrand L, Cheifetz S, Massague J (1991) Purification of the transforming growth factor-β (TGF-β) binding proteoglycan betaglycan. J Biol Chem 266(34):23282–23287

    PubMed  CAS  Google Scholar 

  • Antonescu CR, Zhang L, Nielsen GP, Rosenberg AE, Dal Cin P, Fletcher CD (2011) Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Genes Chromosomes Cancer 50(10):757–764. doi:10.1002/gcc.20897

    PubMed  CAS  Google Scholar 

  • Baba T, Kariya M, Higuchi T, Mandai M, Matsumura N, Kondoh E, Miyanishi M, Fukuhara K, Takakura K, Fujii S (2007) Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol Oncol 105(3):703–711

    PubMed  CAS  Google Scholar 

  • Bae HJ, Eun JW, Noh JH, Kim JK, Jung KH, Xie HJ, Park WS, Lee JY, Nam SW (2009) Down-regulation of transforming growth factor β receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity. Oncol Rep 22(3): 475–480

    PubMed  CAS  Google Scholar 

  • Bandyopadhyay A, Lopez-Casillas F, Malik SN (2002a) Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 63:4690–4695

    Google Scholar 

  • Bandyopadhyay A, Wang L, Lopez-Casillas F, Mendoza V, Yeh IT, Sun L (2005) Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer. Prostate 63(1):81–90

    PubMed  Google Scholar 

  • Bandyopadhyay A, Zhu Y, Cibull LB (1999a) A soluble transforming growth factor β type III receptor suppresses tumorigenicity and metastasis of human breast MDA-MB-231 cells. Cancer Res 59:5041–5046

    PubMed  CAS  Google Scholar 

  • Bandyopadhyay A, Zhu Y, Cibull LB, Chen C, Sun L-Z (1999b) A soluble transforming growth factor β type III receptor suppresses tumorigenicity and metastasis of human breast cancer. Cancer Res 59:5041–5046

    PubMed  CAS  Google Scholar 

  • Bandyopadhyay A, Zhu Y, Malik SN, Kreisberg J, Brattain MG, Sprague E, Luo J, Lopez-Casillas F, Sun L-Z (2002b) Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells. Oncogene 21:3541–3551

    PubMed  CAS  Google Scholar 

  • Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, Sotiropoulou PA, Loges S, Lapouge G, Candi A, Mascre G, Drogat B, Dekoninck S, Haigh JJ, Carmeliet P, Blanpain C (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478(7369):399–403. doi:10.1038/nature10525

    PubMed  CAS  Google Scholar 

  • Benhattar J, Losi L, Chaubert P, Givel JC, Costa J (1993) Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology 104(4):1044–1048

    PubMed  CAS  Google Scholar 

  • Berge M, Allanic D, Bonnin P, de Montrion C, Richard J, Suc M, Boivin JF, Contreres JO, Lockhart BP, Pocard M, Levy BI, Tucker GC, Tobelem G, Merkulova-Rainon T (2011) Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodeling. J Hepatol 55(4):866–875

    PubMed  CAS  Google Scholar 

  • Bernabeu C, Lopez-Novoa JM, Quintanilla M (2009) The emerging role of TGF-β superfamily coreceptors in cancer. Biochim Biophys Acta 1792(10):954–973. doi:10.1016/j.bbadis. 2009.07.003

    PubMed  CAS  Google Scholar 

  • Bilandzic M, Chu S, Farnworth PG, Harrison C, Nicholls P, Wang Y, Escalona RM, Fuller PJ, Findlay JK, Stenvers KL (2009) Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Mol Endocrinol 23(4):539–548. doi:me.2008-0300 [pii] 10.1210/me.2008-0300

    PubMed  CAS  Google Scholar 

  • Blobe GC, Liu X, Fang SJ, How T, Lodish HF (2001) A novel mechanism for regulating transforming growth factor β (TGF-β) signaling. Functional modulation of type III TGF-β receptor expression through interaction with the PDZ domain protein, GIPC. J Biol Chem 276(43): 39608–39617

    PubMed  CAS  Google Scholar 

  • Bock AJ, Tuft Stavnes H, Kaern J, Berner A, Staff AC, Davidson B (2011) Endoglin (CD105) expression in ovarian serous carcinoma effusions is related to chemotherapy status. Tumour Biol 32(3):589–596

    PubMed  CAS  Google Scholar 

  • Borges L, Iacovino M, Mayerhofer T, Koyano-Nakagawa N, Baik J, Garry D, Kyba M, Letarte M, Perlingeiro RCR (2012) A critical role for endoglin in the emergence of blood during embryonic development. Blood 119:5417–5428

    PubMed  CAS  Google Scholar 

  • Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104:1343–1351

    PubMed  CAS  Google Scholar 

  • Brewer CA, Setterdahl JJ, Li MJ, Johnston JM, Mann JL, McAsey ME (2000) Endoglin expression as a measure of microvessel density in cervical cancer. Obstet Gynecol 96(2):224–228

    PubMed  CAS  Google Scholar 

  • Burke JP, Watson RW, Murphy M, Docherty NG, Coffey JC, O'Connell PR (2009) Simvastatin impairs smad-3 phosphorylation and modulates transforming growth factor β1-mediated activation of intestinal fibroblasts. Br J Surg 96(5):541–551. doi:10.1002/bjs.6577

    PubMed  CAS  Google Scholar 

  • Cabello-Verrugio C, Brandan E (2007) A novel modulatory mechanism of transforming growth factor-β signaling through decorin and LRP-1. J Biol Chem 282(26):18842–18850. doi:10.1074/jbc.M700243200

    PubMed  CAS  Google Scholar 

  • Cai Y, Wang R, Zhao YF, Jia J, Sun ZJ, Chen XM (2010) Expression of Neuropilin-2 in salivary adenoid cystic carcinoma: its implication in tumor progression and angiogenesis. Pathol Res Pract 206(12):793–799

    PubMed  CAS  Google Scholar 

  • Cai H, Reed RR (1999) Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 19(15):6519–6527

    PubMed  CAS  Google Scholar 

  • Calabro L, Fonsatti E, Bellomo G, Alonci A, Colizzi F, Sigalotti L, Altomonte M, Musolino C, Maio M (2003) Differential levels of soluble endoglin (CD105) in myeloid malignancies. J Cell Physiol 194(2):171–175

    PubMed  CAS  Google Scholar 

  • Cao S, Yaqoob U, Das A, Shergill U, Jagavelu K, Huebert RC, Routray C, Abdelmoneim S, Vasdev M, Leof E, Charlton M, Watts RJ, Mukhopadhyay D, Shah VH (2010a) Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells. J Clin Invest 120(7):2379–2394. doi:10.1172/JCI41203

    PubMed  CAS  Google Scholar 

  • Cao Y, Szabolcs A, Dutta SK, Yaqoob U, Jagavelu K, Wang L, Leof EB, Urrutia RA, Shah VH, Mukhopadhyay D (2010b) Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem 285(41):31840–31848. doi:10.1074/jbc.M110.151696

    PubMed  CAS  Google Scholar 

  • Castonguay R, Werner ED, Matthews RG, Presman E, Mulivor AW, Solban N, Sako D, Pearsall RS, Underwood KW, Seehra J, Kumar R, Grinberg AV (2011) Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. J Biol Chem 286(34):30034–30046. doi:10.1074/jbc.M111.260133

    PubMed  CAS  Google Scholar 

  • Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M (1992) Endoglin is a component of the transforming growth factor-β receptor system in human endothelial cells. J Biol Chem 267(27):19027–19030

    PubMed  CAS  Google Scholar 

  • Chen CZ, Li M, de Graaf D, Monti S, Gottgens B, Sanchez MJ, Lander ES, Golub TR, Green AR, Lodish HF (2002) Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. Proc Natl Acad Sci USA 99(24):15468–15473. doi:10.1073/pnas.202614899

    PubMed  CAS  Google Scholar 

  • Chen E, Hermanson S, Ekker SC (2004a) Syndecan-2 is essential for angiogenic sprouting during zebrafish development. Blood 103(5):1710–1719. doi:10.1182/blood-2003-06-1783

    PubMed  CAS  Google Scholar 

  • Chen L, Klass C, Woods A (2004b) Syndecan-2 regulates transforming growth factor-β signaling. J Biol Chem 279(16):15715–15718. doi:10.1074/jbc.C300430200 C300430200 [pii]

    PubMed  CAS  Google Scholar 

  • Chen W, Kirkbride KC, How T, Nelson CD, Mo J, Frederick JP, Wang XF, Lefkowitz RJ, Blobe GC (2003) Beta-arrestin 2 mediates endocytosis of type III TGF-β receptor and down-regulation of its signaling. Science 301(5638):1394–1397

    PubMed  CAS  Google Scholar 

  • Chittenden TW, Claes F, Lanahan AA, Autiero M, Palac RT, Tkachenko EV, Elfenbein A, Ruiz de Almodovar C, Dedkov E, Tomanek R, Li W, Westmore M, Singh JP, Horowitz A, Mulligan-Kehoe MJ, Moodie KL, Zhuang ZW, Carmeliet P, Simons M (2006) Selective regulation of arterial branching morphogenesis by synectin. Dev Cell 10(6):783–795

    PubMed  CAS  Google Scholar 

  • Choi Y, Kim H, Chung H, Hwang JS, Shin JA, Han IO, Oh ES (2010) Syndecan-2 regulates cell migration in colon cancer cells through Tiam1-mediated Rac activation. Biochem Biophys Res Commun 391(1):921–925. doi:10.1016/j.bbrc.2009.11.165

    PubMed  CAS  Google Scholar 

  • Cohen T, Gluzman-Poltorak Z, Brodzky A, Meytal V, Sabo E, Misselevich I, Hassoun M, Boss JH, Resnick M, Shneyvas D, Eldar S, Neufeld G (2001) Neuroendocrine cells along the digestive tract express neuropilin-2. Biochem Biophys Res Commun 284(2):395–403

    PubMed  CAS  Google Scholar 

  • Cohen T, Herzog Y, Brodzky A, Greenson JK, Eldar S, Gluzman-Poltorak Z, Neufeld G, Resnick MB (2002) Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours. J Pathol 198(1):77–82

    PubMed  CAS  Google Scholar 

  • Compton LA, Potash DA, Brown CB, Barnett JV (2007) Coronary vessel development is dependent on the type III transforming growth factor β receptor. Circ Res 101(8):784–791. doi:CIRCRESAHA.107.152082 [pii] 10.1161/CIRCRESAHA.107.152082

    PubMed  CAS  Google Scholar 

  • Conley BA, Koleva R, Smith JD, Kacer D, Zhang D, Bernabeu C, Vary CP (2004) Endoglin controls cell migration and composition of focal adhesions: function of the cytosolic domain. J Biol Chem 279(26):27440–27449. doi:10.1074/jbc.M312561200

    PubMed  CAS  Google Scholar 

  • Cooper SJ, Zou H, Legrand SN, Marlow LA, von Roemeling CA, Radisky DC, Wu KJ, Hempel N, Margulis V, Tun HW, Blobe GC, Wood CG, Copland JA (2010) Loss of type III transforming growth factor-β receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene 29(20):2905–2915. doi:onc201064 [pii] 10.1038/onc.2010.64

    PubMed  CAS  Google Scholar 

  • Copland JA, Luxon BA, Ajani L, Maity T, Campagnaro E, Guo H, LeGrand SN, Tamboli P, Wood CG (2003) Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression. Oncogene 22(39):8053–8062. doi:10.1038/sj.onc.1206835 1206835 [pii]

    PubMed  Google Scholar 

  • Coral-Alvarado PX, Garces MF, Caminos JE, Iglesias-Gamarra A, Restrepo JF, Quintana G (2010) Serum endoglin levels in patients suffering from systemic sclerosis and elevated systolic pulmonary arterial pressure. Int J Rheumatol. doi:10.1155/2010/969383

    Google Scholar 

  • Criswell TL, Arteaga CL (2007) Modulation of NFκB activity and E-cadherin by the type III transforming growth factor β receptor regulates cell growth and motility. J Biol Chem 282(44):32491–32500. doi:10.1074/jbc.M704434200

    PubMed  CAS  Google Scholar 

  • Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ, Ellis LM (2008) Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin Cancer Res 14(7):1931–1937. doi:10.1158/1078-0432.CCR-07-4478

    PubMed  CAS  Google Scholar 

  • Davidson B, Stavnes HT, Forsund M, Berner A, Staff AC (2010) CD105 (endoglin) expression in breast carcinoma effusions is a marker of poor survival. Breast 19(6):493–498

    PubMed  Google Scholar 

  • De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200(4): 429–447

    PubMed  Google Scholar 

  • Dharmapatni AA, Smith MD, Ahern MJ, Simpson A, Li C, Kumar S, Roberts-Thomson PJ (2001) The TGF β receptor endoglin in systemic sclerosis. Asian Pac J Allergy Immunol 19(4):275–282

    PubMed  CAS  Google Scholar 

  • Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC (2007) The type III TGF-β receptor suppresses breast cancer progression. J Clin Invest 117(1):206–217

    PubMed  CAS  Google Scholar 

  • Drenberg CD, Livingston S, Chen R, Kruk PA, Nicosia SV (2009) Expression of Semaphorin 3F and its receptors in epithelial ovarian cancer, fallopian tubes, and secondary mullerian tissues. Obstet Gynecol Int (epub). doi:10.1155/2009/730739

    Google Scholar 

  • Duwel A, Eleno N, Jerkick M, Arevalo M, Blolanos JP, Bernabeu C, Lopez-Novoa JM (2007) Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice. Tumour Biol 28(1):1–8

    PubMed  Google Scholar 

  • Elliott RL, Blobe GC (2005) Role of transforming growth factor β in human cancer. J Clin Oncol 23(9):2078–2093

    PubMed  CAS  Google Scholar 

  • Essner JJ, Chen E, Ekker SC (2006) Syndecan-2. Int J Biochem Cell Biol 38(2):152–156. doi:10.1016/j.biocel.2005.08.012

    PubMed  CAS  Google Scholar 

  • Fansatti E, Vecchio LD, Altomonte M, Sigalotti L, Nicotra MR, Coral S, Natali PG, Maio M (2001) Endoglin: an accessory component of the TGF-β-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J Cell Physiol 188:1–7

    Google Scholar 

  • Fears CY, Gladson CL, Woods A (2006) Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem 281(21):14533–14536. doi:C600075200 [pii] 10.1074/jbc.C600075200

    PubMed  CAS  Google Scholar 

  • Finley DJ, Arora N, Zhu B, Gallagher L, Fahey TJ 3rd (2004) Molecular profiling distinguishes papillary carcinoma from benign thyroid nodules. J Clin Endcrinol Metab 89(7):3214–3223

    CAS  Google Scholar 

  • Finger EC, Turley RS, Dong M, How T, Fields TA, Blobe GC (2008) TβRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis 29(3):528–535. doi:bgm289 [pii] 10.1093/carcin/bgm289

    PubMed  CAS  Google Scholar 

  • Finnson KW, Tam BY, Liu K, Marcoux A, Lepage P, Roy S, Bizet AA, Philip A (2006) Identification of CD109 as part of the TGF-β receptor system in human keratinocytes. FASEB J 20(9):1525–1527. doi:10.1096/fj.05-5229fje

    PubMed  CAS  Google Scholar 

  • Florio P, Ciarmela P, Reis FM, Toti P, Galleri L, Santopietro R, Tiso E, Tosi P, Petraglia F (2005) Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. Eur J Endocrinol 152(2):277–284

    PubMed  CAS  Google Scholar 

  • Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339(6219):58–61

    PubMed  CAS  Google Scholar 

  • Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M (2003) Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene 22(42):6557–6563. doi:10.1038/sj.onc.1206813

    PubMed  CAS  Google Scholar 

  • Fonsatti E, Nicolay HJ, Altomonte M, Covre A, Maio M (2010) Targeting cancer vasculature via endoglin/CD105: a novel antibody-based diagnostic and therapeutic strategy in solid tumours. Cardiovasc Res 86(1):12–19. doi:10.1093/cvr/cvp332

    PubMed  CAS  Google Scholar 

  • Gatza CE, Holtzhausen A, Kirkbride KC, Morton A, Gatza ML, Datto MB, Blobe GC (2012) Type III TGF-β receptor enhances colon cancer cell migration and anchorage-independent growth. Neoplasia 13(8):758–770

    Google Scholar 

  • Gatza CE, Oh SY, Blobe GC (2010) Roles for the type III TGF-β receptor in human cancer. Cell Signal 22(8):1163–1174. doi:S0898-6568(10)00033-1 [pii] 10.1016/j.cellsig.2010.01.016

    PubMed  CAS  Google Scholar 

  • Geretti E, Klagsbrun M (2007) Neuropilins: novel targets for anti-angiogenesis therapies. Cell Adh Migr 1(2):56–61

    PubMed  Google Scholar 

  • Glinka Y, Prud'homme GJ (2008) Neuropilin-1 is a receptor for transforming growth factor β-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84(1):302–310. doi:10.1189/jlb.0208090

    PubMed  CAS  Google Scholar 

  • Gordon KJ, Dong M, Chislock EM, Fields TA, Blobe GC (2008) Loss of type III transforming growth factor β receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis 29(2):252–262. doi:bgm249 [pii] 10.1093/carcin/bgm249

    PubMed  CAS  Google Scholar 

  • Gordon KJ, Kirkbride KC, How T, Blobe GC (2009) Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2. Carcinogenesis 30(2):238–248. doi:10.1093/carcin/bgn274

    PubMed  CAS  Google Scholar 

  • Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL, Chung GG (2008) High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum Pathol 39(12): 1835–1843

    PubMed  CAS  Google Scholar 

  • Gougos A, St Jacques S, Greaves A, O'Connell PJ, d'Apice AJ, Burhring HJ, Bernabeu C, van Mourik JA, Letarte M (1992) Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells, and syncytiotrophoblasts. Int Immunol 4(1):83–92

    PubMed  CAS  Google Scholar 

  • Goumans M-J, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J 21(7):1743–1752

    PubMed  CAS  Google Scholar 

  • Grandclement C, Pallandre JR, Degano SV, Viel E, Bouard A, Balland J, Remy-Martin J-P, Simon B, Rouleau A, Boireau W, Klagsbrun M, Ferrand C, Borg C (2011) Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS One 6(7):e20444. doi:10.1371/journal.pone.0020444.t001

    PubMed  CAS  Google Scholar 

  • Gray MJ, Van Buren G, Dallas NA, Xia L, Wang X, Yang AD, Somcio RJ, Lin YG, Lim S, Fan F, Mangala LS, Arumugam T, Logsdon CD, Lopez-Berestein G, Sood AK, Ellis LM (2008) Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J Natl Cancer Inst 100(2):109–120

    PubMed  CAS  Google Scholar 

  • Grotenhuis BA, Wijnhoven BP, van Lanschot JJ (2012) Cancer stem cells and their potential implications for the treatment of solid tumors. J Surg Oncol. doi:10.1002/jso.23069

    PubMed  Google Scholar 

  • Guerrero-Esteo M, Lastres P, Letamendía A, Pérez-Alvarez MJ, Langa C, López LA, Fabra A, García-Pardo A, Vera S, Letarte M, Bernabéu C (1999) Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts. Eur J Cell Biol 78(9):614–623. doi:10.1016/s0171-9335(99)80046-6

    PubMed  CAS  Google Scholar 

  • Gulyas M, Hjerpe A (2003) Proteoglycans and WT1 as markers for distinguishing adenocarcinoma, epithelioid mesothelioma, and benign mesothelium. J Pathol 199(4):179–187

    Google Scholar 

  • Hamerlik P, Lathia JD, Rasmussen R, Wu Q, Bartkova J, Lee M, Moudry P, Bartek J Jr, Fischer W, Lukas J, Rich JN, Bartek J (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209(3):507–520. doi:10.1084/jem.20111424

    PubMed  CAS  Google Scholar 

  • Handa A, Tokunaga T, Tsuchida T, Lee YH, Kijima H, Yamazaki H, Ueyama Y, Fukuda H, Nakamura M (2000) Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int J Oncol 17(2):291–296

    PubMed  CAS  Google Scholar 

  • Hansel DE, Wilentz RE, Yeo CJ, Schulick RD, Montgomery E, Maitra A (2004) Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol 28:347–356

    PubMed  Google Scholar 

  • Hawinkels LJ, Ten Dijke P (2011) Exploring anti-TGF-β therapies in cancer and fibrosis. Growth Factors 29(4):140–152. doi:10.3109/08977194.2011.595411

    PubMed  CAS  Google Scholar 

  • Hempel N, How T, Cooper SJ, Green TR, Dong M, Copland JA, Wood CG, Blobe GC (2008) Expression of the type III TGF-β receptor is negatively regulated by TGF-β. Carcinogenesis 29(5):905–912. doi:10.1093/carcin/bgn049

    PubMed  CAS  Google Scholar 

  • Hempel N, How T, Dong M, Murphy SK, Fields TA, Blobe GC (2007) Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Res 67(11):5231–5238

    PubMed  CAS  Google Scholar 

  • Henry LA, Johnson DA, Sarrio D, Lee S, Quinlan PR, Crook T, Thompson AM, Reis-Filho JS, Isacke CM (2011) Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome. Oncogene 30(9):1046–1058. doi:10.1038/onc.2010.488

    PubMed  CAS  Google Scholar 

  • Hermida N, Lopez B, Gonzalez A, Dotor J, Lasarte JJ, Sarobe P, Borras-Cuesta F, Diez J (2009) A synthetic peptide from transforming growth factor-β1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats. Cardiovasc Res 81(3):601–609. doi:10.1093/cvr/cvn315

    PubMed  CAS  Google Scholar 

  • Holmes AM, Ponticos M, Shi-Wen X, Denton CP, Abraham DJ (2011) Elevated CCN2 expression in scleroderma: a putative role for the TGFβ accessory receptors TGFβRIII and endoglin. J Cell Commun Signal 5(3):173–177. doi:10.1007/s12079-011-0140-4

    PubMed  Google Scholar 

  • Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE (2012) The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer 106(12):1901–1906. doi:10.1038/bjc.2012.201

    PubMed  CAS  Google Scholar 

  • Howe JR, Haidle JL, Lal G, Bair J, Song C, Pechman B, Chinnathambi S, Lynch HT (2007) ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis. Clin Genet 71(1):91–92. doi:10.1111/j.1399-0004.2007.00734.x

    PubMed  CAS  Google Scholar 

  • Hu D, Wang X, Mao Y, Zhou L (2012) Identification of CD105 (endoglin)-positive stem-like cells in rhabdoid meningioma. J Neurooncol 106(3):505–517. doi:10.1007/s11060-011-0705-3

    PubMed  Google Scholar 

  • Huang X, Xiao D-W, Xu L-Y, Zhong H-J, Liao L-D, Xie Z-F, Li E-M (2009) Prognostic significance of altered expression of SDC2 and CYR61 in esophageal squamous cell carcinoma. Oncol Rep 21(4):1123–1129

    PubMed  CAS  Google Scholar 

  • Iolascon A, Giordani L, Borriello A, Carbone R, Izzo A, Tonini GP, Gambini C, Della Ragione F (2000) Reduced expression of transforming growth factor-β receptor type III in high stage neuroblastomas. Br J Cancer 82(6):1171–1176

    PubMed  CAS  Google Scholar 

  • Jelinek DF, R.C. T, Stolovitzky GA (2003) Identification of a global gene expression signature of B-chronic lymphocytic leukemia. Mol Cancer Res 1:346–361

    PubMed  CAS  Google Scholar 

  • Jia H, Bagherzadeh A, Hartzoulakis B, Jarvis A, Lohr M, Shaikh S, Aqil R, Cheng L, Tickner M, Esposito D, Harris R, Driscoll PC, Selwood DL, Zachary IC (2006) Characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist (EG3287) reveals importance of vascular endothelial growth factor exon 8 for NP-1 binding and role of NP-1 in KDR signaling. J Biol Chem 281(19):13493–13502. doi:10.1074/jbc.M512121200

    PubMed  CAS  Google Scholar 

  • Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D, Zachary I (2010) Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity. Br J Cancer 102(3):541–552. doi:10.1038/sj.bjc.6605539

    PubMed  CAS  Google Scholar 

  • Jones EA, Yuan L, Breant C, Watts RJ, Eichmann A (2008) Separating genetic and hemodynamic defects in neuropilin 1 knockout embryos. Development 135(14):2479–2488. doi:10.1242/dev.014902

    PubMed  CAS  Google Scholar 

  • Kassouf W, Ismail HR, Aprikian AG, Chevalier S (2004) Whole-mount prostate sections reveal differential endoglin expression in stromal, epithelial, and endothelial cells with the development of prostate cancer. Prostate Cancer Prostatic Dis 7(2):105–110

    PubMed  CAS  Google Scholar 

  • Kawakami T, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Abe Y, Osamura Y, Inoue H, Ueyama Y, Nakamura M (2002) Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer 95(10):2196–2201. doi:10.1002/cncr.10936

    PubMed  CAS  Google Scholar 

  • Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194(11):1625–1638

    PubMed  CAS  Google Scholar 

  • Kopczynska E, Dancewicz M, Kowalewski J, Makarewicz R, Kardymowicz H, Kaczmarczyk A, Tyrakowski T (2012) Influence of surgical resection on plasma endoglin (CD105) level in non-small cell lung cancer patients. Exp Oncol 34(1):53–56

    PubMed  CAS  Google Scholar 

  • Kramer KL, Barnette JE, Yost HJ (2002) PKCγ regulates syndecan-2 inside-out signaling during xenopus left-right development. Cell 111(7):981–990

    PubMed  CAS  Google Scholar 

  • Kramer KL, Yost HJ (2002) Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous Vg1 cofactor. Dev Cell 2(1):115–124

    PubMed  CAS  Google Scholar 

  • Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, Bundred N (1999) Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res 59:856–861

    PubMed  CAS  Google Scholar 

  • Lacal PM, Failla CM, Pagani E, Odorisio T, Schietroma C, Falcinelli S, Zambruno G, D’Atri S (2000) Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 115:1000–1007

    PubMed  CAS  Google Scholar 

  • Lakshman M, Huang X, Ananthanarayanan V, Jovanovic B, Liu Y, Craft CS, Romero D, Vary CP, Bergan RC (2011) Endoglin suppresses human prostate cancer metastasis. Clin Exp Metastasis 28(1):39–53. doi:10.1007/s10585-010-9356-6

    PubMed  CAS  Google Scholar 

  • Lambert KE, Huang H, Mythreye K, Blobe GC (2011) The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Mol Biol Cell 22(9):1463–1472. doi:10.1091/mbc.E10-11-0877

    PubMed  CAS  Google Scholar 

  • Latil A, Bieche I, Pesche S, Valeri A, Fournier G, Cussenot O, Lidereau R (2000) VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms. Int J Cancer 89:167–171

    PubMed  CAS  Google Scholar 

  • Lebrin F, Goumans M-J, Jonker L, Carvalho RLC, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J 23:4018–4028. doi:10.1038/

    PubMed  CAS  Google Scholar 

  • Lee JD, Hempel N, Lee NY, Blobe GC (2010) The type III TGF-β receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-β signaling. Carcinogenesis 31(2):175–183. doi:bgp271 [pii] 10.1093/carcin/bgp271

    PubMed  CAS  Google Scholar 

  • Lee JH, Park H, Chung H, Choi S, Kim Y, Yoo H, Kim TY, Hann HJ, Seong I, Kim J, Kang KG, Han IO, Oh ES (2009) Syndecan-2 regulates the migratory potential of melanoma cells. J Biol Chem 284(40):27167–27175. doi:10.1074/jbc.M109.034678

    PubMed  CAS  Google Scholar 

  • Lee NY, Blobe GC (2007) The interaction of endoglin with β-arrestin2 regulates transforming growth factor-β-mediated ERK activation and migration in endothelial cells. J Biol Chem 282(29):21507–21517. doi:M700176200 [pii] 10.1074/jbc.M700176200

    PubMed  CAS  Google Scholar 

  • Lee NY, Golzio C, Gatza CE, Sharma A, Katsanis N, Blobe GC (2012) Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis. Mol Biol Cell 23(13):2412–2423

    PubMed  CAS  Google Scholar 

  • Lee NY, Ray B, How T, Blobe GC (2008) Endoglin promotes transforming growth factor β-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J Biol Chem 283(47):32527–32533. doi:M803059200 [pii] 10.1074/jbc.M803059200

    PubMed  CAS  Google Scholar 

  • Li C, Hampson IN, Hampson L, Kumar P, Bernabeu C, Kumar S (2000) CD105 antagonizes the inhibitory signaling of transforming growth factor β1 on human vascular endothelial cells. FASEB J 14:55–64

    PubMed  CAS  Google Scholar 

  • Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284(5419):1534–1537

    PubMed  CAS  Google Scholar 

  • Li Q, Shirabe K, Kuwada JY (2004) Chemokine signaling regulates sensory cell migration in zebrafish. Dev Biol 269(1):123–136

    PubMed  CAS  Google Scholar 

  • Liu M, Suga M, Maclean AA, St George JA, Souza DW, Keshavjee S (2002) Soluble transforming growth factor-β type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans. Am J Respir Crit Care Med 165(3):419–423

    PubMed  Google Scholar 

  • Lopez-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massague J (1991) Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor system. Cell 67(4):785–795

    PubMed  CAS  Google Scholar 

  • Lopez-Casillas F, Wrana JL, Massague J (1993) Betaglycan presents ligand to the TGF β signaling receptor. Cell 73(7):1435–1444. doi:0092-8674(93)90368-Z [pii]

    PubMed  CAS  Google Scholar 

  • Ma X, Labinaz M, Goldstein J, Miller H, Keon WJ, Letarte M, O’Brien E (2000) Endoglin is overexpressed after arterial injury and is required for transforming growth factor-β-induced inhibition of smooth muscle cell migration. Arterioscler Thromb Vasc Biol 20(12):2546–2552. doi:10.1161/01.atv.20.12.2546

    PubMed  CAS  Google Scholar 

  • Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA, Gouvin LM, Sharma VM, Mercurio AM (2010) ERβ impedes prostate cancer EMT by destabilizing HIF-1α and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 17(4):319–332. doi:10.1016/j.ccr.2010.02.030

    PubMed  CAS  Google Scholar 

  • Margulis V, Maity T, Zhang XY, Cooper SJ, Copland JA, Wood CG (2008) Type III transforming growth factor-β (TGF-β) receptor mediates apoptosis in renal cell carcinoma independent of the canonical TGF-β signaling pathway. Clin Cancer Res 14(18):5722–5730. doi:14/18/5722 [pii] 10.1158/1078-0432.CCR-08-0546

    PubMed  CAS  Google Scholar 

  • Marzioni D, Lorenzi T, Mazzucchelli R, Capparuccia L, Morroni M, Fiorini R, Bracalenti C, Catalano A, David G, Castellucci M, Muzzonigro G, Montironi R (2009) Expression of basic fibroblast growth factor, its receptors and syndecans in bladder cancer. Int J Immunopathol Pharmacol 22(3):627–638

    PubMed  CAS  Google Scholar 

  • Maring JA, Trojanowska M, ten Dijke P (2012) Role of endoglin in fibrosis and scleroderma. Int Rev Cell Mol Biol 297:295–308

    PubMed  CAS  Google Scholar 

  • Massague J (1998) TGF-β signal transduction. Annu Rev Biochem 67:753–791

    PubMed  CAS  Google Scholar 

  • Massague J (2008) TGFβ in cancer. Cell 134:215–230. doi:10.1016/j.cell.2008.07.001

    PubMed  CAS  Google Scholar 

  • Matsuno F, Haruta Y, Kondo M, Tsai IY, Barcos M, Seon BK (1999) Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res 5:371–382

    PubMed  CAS  Google Scholar 

  • Maynard SE, Karumanchi SA (2011) Angiogenic factors and preeclampsia. Semin Nephrol 31(1):33–46. doi:10.1016/j.semnephrol.2010.10.004

    PubMed  CAS  Google Scholar 

  • McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbodl EA, Markel DS, McKinnon WC, Murrell J, McCormick MK, Pericak-Vance MA, Heutink P, Oostra BA, Haitjema T, Westerman CJJ, Porteous ME, Guttmacher AE, Letarte M, Marchuk DA (1994) Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351

    PubMed  CAS  Google Scholar 

  • Meng Q, Lux A, Holloschi A, Li J, Hughes JM, Foerg T, McCarthy JE, Heagerty AM, Kioschis P, Hafner M, Garland JM (2006) Identification of Tctex2β, a novel dynein light chain family member that interacts with different transforming growth factor-β receptors. J Biol Chem 281(48):37069–37080. doi:10.1074/jbc.M608614200

    PubMed  CAS  Google Scholar 

  • Meng W, Xia Q, Wu L, Chen S, He X, Zhang L, Gao Q, Zhou H (2011) Downregulation of TGF-β receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts. BMC Cancer 11:88. doi:10.1186/1471-2407-11-88

    PubMed  Google Scholar 

  • Molema G, Griffioen AW (1998) Rocking the foundations of solid tumor growth by attacking the tumor's blood supply. Immunol Today 19(9):392–394

    PubMed  CAS  Google Scholar 

  • Mythreye K, Blobe GC (2009a) Proteoglycan signaling co-receptors: roles in cell adhesion, migration and invasion. Cell Signal 21:1548–1558. doi:S0898-6568(09)00154-5 [pii] 10.1016/j.cellsig.2009.05.001

    PubMed  CAS  Google Scholar 

  • Mythreye K, Blobe GC (2009b) The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42. Proc Natl Acad Sci USA 106(20):8221–8226. doi:10.1073/pnas.0812879106

    PubMed  CAS  Google Scholar 

  • Mythreye K, Knelson EH, Gatza CE, Gatza ML, Blobe GC (2012) TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells. Oncogene. doi:10.1038/onc.2012.157

    PubMed  Google Scholar 

  • Narazaki M, Tosato G (2006) Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A. Blood 107:3892–3901. doi:10.1182/blood-2005-10-4113 10.1182/blood-2005-104113

    PubMed  CAS  Google Scholar 

  • Neri D, Bicknell R (2005) Tumour vascular targeting. Nat Rev Cancer 5(6):436–446. doi:10.1038/nrc1627

    PubMed  CAS  Google Scholar 

  • Noguer O, Villena J, Lorita J, Vilaro S, Reina M (2009) Syndecan-2 downregulation impairs angiogenesis in human microvascular endothelial cells. Exp Cell Res 315(5):795–808. doi:10.1016/j.yexcr.2008.11.016

    PubMed  CAS  Google Scholar 

  • O'Connor JC, Farach-Carson MC, Schneider CJ, Carson DD (2007) Coculture with prostate cancer cells alters endoglin expression and attenuates transforming growth factor-β signaling in reactive bone marrow stromal cells. Mol Cancer Res 5(6):585–603. doi:10.1158/1541-7786.MCR-06-0408

    PubMed  Google Scholar 

  • Orosco A, Fromigue O, Bazille C, Entz-Werle N, Levillain P, Marie PJ, Modrowski D (2007) Syndecan-2 affects the basal and chemotherapy-induced apoptosis in osteosarcoma. Cancer Res 67(8):3708–3715. doi:10.1158/0008-5472.CAN-06-4164

    PubMed  CAS  Google Scholar 

  • Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, Ross S, Cheng Z, Le Couter J, Plowman G, Peale F, Koch AW, Wu Y, Bagri A, Tessier-Lavigne M, Watts RJ (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11(1):53–67. doi:S1535-6108(06)00367-9 [pii] 10.1016/j.ccr.2006.10.018

    PubMed  CAS  Google Scholar 

  • Pardali E, van der Schaft DW, Wiercinska E, Gorter A, Hogendoorn PC, Griffioen AW, ten Dijke P (2011) Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma. Oncogene 30(3):334–345. doi:10.1038/onc.2010.418

    PubMed  CAS  Google Scholar 

  • Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM (2004) Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol 164(6):2139–2151

    PubMed  CAS  Google Scholar 

  • Park H, Han I, Kwon HJ, Oh ES (2005) Focal adhesion kinase regulates syndecan-2-mediated tumorigenic activity of HT1080 fibrosarcoma cells. Cancer Res 65(21):9899–9905. doi:10.1158/0008-5472.CAN-05-1386

    PubMed  CAS  Google Scholar 

  • Park H, Kim Y, Lim Y, Han I, Oh ES (2002) Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells. J Biol Chem 277(33):29730–29736. doi:10.1074/jbc.M202435200

    PubMed  CAS  Google Scholar 

  • Pimanda JE, Chan WY, Wilson NK, Smith AM, Kinston S, Knezevic K, Janes ME, Landry JR, Kolb-Kokocinski A, Frampton J, Tannahill D, Ottersbach K, Follows GA, Lacaud G, Kouskoff V, Gottgens B (2008) Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. Blood 112(12):4512–4522. doi:10.1182/blood-2008-05-157560

    PubMed  CAS  Google Scholar 

  • Popovic A, Demirovic A, Spajic B, Stimac G, Kruslin B, Tomas D (2010) Expression and prognostic role of syndecan-2 in prostate cancer. Prostate Cancer Prostate Dis 13(1):78–82

    CAS  Google Scholar 

  • Ray BN, Lee NY, How T, Blobe GC (2010) ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration. Carcinogenesis 31(3):435–441. doi:bgp327 [pii] 10.1093/carcin/bgp327

    PubMed  CAS  Google Scholar 

  • Rodriguez-Barbero A, Obreo J, Alvarez-Munoz P, Pandiella A, Bernabeu C, Lopez-Novoa JM (2006) Endoglin modulation of TGF-β1-induced collagen synthesis is dependent on ERK1/2 MAPK activation. Cell Physiol Biochem 18(1–3):135–142. doi:10.1159/000095181

    PubMed  CAS  Google Scholar 

  • Rokhlin OW, Cohen MB, Kubagawa H, Letarte M, Cooper MD (1995) Differential expression of endoglin on fetal and adult hematopoietic cells in human bone marrow. J Immunol 154(9): 4456–4465

    PubMed  CAS  Google Scholar 

  • Romero D, O'Neill C, Terzic A, Contois L, Young K, Conley BA, Bergan RC, Brooks PC, Vary CP (2011) Endoglin regulates cancer-stromal cell interactions in prostate tumors. Cancer Res 71(10):3482–3493. doi:10.1158/0008-5472.CAN-10-2665

    PubMed  CAS  Google Scholar 

  • Romero D, Terzic A, Conley BA, Craft CS, Jovanovic B, Bergan RC, Vary CP (2010) Endoglin phosphorylation by ALK2 contributes to the regulation of prostate cancer cell migration. Carcinogenesis 31(3):359–366. doi:10.1093/carcin/bgp217

    PubMed  CAS  Google Scholar 

  • Rosen LS, Gordon MS, Hurwitz HI, Mendelson DS, Kleinzweig D, Adams BJ, C.P. T (2008) Early evidence of toelrability and clinical activity from a phase 1 study of TRC105 (anti-CD105 antibody) in patients with advanced refractory cancer. Eur J Cancer Supplements 6(126)

    Google Scholar 

  • Rosen LS, Hurwitz HI, Wong MK, Goldman J, Mendelson DS, Fig. WD, Spencer S, Adams BJ, Alvarez D, Seon BK, Theuer CP, Leigh B, Gordon MS (2012) A phase 1 first-in-human study of TRC105 (anti-endoglin antibody) in patients with advanced cancer. Clin Cancer Res 18(17):4820–4829. doi:10.1158/1078-0432.CCR-12-0098

    PubMed  CAS  Google Scholar 

  • Rushing EC, Stine MJ, Hahn SJ, Shea S, Eller MS, Naif A, Khanna S, Westra WH, Jungbluth AA, Busam KJ, Mahalingam M, Alani RM (2012) Neuropilin-2: a novel biomarker for malignant melanoma? Hum Pathol 43(3):381–389

    PubMed  CAS  Google Scholar 

  • Ryu HY, Lee J, Yang S, Park H, Choi S, Jung KC, Lee ST, Seong JK, Han IO, Oh ES (2009) Syndecan-2 functions as a docking receptor for pro-matrix metalloproteinase-7 in human colon cancer cells. J Biol Chem 284(51):35692–35701. doi:10.1074/jbc.M109.054254

    PubMed  CAS  Google Scholar 

  • Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, Silverman JF (2004) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers. Mod Pathol 17(2):197–203

    PubMed  CAS  Google Scholar 

  • Sanchez NS, Hill CR, Love JD, Soslow JH, Craig E, Austin AF, Brown CB, Czirok A, Camenisch TD, Barnett JV (2011) The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. Dev Biol 358(2):331–343. doi:10.1016/j.ydbio.2011.08.008

    PubMed  CAS  Google Scholar 

  • Santander C, Brandan E (2006) Betaglycan induces TGF-β signaling in a ligand-independent manner, through activation of the p38 pathway. Cell Signal 18(9):1482–1491. doi:S0898- 6568(05)00327-X [pii] 10.1016/j.cellsig.2005.11.011

    PubMed  CAS  Google Scholar 

  • Santibanez JF, Perez-Gomez E, Fernandez LA, Garrido-Martin EM, Carnero A, Malumbres M, Vary CP, Quintanilla M, Bernabeu C (2010) The TGF-β co-receptor endoglin modulates the expression and transforming potential of H-Ras. Carcinogenesis 31(12):2145–2154. doi:10.1093/carcin/bgq199

    PubMed  CAS  Google Scholar 

  • Sanz-Rodriguez F, Guerrero-Esteo M, Botella LM, Banville D, Vary CP, Bernabeu C (2004) Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J Biol Chem 279(31):32858–32868. doi:10.1074/jbc.M400843200

    PubMed  CAS  Google Scholar 

  • Sarraj MA, Chua HK, Umbers A, Loveland KL, Findlay JK, Stenvers KL (2007) Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Growth Factors 25(5):334–345. doi:789171518 [pii] 10.1080/08977190701833619

    PubMed  CAS  Google Scholar 

  • Sarraj MA, Escalona RM, Umbers A, Chua HK, Small C, Griswold M, Loveland K, Findlay JK, Stenvers KL (2010) Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (β glycan) knockout mice. Biol Reprod 82(1):153–162. doi:biolreprod.109.078766 [pii]10.1095/biolreprod.109.078766

    PubMed  CAS  Google Scholar 

  • Schimming R, Marme D (2001) Endoglin (CD105) expression in squamous cell carcinoma of the oral cavity. Head Neck 24(2):151–156

    Google Scholar 

  • Seon BK, Matsuno F, Haruta Y, Kondo M, Barcos M (1997) Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. Clin Cancer Res 3:1031–1044

    PubMed  CAS  Google Scholar 

  • Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Puschel AW, Bussolino F (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397. doi:10.1038/nature01784 nature01784 [pii]

    PubMed  CAS  Google Scholar 

  • Shariat SF, Karam JA, Walz J, Roehrborn CG, Montorsi F, Margulis V, Saad F, Slawin KM, Karakiewicz PI (2008) Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers. Clin Cancer Res 14(12):3785–3791. doi:10.1158/1078-0432.CCR-07-4969

    PubMed  CAS  Google Scholar 

  • Sharifi N, Hurt EM, Kawasaki BT, Farrar WL (2007) TGFBR3 loss and consequences in prostate cancer. Prostate 67(3):301–311. doi:10.1002/pros.20526

    PubMed  Google Scholar 

  • Shyu HY, Fong CS, Fu YP, Shieh JC, Yin JH, Chang CY, Wang HW, Cheng CW (2010) Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke. Clin Chim Acta 411(11–12):840–845. doi:10.1016/j.cca.2010.02.071

    PubMed  CAS  Google Scholar 

  • Soker S, Gollamudi-Payne S, Fidder H, Charmahelli H, Klagsbrun M (1997) Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165. J Biol Chem 272(50):31582–31588

    Google Scholar 

  • Sorensen I, Adams RH, Gossler A (2009) DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 113(22):5680–5688. doi:10.1182/blood-2008-08-174508

    PubMed  Google Scholar 

  • Sorensen LK, Brooke BS, Li DY, Urness LD (2003) Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFβ coreceptor. Dev Biol 261(1): 235–250

    PubMed  CAS  Google Scholar 

  • Staton CA, Kumar I, Reed MW, Brown NJ (2007) Neuropilins in physiological and pathological angiogenesis. J Pathol 212(3):237–248. doi:10.1002/path.2182

    PubMed  CAS  Google Scholar 

  • Steg AD, Bevis KS, Katre AA, Ziebarth A, Dobbin ZC, Alvarez RD, Zhang K, Conner M, Landen CN (2012) Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 18(3):869–881. doi:10.1158/1078-0432.CCR-11-2188

    PubMed  CAS  Google Scholar 

  • Stenvers KL, Tursky ML, Harder KW, Kountouri N, Amatayakul-Chantler S, Grail D, Small C, Weinberg RA, Sizeland AM, Zhu HJ (2003) Heart and liver defects and reduced transforming growth factor β2 sensitivity in transforming growth factor β type III receptor-deficient embryos. Mol Cell Biol 23(12):4371–4385

    PubMed  CAS  Google Scholar 

  • Stephenson JM, Banerjee S, Saxena NK, Cherian R, Banerjee SK (2002) Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: a possible marker for the progression of breast cancer. Int J Cancer 101(5):409–414. doi:10.1002/ijc.10611

    PubMed  CAS  Google Scholar 

  • Sun L, Chen C (1997) Expression of transforming growth factor β type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem 272(40): 25367–25372

    PubMed  CAS  Google Scholar 

  • Sweet K, Willis J, Zhou X, Gallione C, Sawada T, Alhopuro P, Khoo S, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior T, Rebourg T, Teh B, Marchuk D, Aaltonen L, Eng C (2005) Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294(19):2465–2473

    PubMed  CAS  Google Scholar 

  • Tabata M, Kondo M, Haruta Y, Seon BK (1999) Antiangiogenic radioimmunotherapy of human solid tumors in SCID mice using 125I-labeled anti-endoglin monoclonal antibodies. Int J Cancer 82:737–742

    PubMed  CAS  Google Scholar 

  • Takahashi N, Haba A, Matsuno F, Seon BK (2001) Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimerias by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res 61:7846–7854

    PubMed  CAS  Google Scholar 

  • Tanaka F, Otake Y, Yanagihara K, Kawano Y, Miyahara R, Li M, Yamada T, Hanaoka N, Inui K, Wada H (2001) Evaluation of angiogenesis in non-small cell lung cancer: comparison between anti-CD35 antibody and anti-CD105 antibody. Clin Cancer Res 7:3410–3415

    PubMed  CAS  Google Scholar 

  • Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK (2010) Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J 277(19):3904–3923. doi:10.1111/j.1742-4658.2010.07800.x

    PubMed  CAS  Google Scholar 

  • Tsujie M, Tsujie T, Toi H, Uneda S, Shiozaki K, Tsai H, Seon BK (2008) Anti-tumor activity of an anti-endoglin monoclonal antibody is enhanced in immunocompetent mice. Int J Cancer 122(10):2266–2273. doi:10.1002/ijc.23314

    PubMed  CAS  Google Scholar 

  • Turley RS, Finger EC, Hempel N, How T, Fields TA, Blobe GC (2007) The type III transforming growth factor-β receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res 67(3):1090–1098. doi:10.1158/0008-5472.CAN-06-3117

    PubMed  CAS  Google Scholar 

  • Uneda S, Toi H, Tsujie T, Tsujie M, Harada N, Tsai H, Seon BK (2009) Anti-endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature. Int J Cancer 125(6):1446–1453. doi:10.1002/ijc.24482

    PubMed  CAS  Google Scholar 

  • Valdembri D, Caswell PT, Anderson KI, Schwarz JP, Konig I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F, Serini G (2009) Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biol 7(1):e25. doi:08-PLBI-RA-0162 [pii] 10.1371/journal.pbio.1000025

    PubMed  Google Scholar 

  • von Wronski MA, Raju N, Pillai R, Bogdan NJ, Marinelli ER, Nanjappan P, Ramalingam K, Arunachalam T, Eaton S, Linder KE, Yan F, Pochon S, Tweedle MF, Nunn AD (2006) Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor. J Biol Chem 281(9):5702–5710. doi:10.1074/jbc.M511941200

    Google Scholar 

  • Wang L, Mukhopadhyay D, Xu X (2006) C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis. FASEB J 20(9):1513–1515. doi:fj.05-5504fje [pii] 10.1096/fj.05-5504fje

    PubMed  CAS  Google Scholar 

  • Wang XF, Lin HY, Ng-Eaton E, Downward J, Lodish HF, Weinberg RA (1991) Expression cloning and characterization of the TGF-β type III receptor. Cell 67(4):797–805. doi:0092-8674(91)90074-9 [pii]

    PubMed  CAS  Google Scholar 

  • Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70(23):9621–9630. doi:10.1158/0008-5472.CAN-10-1722

    PubMed  CAS  Google Scholar 

  • Wikstrom P, Lissbrant IF, Stattin P, Egevad L, Bergh A (2002) Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate 51(4):268–275. doi:10.1002/pros.10083

    PubMed  CAS  Google Scholar 

  • Wild JR, Staton CA, Chapple K, Corfe BM (2012) Neuropilins: expression and roles in the epithelium. Int J Exp Pathol 93(2):81–103. doi:10.1111/j.1365-2613.2012.00810.x

    PubMed  CAS  Google Scholar 

  • Wipff J, Avouac J, Borderie D, Zerkak D, Lemarechal H, Kahan A, Boileau C, Allanore Y (2008) Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin. Rheumatology (Oxford) 47(7):972–975. doi:10.1093/rheumatology/ken100

    CAS  Google Scholar 

  • Wong VC, Chan PL, Bernabeu C, Law S, Wang LD, Li JL, Tsao SW, Srivastava G, Lung ML (2008) Identification of an invasion and tumor-suppressing gene, Endoglin (ENG), silenced by both epigenetic inactivation and allelic loss in esophageal squamous cell carcinoma. Int J Cancer 123(12):2816–2823. doi:10.1002/ijc.23882

    PubMed  CAS  Google Scholar 

  • Woszczyk D, Gola J, Jurzak M, Mazurek U, Mykala-Ciesla J, Wilczok T (2004) Expression of TGF β1 genes and their receptor types I, II, and III in low- and high-grade malignancy non-Hodgkin's lyphomas. Med Sci Monit 10(1):CR33–CR37

    PubMed  CAS  Google Scholar 

  • Yacoub M, Coulon A, Celhay O, Irani J, Cussenot O, Fromont G (2009) Differential expression of the semaphorin 3A pathway in prostatic cancer. Histopathology 55(4):392–398

    PubMed  Google Scholar 

  • Yasuoka H, Kodama R, Tsujimoto M, Yoshidome K, Akamatsu H, Nakahara M, Inagaki M, Sanke T, Nakamura Y (2009) Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression. BMC Cancer 9:220

    PubMed  Google Scholar 

  • You HJ, How T, Blobe GC (2009) The type III transforming growth factor-β receptor negatively regulates nuclear factor κ B signaling through its interaction with β-arrestin2. Carcinogenesis 30(8):1281–1287. doi:bgp071 [pii] 10.1093/carcin/bgp071

    PubMed  CAS  Google Scholar 

  • Younan S, Elhoseiny S, Hammam A, Gawdat R, El-Wakil M, Fawzy M (2012) Role of neuropilin-1 and its expression in Egyptian acute myeloid and acute lymphoid leukemia patients. Leuk Res 36(2):169–173

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Medical Oncology, Departments of Medicine, Pharmacology and Cancer Biology, Duke University Medical Center, 450 Research Dr. LSRC B354, Durham, NC, 27708, USA

    Alison E. Meyer, Karthikeyan Mythreye & Gerard C. Blobe

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  1. Alison E. Meyer
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  2. Karthikeyan Mythreye
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  3. Gerard C. Blobe
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Correspondence to Gerard C. Blobe .

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  1. , Dept Medical Biochem Microbiol, Uppsala University, Box 582, Uppsala, SE-751 23, Sweden

    Aristidis Moustakas

  2. , Interdiscip. Grad. Sch. Med. Eng., University of Yamanashi, 1110 Shimokato, Chuo, 409-3898, Yamanashi, Japan

    Keiji Miyazawa

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Meyer, A.E., Mythreye, K., Blobe, G.C. (2013). Emerging Roles of TGF-β Co-receptors in Human Disease. In: Moustakas, A., Miyazawa, K. (eds) TGF-β in Human Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54409-8_3

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