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TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

  • Original Paper
  • Published:
Cancer Microenvironment

Abstract

Breast cancer is the most prevalent cancer among females worldwide. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ∼70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by bone destruction, bone fractures, pain, and hypercalcemia, causing severe morbidity and hospitalization. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.

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Abbreviations

ALK:

Activin receptor-like kinase

ASO:

Antisense oligonucleotides

BMP:

Bone morphogenetic protein

BSP:

Bone sialoprotein

CAT:

Cambridge antibody technology

CSC:

Cancer stem cell

DN:

Dominant negative

EMT:

Epithelial-to-mesenchymal transition

GM-CSF:

Granulocyte macrophage colony stimulating factor (a.k.a. CSF2)

Hfg:

Halofuginone

HIF:

Hypoxia inducible factor

HMEC:

Human mammary epithelial cells

i.v.:

Intravenous

i.p.:

Intraperitoneal

IGF:

Insulin growth factor

IL:

Interleukin

JNK:

JunN-terminal kinase

MAPK:

Mitogen-activated protein kinase

MET:

Mesenchymal-to-epithelial transition

MMTV:

Mouse mammary tumor virus

OPG:

Osteoprotegerin

OPN:

Osteopontin

PDGF:

Platelet-derived growth factor

PTHrP:

Parathyroid hormone-related protein

R-Smads:

Receptor-regulated Smads

RANK:

Receptor activator of nuclear factor κB

RANKL:

Receptor activator of nuclear factor κB ligand

s.c.:

Subcutaneous

SDF-1:

Stromal derived growth factor-1

TβRI:

Transforming growth factor-β type I receptor (a.k.a ALK5)

TβRII:

Transforming growth factor-β type II receptor

TGF-β:

Transforming growth factor-β

VEGF:

Vascular endothelial growth factor

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Canc J Clin 61(2):69–90. doi:10.3322/caac.20107

    Google Scholar 

  2. Buijs JT, van der Pluijm G (2009) Osteotropic cancers: from primary tumor to bone. Canc Lett 273(2):177–193. doi:10.1016/j.canlet.2008.05.044

    CAS  Google Scholar 

  3. Coleman RE (1997) Skeletal complications of malignancy. Cancer 80(8 Suppl):1588–1594. doi:10.1002/(SICI)1097-0142(19971015)80:8

    PubMed  CAS  Google Scholar 

  4. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Canc 2(8):584–593. doi:10.1038/nrc867

    CAS  Google Scholar 

  5. Roodman GD (2004) Mechanisms of bone metastasis. New Engl J Med 350(16):1655–1664. doi:10.1056/NEJMra030831

    PubMed  CAS  Google Scholar 

  6. Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y (2009) Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15(8):960–966. doi:10.1038/nm.1943

    PubMed  CAS  Google Scholar 

  7. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J (2003) A multigenic program mediating breast cancer metastasis to bone. Canc Cell 3(6):537–549

    CAS  Google Scholar 

  8. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, Massague J, Mundy GR, Guise TA (1999) TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Investig 103(2):197–206. doi:10.1172/JCI3523

    PubMed  CAS  Google Scholar 

  9. Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3(12):1011–1022. doi:10.1038/nrd1580

    PubMed  CAS  Google Scholar 

  10. Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103(2):295–309

    PubMed  CAS  Google Scholar 

  11. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. New Engl J Med 342(18):1350–1358

    PubMed  CAS  Google Scholar 

  12. ten Dijke P, Arthur HM (2007) Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol 8(11):857–869. doi:10.1038/nrm2262

    PubMed  Google Scholar 

  13. Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1(3):169–178. doi:10.1038/35043051

    PubMed  CAS  Google Scholar 

  14. Feng XH, Derynck R (2005) Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 21:659–693. doi:10.1146/annurev.cellbio.21.022404.142018

    PubMed  CAS  Google Scholar 

  15. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584. doi:10.1038/nature02006

    PubMed  CAS  Google Scholar 

  16. Wu MY, Hill CS (2009) Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell 16(3):329–343. doi:10.1016/j.devcel.2009.02.012

    PubMed  CAS  Google Scholar 

  17. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700

    PubMed  CAS  Google Scholar 

  18. Ikushima H, Komuro A, Isogaya K, Shinozaki M, Hellman U, Miyazawa K, Miyazono K (2008) An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-beta signalling. EMBO J 27(22):2955–2965. doi:10.1038/emboj.2008.218

    PubMed  CAS  Google Scholar 

  19. Ikushima H, Miyazono K (2010) TGFbeta signalling: a complex web in cancer progression. Nat Rev Canc 10(6):415–424. doi:10.1038/nrc2853

    CAS  Google Scholar 

  20. Daly AC, Randall RA, Hill CS (2008) Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol 28(22):6889–6902. doi:10.1128/MCB.01192-08

    PubMed  CAS  Google Scholar 

  21. Liu IM, Schilling SH, Knouse KA, Choy L, Derynck R, Wang XF (2009) TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J 28(2):88–98. doi:10.1038/emboj.2008.266

    PubMed  CAS  Google Scholar 

  22. Pardali E, Goumans MJ, Ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20(9):556–567. doi:10.1016/j.tcb.2010.06.006

    PubMed  CAS  Google Scholar 

  23. Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 12(4):817–828

    PubMed  CAS  Google Scholar 

  24. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 21(7):1743–1753. doi:10.1093/emboj/21.7.1743

    PubMed  CAS  Google Scholar 

  25. Siegel PM, Shu W, Massague J (2003) Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. J Biol Chem 278(37):35444–35450. doi:10.1074/jbc.M301413200

    PubMed  CAS  Google Scholar 

  26. Derynck R, Akhurst RJ (2007) Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol 9(9):1000–1004. doi:10.1038/ncb434

    PubMed  CAS  Google Scholar 

  27. Massague J, Chen YG (2000) Controlling TGF-beta signaling. Gene Dev 14(6):627–644

    PubMed  CAS  Google Scholar 

  28. Calonge MJ, Massague J (1999) Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. J Biol Chem 274(47):33637–33643

    PubMed  CAS  Google Scholar 

  29. Massague J (2008) TGFbeta in Cancer. Cell 134(2):215–230. doi:10.1016/j.cell.2008.07.001

    PubMed  CAS  Google Scholar 

  30. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    PubMed  CAS  Google Scholar 

  31. Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G, Wakefield LM (2002) Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Investig 109(12):1607–1615. doi:10.1172/JCI15333

    PubMed  CAS  Google Scholar 

  32. Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL (2003) Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol 163(4):1539–1549

    PubMed  CAS  Google Scholar 

  33. Lenferink AE, Magoon J, Pepin MC, Guimond A, O’Connor-McCourt MD (2003) Expression of TGF-beta type II receptor antisense RNA impairs TGF-beta signaling in vitro and promotes mammary gland differentiation in vivo. Int J Canc 107(6):919–928. doi:10.1002/ijc.11494

    CAS  Google Scholar 

  34. Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE, Moses HL, Arteaga CL (2003) Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 23(23):8691–8703

    PubMed  CAS  Google Scholar 

  35. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J (2003) Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 100(14):8430–8435. doi:10.1073/pnas.0932636100

    PubMed  CAS  Google Scholar 

  36. Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR, Muller WJ, Moses HL (2005) Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Canc Res 65(6):2296–2302. doi:10.1158/0008-5472.CAN-04-3272

    CAS  Google Scholar 

  37. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, Zent R, Arteaga CL (2006) Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25(24):3408–3423. doi:10.1038/sj.onc.1208964

    PubMed  CAS  Google Scholar 

  38. Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA (1992) Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Canc Res 52(24):6949–6952

    CAS  Google Scholar 

  39. Tan AR, Alexe G, Reiss M (2009) Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Canc Res Treat 115(3):453–495. doi:10.1007/s10549-008-0184-1

    CAS  Google Scholar 

  40. Travers MT, Barrett-Lee PJ, Berger U, Luqmani YA, Gazet JC, Powles TJ, Coombes RC (1988) Growth factor expression in normal, benign, and malignant breast tissue. Br Med J (Clin Res Ed) 296(6637):1621–1624

    CAS  Google Scholar 

  41. de Jong JS, van Diest PJ, van der Valk P, Baak JP (1998) Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis. J Pathol 184(1):53–57. doi:10.1002/(SICI)1096-9896(199801)184:1

    PubMed  Google Scholar 

  42. Grau AM, Wen W, Ramroopsingh DS, Gao YT, Zi J, Cai Q, Shu XO, Zheng W (2008) Circulating transforming growth factor-beta-1 and breast cancer prognosis: results from the Shanghai Breast Cancer Study. Breast Canc Res Treat 112(2):335–341. doi:10.1007/s10549-007-9845-8

    CAS  Google Scholar 

  43. Ivanovic V, Todorovic-Rakovic N, Demajo M, Neskovic-Konstantinovic Z, Subota V, Ivanisevic-Milovanovic O, Nikolic-Vukosavljevic D (2003) Elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1) in patients with advanced breast cancer: association with disease progression. Eur J Canc 39(4):454–461

    CAS  Google Scholar 

  44. Kong FM, Anscher MS, Murase T, Abbott BD, Iglehart JD, Jirtle RL (1995) Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg 222(2):155–162

    PubMed  CAS  Google Scholar 

  45. Sheen-Chen SM, Chen HS, Sheen CW, Eng HL, Chen WJ (2001) Serum levels of transforming growth factor beta1 in patients with breast cancer. Arch Surg 136(8):937–940

    PubMed  CAS  Google Scholar 

  46. Baselga J, Rothenberg ML, Tabernero J, Seoane J, Daly T, Cleverly A, Berry B, Rhoades SK, Ray CA, Fill J, Farrington DL, Wallace LA, Yingling JM, Lahn M, Arteaga C, Carducci M (2008) TGF-beta signalling-related markers in cancer patients with bone metastasis. Biomarkers 13(2):217–236. doi:10.1080/13547500701676019

    PubMed  CAS  Google Scholar 

  47. Buck MB, Fritz P, Dippon J, Zugmaier G, Knabbe C (2004) Prognostic significance of transforming growth factor beta receptor II in estrogen receptor-negative breast cancer patients. Clin Canc Res 10(2):491–498

    CAS  Google Scholar 

  48. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988. doi:10.1073/pnas.0530291100

    PubMed  CAS  Google Scholar 

  49. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Canc Res 65(23):10946–10951. doi:10.1158/0008-5472.CAN-05-2018

    CAS  Google Scholar 

  50. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110. doi:10.1038/nature05372

    PubMed  Google Scholar 

  51. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111. doi:10.1038/35102167

    PubMed  CAS  Google Scholar 

  52. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115. doi:10.1038/nature05384

    PubMed  CAS  Google Scholar 

  53. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401. doi:10.1038/nature03128

    PubMed  CAS  Google Scholar 

  54. van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman-Ramirez N, Hamdy FC, Eaton CL, Thalmann GN, Cecchini MG, Pelger RC, van der Pluijm G (2010) High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Canc Res 70(12):5163–5173. doi:10.1158/0008-5472.CAN-09-3806

    Google Scholar 

  55. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS et al (2007) Molecular definition of breast tumor heterogeneity. Canc Cell 11(3):259–273. doi:10.1016/j.ccr.2007.01.013

    CAS  Google Scholar 

  56. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi:10.1016/j.cell.2008.03.027

    PubMed  CAS  Google Scholar 

  57. Seyedin SM, Thomas TC, Thompson AY, Rosen DM, Piez KA (1985) Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc Natl Acad Sci USA 82(8):2267–2271

    PubMed  CAS  Google Scholar 

  58. Seyedin SM, Thompson AY, Bentz H, Rosen DM, McPherson JM, Conti A, Siegel NR, Galluppi GR, Piez KA (1986) Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem 261(13):5693–5695

    PubMed  CAS  Google Scholar 

  59. Janssens K, ten Dijke P, Janssens S, Van Hul W (2005) Transforming growth factor-beta1 to the bone. Endocr Rev 26(6):743–774. doi:10.1210/er.2004-0001

    PubMed  CAS  Google Scholar 

  60. Iqbal J, Sun L, Zaidi M (2009) Coupling bone degradation to formation. Nat Med 15(7):729–731. doi:10.1038/nm0709-729

    PubMed  CAS  Google Scholar 

  61. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Wan M, Cao X (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15(7):757–765. doi:10.1038/nm.1979

    PubMed  CAS  Google Scholar 

  62. Wu X, Pang L, Lei W, Lu W, Li J, Li Z, Frassica FJ, Chen X, Wan M, Cao X (2010) Inhibition of sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Cell Stem Cell. doi:10.1016/j.stem.2010.09.012

  63. Canalis E (2009) Growth factor control of bone mass. J Cell Biochem 108(4):769–777. doi:10.1002/jcb.22322

    PubMed  CAS  Google Scholar 

  64. Alliston T, Choy L, Ducy P, Karsenty G, Derynck R (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 20(9):2254–2272. doi:10.1093/emboj/20.9.2254

    PubMed  CAS  Google Scholar 

  65. Maeda S, Hayashi M, Komiya S, Imamura T, Miyazono K (2004) Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. EMBO J 23(3):552–563. doi:10.1038/sj.emboj.7600067

    PubMed  CAS  Google Scholar 

  66. Karsdal MA, Andersen TA, Bonewald L, Christiansen C (2004) Matrix metalloproteinases (MMPs) safeguard osteoblasts from apoptosis during transdifferentiation into osteocytes: MT1-MMP maintains osteocyte viability. DNA Cell Biol 23(3):155–165. doi:10.1089/104454904322964751

    PubMed  CAS  Google Scholar 

  67. Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T, Martin TJ, Gillespie MT (2001) Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res 16(10):1787–1794. doi:10.1359/jbmr.2001.16.10.1787

    PubMed  CAS  Google Scholar 

  68. Sells Galvin RJ, Gatlin CL, Horn JW, Fuson TR (1999) TGF-beta enhances osteoclast differentiation in hematopoietic cell cultures stimulated with RANKL and M-CSF. Biochem Biophys Res Commun 265(1):233–239. doi:10.1006/bbrc.1999.1632

    PubMed  CAS  Google Scholar 

  69. Balooch G, Balooch M, Nalla RK, Schilling S, Filvaroff EH, Marshall GW, Marshall SJ, Ritchie RO, Derynck R, Alliston T (2005) TGF-beta regulates the mechanical properties and composition of bone matrix. Proc Natl Acad Sci USA 102(52):18813–18818. doi:10.1073/pnas.0507417102

    PubMed  CAS  Google Scholar 

  70. Erlebacher A, Derynck R (1996) Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype. J Cell Biol 132(1–2):195–210

    PubMed  CAS  Google Scholar 

  71. Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DH, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T (2009) Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One 4(4):e5275. doi:10.1371/journal.pone.0005275

    PubMed  Google Scholar 

  72. DaCosta BS, Major C, Laping NJ, Roberts AB (2004) SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 65(3):744–752. doi:10.1124/mol.65.3.744

    Google Scholar 

  73. Inman GJ, Nicolas FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62(1):65–74

    PubMed  CAS  Google Scholar 

  74. Petersen M, Thorikay M, Deckers M, van Dinther M, Grygielko ET, Gellibert F, de Gouville AC, Huet S, ten Dijke P, Laping NJ (2008) Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int 73(6):705–715. doi:10.1038/sj.ki.5002717

    PubMed  CAS  Google Scholar 

  75. Tojo M, Hamashima Y, Hanyu A, Kajimoto T, Saitoh M, Miyazono K, Node M, Imamura T (2005) The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Canc Sci 96(11):791–800. doi:10.1111/j.1349-7006.2005.00103.x

    CAS  Google Scholar 

  76. Eijken M, Swagemakers S, Koedam M, Steenbergen C, Derkx P, Uitterlinden AG, van der Spek PJ, Visser JA, de Jong FH, Pols HA, van Leeuwen JP (2007) The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J 21(11):2949–2960. doi:10.1096/fj.07-8080com

    PubMed  Google Scholar 

  77. Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar R, Pobre E, Grinberg A, Werner ED, Glatt V, Stadmeyer L, Smith D, Seehra J, Bouxsein ML (2008) A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc Natl Acad Sci USA 105(19):7082–7087. doi:10.1073/pnas.0711263105

    PubMed  CAS  Google Scholar 

  78. Edwards JR, Nyman JS, Lwin ST, Moore MM, Esparza J, O’Quinn EC, Hart AJ, Biswas S, Patil CA, Lonning S, Mahadevan-Jansen A, Mundy GR (2010) Inhibition of TGF-beta signaling by 1D11 antibody treatment increases bone mass and quality in vivo. J Bone Miner Res. doi:10.1002/jbmr.139

  79. Kakonen SM, Selander KS, Chirgwin JM, Yin JJ, Burns S, Rankin WA, Grubbs BG, Dallas M, Cui Y, Guise TA (2002) Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem 277(27):24571–24578. doi:10.1074/jbc.M202561200

    PubMed  CAS  Google Scholar 

  80. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, Yoneda T, Mundy GR (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Investig 98(7):1544–1549. doi:10.1172/JCI118947

    PubMed  CAS  Google Scholar 

  81. Clines GA, Guise TA (2005) Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Canc 12(3):549–583. doi:10.1677/erc.1.00543

    CAS  Google Scholar 

  82. Mundy GR, Edwards JR (2008) PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol 19(4):672–675. doi:10.1681/ASN.2007090981

    PubMed  CAS  Google Scholar 

  83. Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, Gillespie MT (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140(10):4451–4458

    PubMed  CAS  Google Scholar 

  84. Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, Bennett RC, Martin TJ (1991) Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Canc Res 51(11):3059–3061

    CAS  Google Scholar 

  85. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, Bennett RC, Martin TJ (1990) Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Canc Res 50(23):7710–7716

    CAS  Google Scholar 

  86. Bundred NJ, Walker RA, Ratcliffe WA, Warwick J, Morrison JM, Ratcliffe JG (1992) Parathyroid hormone related protein and skeletal morbidity in breast cancer. Eur J Canc 28(2–3):690–692

    CAS  Google Scholar 

  87. Kissin MW, Henderson MA, Danks JA, Hayman JA, Bennett RC, Martin TJ (1993) Parathyroid hormone related protein in breast cancers of widely varying prognosis. Eur J Surg Oncol 19(2):134–142

    PubMed  CAS  Google Scholar 

  88. Henderson M, Danks J, Moseley J, Slavin J, Harris T, McKinlay M, Hopper J, Martin T (2001) Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. J Natl Canc Inst 93(3):234–237

    CAS  Google Scholar 

  89. Henderson MA, Danks JA, Slavin JL, Byrnes GB, Choong PF, Spillane JB, Hopper JL, Martin TJ (2006) Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Canc Res 66(4):2250–2256. doi:10.1158/0008-5472.CAN-05-2814

    CAS  Google Scholar 

  90. Kohno N, Kitazawa S, Sakoda Y, Kanbara Y, Furuya Y, Ohashi O, Kitazawa R (1994) Parathyroid hormone-related protein in breast cancer tissues: relationship between primary and metastatic sites. Breast Canc 1(1):43–49

    Google Scholar 

  91. Guise TA (2009) Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases. Gene Dev 23(18):2117–2123. doi:10.1101/gad.1854909

    PubMed  CAS  Google Scholar 

  92. Lu X, Wang Q, Hu G, Van Poznak C, Fleisher M, Reiss M, Massague J, Kang Y (2009) ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Gene Dev 23(16):1882–1894. doi:10.1101/gad.1824809

    PubMed  CAS  Google Scholar 

  93. Dunn LK, Mohammad KS, Fournier PG, McKenna CR, Davis HW, Niewolna M, Peng XH, Chirgwin JM, Guise TA (2009) Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PLoS One 4(9):e6896. doi:10.1371/journal.pone.0006896

    PubMed  Google Scholar 

  94. Kang Y, Massague J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118(3):277–279. doi:10.1016/j.cell.2004.07.011

    PubMed  CAS  Google Scholar 

  95. Deckers M, van Dinther M, Buijs J, Que I, Lowik C, van der Pluijm G, ten Dijke P (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Canc Res 66(4):2202–2209. doi:10.1158/0008-5472.CAN-05-3560

    CAS  Google Scholar 

  96. Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL, Massague J (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 102(39):13909–13914. doi:10.1073/pnas.0506517102

    PubMed  CAS  Google Scholar 

  97. Sethi N, Dai X, Winter CG, Kang Y (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Canc Cell 19(2):192–205. doi:10.1016/j.ccr.2010.12.022

    CAS  Google Scholar 

  98. Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P, van der Pluijm G (2007) TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 24(8):609–617. doi:10.1007/s10585-007-9118-2

    PubMed  CAS  Google Scholar 

  99. Serganova I, Moroz E, Vider J, Gogiberidze G, Moroz M, Pillarsetty N, Doubrovin M, Minn A, Thaler HT, Massague J, Gelovani J, Blasberg R (2009) Multimodality imaging of TGFbeta signaling in breast cancer metastases. FASEB J 23(8):2662–2672. doi:10.1096/fj.08-126920

    PubMed  CAS  Google Scholar 

  100. Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS (2008) Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Canc 8(3):212–226. doi:10.1038/nrc2345

    CAS  Google Scholar 

  101. Bellahcene A, Kroll M, Liebens F, Castronovo V (1996) Bone sialoprotein expression in primary human breast cancer is associated with bone metastases development. J Bone Miner Res 11(5):665–670. doi:10.1002/jbmr.5650110514

    PubMed  CAS  Google Scholar 

  102. Hotte SJ, Winquist EW, Stitt L, Wilson SM, Chambers AF (2002) Plasma osteopontin: associations with survival and metastasis to bone in men with hormone-refractory prostate carcinoma. Cancer 95(3):506–512. doi:10.1002/cncr.10709

    PubMed  CAS  Google Scholar 

  103. Zhang L, Hou X, Lu S, Rao H, Hou J, Luo R, Huang H, Zhao H, Jian H, Chen Z, Liao M, Wang X (2010) Predictive significance of bone sialoprotein and osteopontin for bone metastases in resected Chinese non-small-cell lung cancer patients: a large cohort retrospective study. Lung Canc 67(1):114–119. doi:10.1016/j.lungcan.2009.03.017

    Google Scholar 

  104. Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Canc 4(6):437–447. doi:10.1038/nrc1367

    CAS  Google Scholar 

  105. Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T (2007) Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Canc Res 67(9):4157–4163. doi:10.1158/0008-5472.CAN-06-2355

    CAS  Google Scholar 

  106. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM (2006) Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem 281(34):24171–24181. doi:10.1074/jbc.M604507200

    PubMed  CAS  Google Scholar 

  107. Lu X, Yan CH, Yuan M, Wei Y, Hu G, Kang Y (2010) In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer. Canc Res 70(10):3905–3914. doi:10.1158/0008-5472.CAN-09-3739[doi]

    CAS  Google Scholar 

  108. Buijs JT, Kuijpers CC, van der Pluijm G (2010) Targeted therapy options for treatment of bone metastases; beyond bisphosphonates. Curr Pharm Des 16(27):13

    Google Scholar 

  109. Kelly RJ, Morris JC (2010) Transforming growth factor-beta: a target for cancer therapy. J Immunotoxicol 7(1):15–26. doi:10.3109/15476910903389920

    PubMed  CAS  Google Scholar 

  110. Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V, Arteaga CL (2002) Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Investig 109(12):1551–1559. doi:10.1172/JCI15234

    PubMed  CAS  Google Scholar 

  111. Muraoka-Cook RS, Kurokawa H, Koh Y, Forbes JT, Roebuck LR, Barcellos-Hoff MH, Moody SE, Chodosh LA, Arteaga CL (2004) Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Canc Res 64(24):9002–9011. doi:10.1158/0008-5472.CAN-04-2111

    CAS  Google Scholar 

  112. Arteaga CL, Carty-Dugger T, Moses HL, Hurd SD, Pietenpol JA (1993) Transforming growth factor beta 1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice. Cell Growth Differ 4(3):193–201

    PubMed  CAS  Google Scholar 

  113. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT (1993) Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Investig 92(6):2569–2576. doi:10.1172/JCI116871

    PubMed  CAS  Google Scholar 

  114. Nam JS, Suchar AM, Kang MJ, Stuelten CH, Tang B, Michalowska AM, Fisher LW, Fedarko NS, Jain A, Pinkas J, Lonning S, Wakefield LM (2006) Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer. Canc Res 66(12):6327–6335. doi:10.1158/0008-5472.CAN-06-0068

    CAS  Google Scholar 

  115. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, Laurence A, Michalowska A, Mamura M, Lonning S, Berzofsky JA, Wakefield LM (2008) Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Canc Res 68(10):3915–3923. doi:10.1158/0008-5472.CAN-08-0206

    CAS  Google Scholar 

  116. Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C, Kohn E, Tang B, Sabzevari H, Anver MR, Lawrence S, Danielpour D, Lonning S, Berzofsky JA, Wakefield LM (2008) An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Canc Res 68(10):3835–3843. doi:10.1158/0008-5472.CAN-08-0215

    CAS  Google Scholar 

  117. Biswas S, Wilburn C, Munoz SA, Sterling JA, Lonning S, Mundy GR (2008) Monoclonal antibody to transforming growth factor b inhibits tumor burden and osteolysis in a pre-clinical model of bone metastasis. J Bone Miner Res 23 (SA187)

  118. Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT (2003) Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44(8):3394–3401

    PubMed  Google Scholar 

  119. Thompson JE, Vaughan TJ, Williams AJ, Wilton J, Johnson KS, Bacon L, Green JA, Field R, Ruddock S, Martins M, Pope AR, Tempest PR, Jackson RH (1999) A fully human antibody neutralising biologically active human TGFbeta2 for use in therapy. J Immunol Meth 227(1–2):17–29

    CAS  Google Scholar 

  120. Cordeiro MF, Gay JA, Khaw PT (1999) Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent. Invest Ophthalmol Vis Sci 40(10):2225–2234

    PubMed  CAS  Google Scholar 

  121. Genzyme (2007) Safety study of GC1008 in patients with focal segmental glomerulosclerosis (FSGS) of single doses of GC1008 in patients with treatment resistant idiopathic FSGS. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00464321. Accessed 2010 Aug 23

  122. Genzyme (2006) Safety and efficacy study of GC1008 to treat renal cell carcinoma or malignant melanoma. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00356460. Accessed 2010 Aug 23

  123. Jersey CIoN (2008) Effects of monoclonal antibody GC1008 in blood samples from patients with unresectable locally advanced or metastatic kidney cancer or malignant melanoma treated on clinical trial NCI-06-C-0200. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00899444. Accessed 2010 Aug 23

  124. Morris JC, Shapiro GI, Tan AR, Lawrence DP, Olencki TE, Dezube BJ, Hsu FJ, Reiss M, Berzofsky JA (2008) Phase I/II Study of GC1008: a human anti-transforming growth factor-beta (TGF-β) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC). J Clin Oncol 26(Suppl):9028

    Google Scholar 

  125. Trachtman H, Fervenza FC, Gipson DS, Heering P, Jayne DR, Peters H, Rota S, Remuzzi G, Rump LC, Sellin LK, Heaton JP, Streisand JB, Hard ML, Ledbetter SR, Vincenti F (2011) A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79(11):1236–1243. doi:10.1038/ki.2011.33

    PubMed  CAS  Google Scholar 

  126. Genzyme (2005) Study of GC1008 in patients with idiopathic pulmonary fibrosis (IPF). National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00125385. Accessed 2010 Aug 24

  127. Mancuso P, Shalinsky DR, Calleri A, Quarna J, Antoniotti P, Jilani I, Hu-Lowe D, Jiang X, Gallo-Stampino C, Bertolini F (2009) Evaluation of ALK-1 expression in circulating endothelial cells (CECs) as an exploratory biomarker for PF-03446962 undergoing phase I trial in cancer patients. J Clin Oncol 27:15s:abstr 3573

  128. Pfizer (2007) A first in patient, study of investigational drug PF-03446962 in patients with advanced solid tumors. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00557856. Accessed 2010 Aug 23

  129. Bandyopadhyay A, Zhu Y, Cibull ML, Bao L, Chen C, Sun L (1999) A soluble transforming growth factor beta type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Canc Res 59(19):5041–5046

    CAS  Google Scholar 

  130. Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J, Sun LZ (2002) Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Canc Res 62(16):4690–4695

    CAS  Google Scholar 

  131. Serrati S, Margheri F, Pucci M, Cantelmo AR, Cammarota R, Dotor J, Borras-Cuesta F, Fibbi G, Albini A, Del Rosso M (2009) TGFbeta1 antagonistic peptides inhibit TGFbeta1-dependent angiogenesis. Biochem Pharmacol 77(5):813–825. doi:10.1016/j.bcp.2008.10.036

    PubMed  CAS  Google Scholar 

  132. ISDIN (2007) Efficacy and safety study of p144 to treat skin fibrosis in systemic sclerosis. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00574613. Accessed 2010 Aug 23

  133. Bennett CF, Swayze EE (2010) RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50:259–293. doi:10.1146/annurev.pharmtox.010909.105654

    PubMed  CAS  Google Scholar 

  134. Crooke ST (2004) Progress in antisense technology. Annu Rev Med 55:61–95. doi:10.1146/annurev.med.55.091902.104408

    PubMed  CAS  Google Scholar 

  135. Hau P, Jachimczak P, Schlingensiepen R, Schulmeyer F, Jauch T, Steinbrecher A, Brawanski A, Proescholdt M, Schlaier J, Buchroithner J, Pichler J, Wurm G, Mehdorn M, Strege R, Schuierer G, Villarrubia V, Fellner F, Jansen O, Straube T, Nohria V et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17(2):201–212. doi:10.1089/oli.2006.0053

    PubMed  CAS  Google Scholar 

  136. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, Balasubramaniam A, Nair S, Oliushine V, Parfenov V, Poverennova I, Zaaroor M, Jachimczak P, Ludwig S, Schmaus S, Heinrichs H, Schlingensiepen KH (2011) Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol 13(1):132–142. doi:10.1093/neuonc/noq142

    PubMed  CAS  Google Scholar 

  137. Antisense Pharma (2008) Efficacy and safety of AP 12009 in patients with recurrent or refractory anaplastic astrocytoma (SAPPHIRE). National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00761280. Accessed 2010 Aug 23

  138. Antisense Pharma (2009) Safety and tolerability of AP 12009, administered I.V. in patients with advanced tumors known to overproduce TGF-beta-2. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00844064. Accessed 2010 Aug 23

  139. Schlingensiepen KH (2004) The TGF-β1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: preclinical studies. Abstract #3132. In: Am Soc Clin Oncol Ann Meet

  140. Fakhrai H, Dorigo O, Shawler DL, Lin H, Mercola D, Black KL, Royston I, Sobol RE (1996) Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci USA 93(7):2909–2914

    PubMed  CAS  Google Scholar 

  141. Fakhrai H, Mantil JC, Liu L, Nicholson GL, Murphy-Satter CS, Ruppert J, Shawler DL (2006) Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Canc Gene Ther 13(12):1052–1060. doi:10.1038/sj.cgt.7700975

    CAS  Google Scholar 

  142. Gradalis I (2008) Phase I trial of TGFB2-antisense-GMCSF gene modified autologous tumor cell (TAG) vaccine for advanced cancer (Auto TAG). National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00684294. Accessed 2010 Aug 23

  143. Byfield SD, Roberts AB (2004) Lateral signaling enhances TGF-beta response complexity. Trends Cell Biol 14(3):107–111

    PubMed  Google Scholar 

  144. Fu K, Corbley MJ, Sun L, Friedman JE, Shan F, Papadatos JL, Costa D, Lutterodt F, Sweigard H, Bowes S, Choi M, Boriack-Sjodin PA, Arduini RM, Sun D, Newman MN, Zhang X, Mead JN, Chuaqui CE, Cheung HK, Cornebise M et al (2008) SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model. Arterioscler Thromb Vasc Biol 28(4):665–671. doi:10.1161/ATVBAHA.107.158030

    PubMed  CAS  Google Scholar 

  145. Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, Gaster L, Callahan JF, Olson BA (2002) Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol 62(1):58–64

    PubMed  CAS  Google Scholar 

  146. Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, Ishikawa Y, Nomura K, Yokoo H, Shimizu T, Ogata E, Miyazono K, Shimizu K, Imamura T (2007) Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Canc Sci 98(1):127–133. doi:10.1111/j.1349-7006.2006.00357.x

    CAS  Google Scholar 

  147. Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, Cornell JE, Pollock BH, Mundy GR, Sun LZ (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Canc Res 66(13):6714–6721. doi:10.1158/0008-5472.CAN-05-3565

    CAS  Google Scholar 

  148. Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, Schreiner G, Barnard N, Reiss M (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Canc Res 12(14 Pt 1):4315–4330. doi:10.1158/1078-0432.CCR-06-0162

    CAS  Google Scholar 

  149. Subramanian G, Schwarz RE, Higgins L, McEnroe G, Chakravarty S, Dugar S, Reiss M (2004) Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. Canc Res 64(15):5200–5211. doi:10.1158/0008-5472.CAN-04-0018

    CAS  Google Scholar 

  150. Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R, Liu YW, Platten M, Herrlinger U, Murphy A, Wong DH, Wick W, Higgins LS, Weller M (2004) SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Canc Res 64(21):7954–7961. doi:10.1158/0008-5472.CAN-04-1013

    CAS  Google Scholar 

  151. Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, O’Young G, Quon D, Henson M, Damm DL, Muiru GT, Murphy A, Higgins LS, Chakravarty S, Wong DH (2007) Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol 72(1):152–161. doi:10.1124/mol.106.029025

    PubMed  CAS  Google Scholar 

  152. Fournier PJ, Mohammad KS, McKenna CR, Peng X, Chirgwin JM, Guise TA (2008) TGF-beta blockade inhibits osteolytic metastases but not osteoblastic prostate cancer metastases. #SA274. In: American Society for Bone and Mineral Research 30th annual meeting, Montreal, QC, Canada

  153. Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, Vessella R, Corey E, Padalecki S, Suva L, Chirgwin JM (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Canc Res 12(20 Pt 2):6213s–6216s. doi:10.1158/1078-0432.CCR-06-1007

    CAS  Google Scholar 

  154. Zhang B, Halder SK, Zhang S, Datta PK (2009) Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Canc Lett 277(1):114–120. doi:10.1016/j.canlet.2008.11.035

    CAS  Google Scholar 

  155. Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ (2008) LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Canc Ther 7(4):829–840. doi:10.1158/1535-7163.MCT-07-0337

    CAS  Google Scholar 

  156. Calvo-Aller E, Baselga J, Glatt S, Cleverly A, Lahn M, Arteaga CL, Rothenberg ML, Carducci MA (2008) First human dose escalation study in patients with metastatic malignancies to determine safety and pharmacokinetics of LY2157299, a small molecule inhibitor of the transforming growth factor-beta receptor I kinase. J Clin Oncol 26(15S):14554, abstract

    Google Scholar 

  157. Cui Q, Lim SK, Zhao B, Hoffmann FM (2005) Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP. Oncogene 24(24):3864–3874. doi:10.1038/sj.onc.1208556

    PubMed  CAS  Google Scholar 

  158. Zhao BM, Hoffmann FM (2006) Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol Biol Cell 17(9):3819–3831. doi:10.1091/mbc.E05-10-0990

    PubMed  CAS  Google Scholar 

  159. Chen D, Zhao M, Mundy GR (2004) Bone morphogenetic proteins. Growth Factors 22(4):233–241. doi:10.1080/08977190412331279890

    PubMed  CAS  Google Scholar 

  160. ten Dijke P (2006) Bone morphogenetic protein signal transduction in bone. Curr Med Res Opin 22(Suppl 1):S7–S11. doi:10.1185/030079906X80576

    PubMed  Google Scholar 

  161. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Gene Dev 9(22):2795–2807

    PubMed  CAS  Google Scholar 

  162. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Gene Dev 9(22):2808–2820

    PubMed  CAS  Google Scholar 

  163. Simic P, Vukicevic S (2005) Bone morphogenetic proteins in development and homeostasis of kidney. Cytokine Growth Factor Rev 16(3):299–308. doi:10.1016/j.cytogfr.2005.02.010

    PubMed  CAS  Google Scholar 

  164. Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, Que I, Schwaninger R, Rentsch C, Ten Dijke P, Cleton-Jansen AM, Driouch K, Lidereau R, Bachelier R, Vukicevic S, Clezardin P, Papapoulos SE, Cecchini MG, Lowik CW, van der Pluijm G (2007) Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Canc Res 67(18):8742–8751. doi:10.1158/0008-5472.CAN-06-2490

    CAS  Google Scholar 

  165. Buijs JT, Petersen M, van der Horst G, van der Pluijm G (2010) Bone morphogenetic proteins and its receptors; therapeutic targets in cancer progression and bone metastasis? Curr Pharm Des 16(11):1291–1300

    PubMed  CAS  Google Scholar 

  166. Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R, Henriquez NV, Ten Dijke P, Borovecki F, Markwalder R, Thalmann GN, Papapoulos SE, Pelger RC, Vukicevic S, Cecchini MG, Lowik CW, van der Pluijm G (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171(3):1047–1057. doi:10.2353/ajpath.2007.070168

    PubMed  CAS  Google Scholar 

  167. Gautschi OP, Frey SP, Zellweger R (2007) Bone morphogenetic proteins in clinical applications. ANZ J Surg 77(8):626–631. doi:10.1111/j.1445-2197.2007.04175.x

    PubMed  Google Scholar 

  168. Institute AAMCTCNC (2009) Topical halofuginone hydrobromide in treating patients with HIV-related Kaposi’s sarcoma. National Cancer Institute (NCI). http://clinicaltrials.gov/ct2/show/NCT00064142, 2010 April 25

  169. Juarez P, Chirgwin J, Mohammad KS, Ryan C, Walton H, Niewolna M, Mauviel A, Guise TA (2009) Halofuginone decreases osteolytic bone metastases. #MO0109. J Bone Miner Res 24:S402. doi:10.1002/jbmr.5650241305

  170. Gadir N, Jackson DN, Lee E, Foster DA (2008) Defective TGF-beta signaling sensitizes human cancer cells to rapamycin. Oncogene 27(8):1055–1062. doi:10.1038/sj.onc.1210721

    PubMed  CAS  Google Scholar 

  171. Filyak Y, Filyak O, Stoika R (2007) Transforming growth factor beta-1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line. Cell Biol Int 31(8):851–855. doi:10.1016/j.cellbi.2007.02.008

    PubMed  CAS  Google Scholar 

  172. Taniguchi Y, Kawano K, Minowa T, Sugino T, Shimojo Y, Maitani Y (2010) Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-beta type I receptor inhibitor. Canc Sci 101(10):7. doi:10.1111/j.1349-7006.2010.01646.x

    Google Scholar 

  173. Mohammad KS, Stebbins EG, Kingsley L, Fournier PGJ, Niewolna M, McKenna CR, Peng X, Higgins L, Wong D, Guise TA (2008) Combined transforming growth factor b receptor I kinase inhibitor and biphosphonates are additve to reduce breast cancer bone metastases. J Bone Miner Res 23:F275, Abstract

    Google Scholar 

  174. Won J, Kim H, Park EJ, Hong Y, Kim SJ, Yun Y (1999) Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor beta receptor therapy. Canc Res 59(6):1273–1277

    CAS  Google Scholar 

  175. Dasch JR, Pace DR, Waegell W, Inenaga D, Ellingsworth L (1989) Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. J Immunol 142(5):1536–1541

    PubMed  CAS  Google Scholar 

  176. Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M (2010) Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Canc 9:122. doi:10.1186/1476-4598-9-122

    Google Scholar 

  177. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL (2007) Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Investig 117(5):1305–1313. doi:10.1172/JCI30740

    PubMed  CAS  Google Scholar 

  178. Antisense Pharma (2008) Efficacy and safety of AP 12009 in patients with recurrent or refractory anaplastic astrocytoma (SAPPHIRE). National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00761280. Accessed 2011 Aug 23

  179. Anitisense Pharma (2009) Safety and tolerability of AP 12009, administered I.V. in patients with advanced tumors known to overproduce TGF-beta-2. National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00844064. Accessed 2011 Aug 23

  180. Lee GT, Hong JH, Mueller TJ, Watson JA, Kwak C, Sheen YY, Kim DK, Kim SJ, Kim IY (2008) Effect of IN-1130, a small molecule inhibitor of transforming growth factor-beta type I receptor/activin receptor-like kinase-5, on prostate cancer cells. J Urol 180(6):2660–2667. doi:10.1016/j.juro.2008.08.008

    PubMed  CAS  Google Scholar 

  181. Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Troconiz IF (2008) Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Canc 44(1):142–150. doi:10.1016/j.ejca.2007.10.008

    CAS  Google Scholar 

  182. Peng SB, Yan L, Xia X, Watkins SA, Brooks HB, Beight D, Herron DK, Jones ML, Lampe JW, McMillen WT, Mort N, Sawyer JS, Yingling JM (2005) Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry 44(7):2293–2304. doi:10.1021/bi048851x

    PubMed  CAS  Google Scholar 

  183. Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T Jr, Herron DK, Li HY, McMillen WT, Mort N, Parsons S, Smith EC, Wagner JR, Yan L, Zhang F, Yingling JM (2004) Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 14(13):3581–3584. doi:10.1016/j.bmcl.2004.04.007

    PubMed  CAS  Google Scholar 

  184. Halder SK, Beauchamp RD, Datta PK (2005) A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia 7(5):509–521

    PubMed  CAS  Google Scholar 

  185. Wiercinska E, Naber HP, Pardali E, van der Pluijm G, van Dam H, Ten Dijke P (2010) The TGF-beta/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Canc Res Treat. doi:10.1007/s10549-010-1147-x

  186. Bonniaud P, Margetts PJ, Kolb M, Schroeder JA, Kapoun AM, Damm D, Murphy A, Chakravarty S, Dugar S, Higgins L, Protter AA, Gauldie J (2005) Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med 171(8):889–898. doi:10.1164/rccm.200405-612OC

    PubMed  Google Scholar 

  187. Rausch MP, Hahn T, Ramanathapuram L, Bradley-Dunlop D, Mahadevan D, Mercado-Pimentel ME, Runyan RB, Besselsen DG, Zhang X, Cheung HK, Lee WC, Ling LE, Akporiaye ET (2009) An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer. Anticancer Res 29(6):2099–2109

    PubMed  CAS  Google Scholar 

  188. Suzuki E, Kim S, Cheung HK, Corbley MJ, Zhang X, Sun L, Shan F, Singh J, Lee WC, Albelda SM, Ling LE (2007) A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Canc Res 67(5):2351–2359. doi:10.1158/0008-5472.CAN-06-2389

    CAS  Google Scholar 

  189. Ishida W, Mori Y, Lakos G, Sun L, Shan F, Bowes S, Josiah S, Lee WC, Singh J, Ling LE, Varga J (2006) Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J Invest Dermatol 126(8):1733–1744. doi:10.1038/sj.jid.5700303

    PubMed  CAS  Google Scholar 

  190. Tran TT, Uhl M, Ma JY, Janssen L, Sriram V, Aulwurm S, Kerr I, Lam A, Webb HK, Kapoun AM, Kizer DE, McEnroe G, Hart B, Axon J, Murphy A, Chakravarty S, Dugar S, Protter AA, Higgins LS, Wick W et al (2007) Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model. Neuro Oncol 9(3):259–270. doi:10.1215/15228517-2007-010

    PubMed  CAS  Google Scholar 

  191. Wojtowicz-Praga S, Verma UN, Wakefield L, Esteban JM, Hartmann D, Mazumder A (1996) Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor beta antibody and interleukin-2. J Immunother Emphasis Tumor Immunol 19(3):169–175

    PubMed  CAS  Google Scholar 

  192. Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C, DeVol E, Maples PB, Liu L, Chamberlin T, Shawler DL, Fakhrai H (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24(29):4721–4730. doi:10.1200/JCO.2005.05.5335

    PubMed  CAS  Google Scholar 

  193. Nemunaitis J, Nemunaitis M, Senzer N, Snitz P, Bedell C, Kumar P, Pappen B, Maples PB, Shawler D, Fakhrai H (2009) Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Canc Gene Ther 16(8):620–624. doi:10.1038/cgt.2009.15

    CAS  Google Scholar 

  194. Phase I Trial of TGFB2-Antisense-GMCSF Gene Modified Autologous Tumor Cell (TAG) Vaccine for Advanced Cancer (Auto TAG) (2008) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00684294. Accessed Mar 11, 2011

  195. Gorelik L, Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181

    PubMed  CAS  Google Scholar 

  196. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90(2):770–774

    PubMed  CAS  Google Scholar 

  197. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699. doi:10.1038/359693a0

    PubMed  CAS  Google Scholar 

  198. Yaswen L, Kulkarni AB, Fredrickson T, Mittleman B, Schiffman R, Payne S, Longenecker G, Mozes E, Karlsson S (1996) Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse. Blood 87(4):1439–1445

    PubMed  CAS  Google Scholar 

  199. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851. doi:10.1126/science.1090922

    PubMed  CAS  Google Scholar 

  200. Cheng N, Chytil A, Shyr Y, Joly A, Moses HL (2008) Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion. Mol Canc Res 6(10):1521–1533. doi:10.1158/1541-7786.MCR-07-2203

    CAS  Google Scholar 

  201. Prud’homme GJ (2007) Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Investig 87(11):1077–1091. doi:10.1038/labinvest.3700669

    PubMed  Google Scholar 

  202. Klopcic B, Maass T, Meyer E, Lehr HA, Metzger D, Chambon P, Mann A, Blessing M (2007) TGF-beta superfamily signaling is essential for tooth and hair morphogenesis and differentiation. Eur J Cell Biol 86(11–12):781–799. doi:10.1016/j.ejcb.2007.03.005

    PubMed  CAS  Google Scholar 

  203. Ruzek MC, Hawes M, Pratt B, McPherson J, Ledbetter S, Richards SM, Garman RD (2003) Minimal effects on immune parameters following chronic anti-TGF-beta monoclonal antibody administration to normal mice. Immunopharmacol Immunotoxicol 25(2):235–257

    PubMed  CAS  Google Scholar 

  204. Siriwardena D, Khaw PT, King AJ, Donaldson ML, Overton BM, Migdal C, Cordeiro MF (2002) Human antitransforming growth factor beta(2) monoclonal antibody–a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study. Ophthalmology 109(3):427–431

    PubMed  Google Scholar 

  205. Liu Z, Kobayashi K, van Dinther M, van Heiningen SH, Valdimarsdottir G, van Laar T, Scharpfenecker M, Lowik CW, Goumans MJ, Ten Dijke P, Pardali E (2009) VEGF and inhibitors of TGFbeta type-I receptor kinase synergistically promote blood-vessel formation by inducing alpha5-integrin expression. J Cell Sci 122(Pt 18):3294–3302. doi:10.1242/jcs.048942

    PubMed  CAS  Google Scholar 

  206. Watabe T, Nishihara A, Mishima K, Yamashita J, Shimizu K, Miyazawa K, Nishikawa S, Miyazono K (2003) TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells. J Cell Biol 163(6):1303–1311. doi:10.1083/jcb.200305147

    PubMed  CAS  Google Scholar 

  207. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P (2006) Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 17(1–2):129–139. doi:10.1016/j.cytogfr.2005.09.002

    PubMed  CAS  Google Scholar 

  208. Bonafoux D, Lee WC (2009) Strategies for TGF-beta modulation: a review of recent patents. Expert Opin Ther Pat 19(12):1759–1769. doi:10.1517/13543770903397400

    PubMed  CAS  Google Scholar 

  209. Hengst V, Oussoren C, Kissel T, Storm G (2007) Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro. Int J Pharm 331(2):224–227. doi:10.1016/j.ijpharm.2006.11.024

    PubMed  CAS  Google Scholar 

  210. Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G, Ten Dijke P (2010) Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene 29(9):1351–1361. doi:10.1038/onc.2009.426

    PubMed  CAS  Google Scholar 

  211. Dalal BI, Keown PA, Greenberg AH (1993) Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am J Pathol 143(2):381–389

    PubMed  CAS  Google Scholar 

  212. Shinto O, Yashiro M, Toyokawa T, Nishii T, Kaizaki R, Matsuzaki T, Noda S, Kubo N, Tanaka H, Doi Y, Ohira M, Muguruma K, Sawada T, Hirakawa K (2010) Phosphorylated smad2 in advanced stage gastric carcinoma. BMC Canc 10:652. doi:10.1186/1471-2407-10-652

    CAS  Google Scholar 

  213. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massague J (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1):66–77. doi:10.1016/j.cell.2008.01.046

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01CA69158, R01DK067333, R01DK065837 and U01CA143057; the Mary Kay Ash Foundation, the V-Foundation, the Jerry W. and Peggy S. Throgmartin Endowment of Indiana University and the Indiana Economic Development Fund (to T.A.G.), Department of Defense - Prostate Cancer Research Program 2010 – Prostate Cancer Training Award (to J.B. and T.A.G.) as well as a grant from the Susan Komen Foundation (T.A.G.).

Potential Conflict of Interests

T.A.G.: Consultant for AMGEN, ROCHE and Novartis. Stock ownership of AMGEN.

J.T.B and K.R.S.: no potential conflict of interests.

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  1. Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, 980 West Walnut Street, Walther Hall R3, #C132, Indianapolis, IN, USA

    Jeroen T. Buijs, Keith R. Stayrook & Theresa A. Guise

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Buijs, J.T., Stayrook, K.R. & Guise, T.A. TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases. Cancer Microenvironment 4, 261–281 (2011). https://doi.org/10.1007/s12307-011-0075-6

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