Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors
Abstract
Aberrant signaling by transforming growth factor-β (TGF-β) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-β signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-β signaling via ALK5 plays a critical role in maintaining heart valve integrity.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Initial dose escalation studies of galunisertib or other TβRI kinase inhibitors mandated monitoring for cardiotoxicity due to heart valve dysplasia that was observed in rats and dogs receiving high doses of drug.
“Initial dose escalation studies of galunisertib or other TβRI kinase inhibitors mandated monitoring for cardiotoxicity due to heart valve dysplasia that was observed in rats and dogs receiving high doses of drug340,341.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [341]
Cites
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Shi, Y., & Massagué, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00432-x · Cited by 5,860 · see citing works
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907 · see citing works
A small molecule–kinase interaction map for clinical kinase inhibitors
Fabian, M. A., Biggs, W., Treiber, D. K., Atteridge, C. E., Azimioara, M. D., Benedetti, M. G., Carter, T. A., Ciceri, P., Edeen, P. T., Floyd, M. B., et al. (2005) · Nature Biotechnology · doi:10.1038/nbt1068 · Cited by 1,901 · see citing works
Valvular heart disease associated with fenfluramine-phentermine
Connolly, H. M., Crary, J. L., McGoon, M. D., Hensrud, D. D., Edwards, B. S., Edwards, W. D., & Schaff, H. V. (1997) · New England Journal of Medicine · doi:10.1056/nejm199708283370901 · Cited by 1,632 · see citing works
Sanford, L. P., Ormsby, I., Groot, A. C. G.-D., Sariola, H., Friedman, R., Boivin, G. P., Cardell, E. L., & Doetschman, T. (1997) · Development · doi:10.1242/dev.124.13.2659 · Cited by 1,447 · see citing works
TGFβ: the molecular Jekyll and Hyde of cancer
Bierie, B., & Moses, H. L. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1926 · Cited by 1,262 · see citing works
Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease
Zanettini, R., Antonini, A., Gatto, G., Gentile, R., Tesei, S., & Pezzoli, G. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa054830 · Cited by 882 · see citing works
Physiological Actions and Clinical Applications of Transforming Growth Factor-β (TGF-β)
Roberts, A. B., & Sporn, M. B. (1993) · Growth Factors · doi:10.3109/08977199309029129 · Cited by 755 · see citing works
Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation
Schade, R., Andersohn, F., Suissa, S., Haverkamp, W., & Garbe, E. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa062222 · Cited by 714 · see citing works
Verrecchia, F., & Mauviel, A. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2002.01641.x · Cited by 669 · see citing works
Role of transforming growth factor-β superfamily signaling pathways in human disease
Gordon, K. J., & Blobe, G. C. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.01.006 · Cited by 644 · see citing works
TGF-β signaling in vascular biology and dysfunction
Goumans, M., Liu, Z., & ten Dijke, P. (2008) · Cell Research · doi:10.1038/cr.2008.326 · Cited by 606 · see citing works
Abnormal angiogenesis but intact hematopoietic potential in TGF‐β type I receptor‐deficient mice
Larsson, J., Goumans, M., Sjöstrand, L. J., van Rooijen, M. A., Ward, D., Levéen, P., Xu, X., ten Dijke, P., Mummery, C. L., & Karlsson, S. (2001) · The EMBO Journal · doi:10.1093/emboj/20.7.1663 · Cited by 563 · see citing works
Serra, R. A., Johnson, M. D., Filvaroff, E. H., LaBorde, J. B., Sheehan, D. M., Derynck, R., & Moses, H. L. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.2.541 · Cited by 476 · see citing works
Regulation of cell proliferation by Smad proteins
ten Dijke, P., Goumans, M., Itoh, F., & Itoh, S. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10066 · Cited by 450 · see citing works
Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine
Fitzgerald, L. W., Burn, T. C., Brown, B. S., Patterson, J. P., Corjay, M. H., Valentine, P. A., Sun, J., Link, J. R., Abbaszade, I. G., Hollis, J. M., et al. (2000) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)26444-0 · Cited by 440 · see citing works
Schoen, F. J. (2008) · Circulation · doi:10.1161/circulationaha.108.805911 · Cited by 421 · see citing works
Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Jing, Y., Almirez, R. G., Mangadu, R., Liu, Y.-W., Platten, M., Herrlinger, U., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1013 · Cited by 414 · see citing works
Valvular Myofibroblast Activation by Transforming Growth Factor-β
Walker, G. A., Masters, K. S. B., Shah, D. N., Anseth, K. S., & Leinwand, L. A. (2004) · Circulation Research · doi:10.1161/01.res.0000136520.07995.aa · Cited by 397 · see citing works
The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb
Yi, S. E., Daluiski, A., Pederson, R., Rosen, V., & Lyons, K. M. (2000) · Development · doi:10.1242/dev.127.3.621 · Cited by 384 · see citing works
TGF‐β signaling: A tale of two responses
Rahimi, R. A., & Leof, E. B. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21501 · Cited by 371 · see citing works
ten Dijke, P., Ichijo, H., Franzèn, P., Schulz, P. J., Saras, J., Toyoshima, H., Heldin, C., & Miyazono, K. (1993) · PubMed · Cited by 351 · see citing works
Carabello, B. A., & Crawford, F. A. (1997) · New England Journal of Medicine · doi:10.1056/nejm199707033370107 · Cited by 301 · see citing works
Transforming Growth Factor-β Signal Transduction in Angiogenesis and Vascular Disorders
Bertolino, P., Deckers, M. M. L., Lebrin, F., & ten Dijke, P. (2005) · CHEST Journal · doi:10.1378/chest.128.6_suppl.585s · Cited by 264 · see citing works
Patterson, G. I., & Padgett, R. W. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(99)01916-2 · Cited by 251 · see citing works
Grygielko, E. T., Martin, W. M., Tweed, C. W., Thornton, P., Harling, J. D., Brooks, D. P., & Laping, N. J. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.082099 · Cited by 193 · see citing works
TGF-β, Smad3 and the process of progressive fibrosis
Gauldie, J., Bonniaud, P., Sime, P. J., Ask, K., & Kolb, M. R. J. (2007) · Biochemical Society Transactions · doi:10.1042/bst0350661 · Cited by 182 · see citing works
Cell biology of valvular interstitial cells.
Mulholland, M. D. L., & Gotlieb, A. I. (1996) · PubMed · Cited by 181 · see citing works
Liu, I. M., Schilling, S. H., Knouse, K. A., Choy, L., Derynck, R., & Wang, X. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.266 · Cited by 174 · see citing works
Signaling via the Tgf-β type I receptor Alk5 in heart development
Sridurongrit, S., Larsson, J., Schwartz, R. J., Ruiz‐Lozano, P., & Kaartinen, V. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.07.038 · Cited by 158 · see citing works
Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart
Wang, J., Sridurongrit, S., Dudáš, M., Thomas, P. S., Nagy, A. R., Schneider, M. D., Epstein, J. A., & Kaartinen, V. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.07.035 · Cited by 158 · see citing works
Gaussin, V., Morley, G. E., Cox, L., Zwijsen, A., Vance, K. M., Emile, L., Tian, Y., Liu, J., Hong, C., Myers, D. C., et al. (2005) · Circulation Research · doi:10.1161/01.res.0000177862.85474.63 · Cited by 142 · see citing works
Drug-induced Valvulopathy: An Update
Elangbam, C. S. (2010) · Toxicologic Pathology · doi:10.1177/0192623310378027 · Cited by 133 · see citing works
TGF-β signaling in vascular biology and dysfunction
Marie-Jose, Goumans, M., Zhen, Liu, Peter, P., ten, & Dijke (2009) · Acta Scientiarum Naturalium Universitatis Sunyatseni · Cited by 116 · see citing works
Suzuki, E., Kim, S., Cheung, H.-K., Corbley, M. J., Zhang, X., Sun, L., Shan, F., Singh, J., Lee, W.-C., Albelda, S. M., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2389 · Cited by 113 · see citing works
Elangbam, C. S., Job, L. E., Zadrozny, L. M., Barton, J. C., Yoon, L. W., Gates, L. D., & Slocum, N. (2008) · Experimental and Toxicologic Pathology · doi:10.1016/j.etp.2008.03.005 · Cited by 110 · see citing works
Seki, T., Hong, K., & Oh, S. P. (2005) · Laboratory Investigation · doi:10.1038/labinvest.3700376 · Cited by 108 · see citing works
Gellibert, F. J., de Gouville, A., Woolven, J. M., Mathews, N., Nguyen, V.-L., Ruault, C., Patikis, A. N., Grygielko, E. T., Laping, N. J., & Huet, S. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0509905 · Cited by 107 · see citing works
Liu, C. A., & Gotlieb, A. I. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.080365 · Cited by 104 · see citing works
Dominant-Negative ALK2 Allele Associates With Congenital Heart Defects
Smith, K., Joziasse, I. C., Chocron, S., van Dinther, M., Guryev, V., Verhoeven, M. C., Rehmann, H., van der Smagt, J. J., Doevendans, P. A., Cuppen, E. P. J. G., et al. (2009) · Circulation · doi:10.1161/circulationaha.108.843714 · Cited by 103 · see citing works
Wallenborn, P. A. (1960) · The Laryngoscope · doi:10.1288/00005537-196001000-00001 · Cited by 94 · see citing works
TGF-β inhibitors for the treatment of cancer
Lahn, M. M. F., Kloeker, S., & Berry, B. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.6.629 · Cited by 83 · see citing works
Essential functions of Alk3 during AV cushion morphogenesis in mouse embryonic hearts
Song, L., Fässler, R., Mishina, Y. M., Jiao, K., & Baldwin, H. S. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.004 · Cited by 83 · see citing works
Endoglin and Alk5 regulate epithelial–mesenchymal transformation during cardiac valve formation
Mercado-Pimentel, M. E., Hubbard, A. D., & Runyan, R. B. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.12.038 · Cited by 75 · see citing works
Li, H., McMillen, W. T., Heap, C. R., McCann, D., Yan, L., Campbell, R. M., Mundla, S. R., King, C.-H. R., Dierks, E. A., Anderson, B. D., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701199p · Cited by 68 · see citing works
Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation.
Lai, Y.-T., Beason, K., Brames, G. P., Desgrosellier, J. S., Clegett, M. C., Shaw, M. V., Brown, C. B., & Barnett, J. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9698 · Cited by 64 · see citing works
Donnelly, K. B. (2008) · Toxicologic Pathology · doi:10.1177/0192623307312707 · Cited by 51 · see citing works
Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats
Frazier, K. S., Thomas, R. A., Scicchitano, M. S., Mirabile, R. C., Boyce, R. W., Zimmerman, D. M., Grygielko, E. T., Nold, J. B., DeGouville, A.-C., Huet, S., et al. (2007) · Toxicologic Pathology · doi:10.1080/01926230701198469 · Cited by 49 · see citing works
HAUCK, A. J., Edwards, W. D., Danielson, G. K., Mullany, C. J., & Bresnahan, D. R. (1990) · PubMed · Cited by 45 · see citing works
Goldberg, F. W., Ward, R. A., Powell, S. J., Debreczeni, J. E., Norman, R. A., Roberts, N. J., Dishington, A. P., Gingell, H., Wickson, K. F., & Roberts, A. L. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900807w · Cited by 45 · see citing works
Self-citationLeask, A. (2010) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-3-8 · Cited by 44 · see citing works
Karlsson, G., Liu, Y., Larsson, J. T., Goumans, M., Lee, J., Thorgeirsson, S. S., Ringnér, M., & Karlsson, S. (2005) · Physiological Genomics · doi:10.1152/physiolgenomics.00303.2004 · Cited by 37 · see citing works
ALK5 inhibition in renal disease
Laping, N. J. (2003) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(03)00002-x · Cited by 30 · see citing works
Inhibition of ALK5 as a New Approach to Treat Liver Fibrotic Diseases
de Gouville, A., & Huet, S. (2006) · Drug News & Perspectives · doi:10.1358/dnp.2006.19.2.977444 · Cited by 30 · see citing works
Elangbam, C. S., Wehe, J. G., Barton, J. C., Krull, D., Nyska, A., Crabbs, T. A., & Kissling, G. E. (2006) · Experimental and Toxicologic Pathology · doi:10.1016/j.etp.2006.08.001 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Transforming Growth Factor-β Signaling in Immunity and Cancer
Batlle, E., & Massagué, J. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.024 · Cited by 2,366 · see citing works
Targeting the TGFβ signalling pathway in disease
Akhurst, R. J., & Hata, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3810 · Cited by 1,466 · see citing works
Targeting TGF-β Signaling in Cancer
Colak, S., & ten Dijke, P. (2017) · Trends in cancer · doi:10.1016/j.trecan.2016.11.008 · Cited by 1,003 · see citing works
TGFβ biology in cancer progression and immunotherapy
Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer
Du, B., & Shim, J. S. (2016) · Molecules · doi:10.3390/molecules21070965 · Cited by 810 · see citing works
Navigating CAR-T cells through the solid-tumour microenvironment
Hou, A. J., Chen, L. C., & Chen, Y. Y. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00189-2 · Cited by 556 · see citing works
Lahn, M. M. F., Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T., Cleverly, A., Desaiah, D., Guba, S. C., et al. (2015) · Drug Design Development and Therapy · doi:10.2147/dddt.s86621 · Cited by 558 · see citing works
Lan, Y., Zhang, D., Xu, C., Hance, K. W., Marelli, B., Qi, J., Yu, H., Qin, G., Sircar, A., Hernández, V. M., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan5488 · Cited by 494 · see citing works
Big opportunities for small molecules in immuno-oncology
Adams, J. L., Smothers, J. F., Srinivasan, R., & Hoos, A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4596 · Cited by 481 · see citing works
Jackstadt, R., van Hooff, S. R., Leach, J. D. G., Cortés-Lavaud, X., Lohuis, J. O., Ridgway, R. A., Wouters, V. M., Roper, J., Kendall, T. J., Roxburgh, C. S. D., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.08.003 · Cited by 427 · see citing works
Overcoming TGFβ-mediated immune evasion in cancer
Tauriello, D. V. F., Sancho, E., & Batlle, E. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00413-6 · Cited by 377 · see citing works
TGF-β Signaling in Control of Cardiovascular Function
Goumans, M.-J., & ten Dijke, P. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022210 · Cited by 360 · see citing works
Transforming growth factor-β in myocardial disease
Frangogiannis, N. G. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00646-w · Cited by 348 · see citing works
Epithelial–mesenchymal transition: a new target in anticancer drug discovery
Marcucci, F., Stassi, G., & Maria, R. D. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.13 · Cited by 340 · see citing works
The fibrosis-cell death axis in heart failure
Piek, A., de Boer, R. A., & Silljé, H. H. W. (2016) · Heart Failure Reviews · doi:10.1007/s10741-016-9536-9 · Cited by 304 · see citing works
TGF ‐β as a driver of fibrosis: physiological roles and therapeutic opportunities
Budi, E. H., Schaub, J. R., Decaris, M. L., Turner, S., & Derynck, R. (2021) · The Journal of Pathology · doi:10.1002/path.5680 · Cited by 300 · see citing works
Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261 · see citing works
“Long-term therapy using TGF inhibition raises potential concerns such as carcinogenesis, autoimmunity, or cardiac valvulopathies (47).”
InfluentialClinical development of therapies targeting TGFβ: current knowledge and future perspectives
Ciardiello, D., Élez, E., Tabernero, J. M., & Seoane, J. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.07.009 · Cited by 270 · see citing works
Zhao, Y., Cao, J., Melamed, A., Worley, M. J., Gockley, A. A., Jones, D., Nia, H. T., Zhang, Y., Stylianopoulos, T., Kumar, A. S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818357116 · Cited by 262 · see citing works
Targeting TGF-β Signaling for Therapeutic GainPreprint
Akhurst, R. J. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022301 · Cited by 243 · see citing works
Rodon, J. A., Carducci, M. A., Sepúlveda-Sánchez, J. M., Azaro, A., Calvo, E., Seoane, J., Braña, I., Sicart, E., Gueorguieva, I., Cleverly, A., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1380 · Cited by 235 · see citing works
Martin, C. J., Datta, A., Littlefield, C., Kalra, A., Chapron, C., Wawersik, S., Dagbay, K. B., Brueckner, C. T., Nikiforov, A., Danehy, F. T., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay8456 · Cited by 224 · see citing works
Teixeira, A. F., ten Dijke, P., & Zhu, H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00605 · Cited by 210 · see citing works
Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF
Mercer, P. F., Woodcock, H. V., Eley, J. D., Platé, M., Sulikowski, M. G., Durrenberger, P. F., Franklin, L., Nanthakumar, C. B., Man, Y., Genovese, F., et al. (2016) · Thorax · doi:10.1136/thoraxjnl-2015-207429 · Cited by 206 · see citing works
Dissecting fibrosis: therapeutic insights from the small-molecule toolbox
Nanthakumar, C. B., Hatley, R. J. D., Lemma, S., Gauldie, J., Marshall, R. P., & Macdonald, S. J. F. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4592 · Cited by 206 · see citing works
Current and upcoming therapies to modulate skin scarring and fibrosis.
Coentro, J. Q., Pugliese, E., Hanley, G., Raghunath, M., & Zeugolis, D. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.08.009 · Cited by 184 · see citing works
TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer
Gough, N. R., Xiang, X., & Mishra, L. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.04.064 · Cited by 204 · see citing works
Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?
Sweeney, M., Corden, B., & Cook, S. A. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201910865 · Cited by 195 · see citing works
Molecular and Cellular Aspects of Calcific Aortic Valve Disease
Towler, D. A. (2013) · Circulation Research · doi:10.1161/circresaha.113.300155 · Cited by 193 · see citing works
Targeting transforming growth factor-β receptors in pulmonary hypertension
Guignabert, C., & Humbert, M. J. C. (2020) · European Respiratory Journal · doi:10.1183/13993003.02341-2020 · Cited by 192 · see citing works
Mastikhina, O., Moon, B., Williams, K., Hatkar, R., Gustafson, D., Mourad, O., Sun, X., Koo, M., Lam, A. Y. L., Sun, Y., et al. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119741 · Cited by 190 · see citing works
Yingling, J. M., McMillen, W. T., Yan, L., Huang, H., Sawyer, J. S., Graff, J., Clawson, D. K., Britt, K. S., Anderson, B. D., Beight, D. W., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.23795 · Cited by 187 · see citing works
Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis
Wei, Y., Kim, T. J., Peng, D. H., Duan, D., Gibbons, D. L., Yamauchi, M., Jackson, J., Saux, C. J. L., Calhoun, C., Peters, J. I., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci94624 · Cited by 185 · see citing works
TGF-β-induced fibrosis: A review on the underlying mechanism and potential therapeutic strategies
Ong, C. H., Tham, C. L., Harith, H. H., Firdaus, N., & Israf, D. A. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174510 · Cited by 189 · see citing works
Zeng, X., Liao, G., Li, S., Liu, H., Zhao, X. H., Li, S., Lei, K., Zhu, S., Chen, Z., Zhao, Y., et al. (2022) · Hepatology · doi:10.1002/hep.32585 · Cited by 183 · see citing works
Therapeutic implications of cancer epithelial-mesenchymal transition (EMT)
Cho, E. S., Kang, H. E., Kim, N. H., & Yook, J. I. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-018-01108-7 · Cited by 179 · see citing works
Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment
Gulley, J. L., Schlom, J., Barcellos‐Hoff, M. H., Wang, X., Seoane, J., Audhuy, F., Lan, Y., Dussault, I., & Moustakas, A. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13146 · Cited by 178 · see citing works
A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment
Huynh, L., Hipolito, C. J., & ten Dijke, P. (2019) · Biomolecules · doi:10.3390/biom9110743 · Cited by 172 · see citing works
Jin, C. H., Krishnaiah, M., Sreenu, D., Subrahmanyam, V. B., Rao, K. S., Lee, H. J., Park, S., Park, H., Lee, K., Sheen, Y. Y., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500115w · Cited by 168 · see citing works
Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor
Mohedas, A. H., Xing, X., Armstrong, K. A., Bullock, A. N., Cuny, G. D., & Yu, P. B. (2013) · ACS Chemical Biology · doi:10.1021/cb300655w · Cited by 164 · see citing works
Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling
Parichatikanond, W., Luangmonkong, T., Mangmool, S., & Kurose, H. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00034 · Cited by 151 · see citing works
Stüber, T. N., Monjezi, R., Wallstabe, L., Kühnemundt, J., Nietzer, S., Dandekar, G., Wöckel, A., Einsele, H., Wischhusen, J., & Hudecek, M. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000676 · Cited by 146 · see citing works
Zheng, Y., Tang, L., Mabardi, L., Kumari, S., & Irvine, D. J. (2017) · ACS Nano · doi:10.1021/acsnano.7b00078 · Cited by 145 · see citing works
A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension
Yung, L., Nikolić, I., Paskin-Flerlage, S. D., Pearsall, R. S., Kumar, R., & Yu, P. B. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201510-1955oc · Cited by 144 · see citing works
Intracellular and extracellular TGF-β signaling in cancer: some recent topics
Miyazono, K., Katsuno, Y., Koinuma, D., Ehata, S., & Morikawa, M. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0646-8 · Cited by 141 · see citing works
TGFβ control of immune responses in cancer: a holistic immuno-oncology perspective
Nixon, B. G., Gao, S., Wang, X., & Li, M. O. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00796-z · Cited by 138 · see citing works
TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis
Sun, T., Huang, Z., Liang, W.-C., Yin, J., Lin, W. Y., Wu, J., Vernes, J.-M., Lutman, J., Caplazi, P., Jeet, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe0407 · Cited by 134 · see citing works
Targeting immunosuppression by TGF-β1 for cancer immunotherapy
de Streel, G., & Lucas, S. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114697 · Cited by 129 · see citing works
Lee, T.-H., Yeh, C., Lee, Y.-T., Shih, Y.-C., Chen, Y.-T., Hung, C., You, M.-Y., Wu, P., Shentu, T., Huang, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18047-x · Cited by 127 · see citing works
Archer, C. R., Sargeant, R., Basak, J., Pilling, J. E., Barnes, J. R., & Pointon, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-28393-y · Cited by 126 · see citing works
Mechanisms of Normal Tissue Injury From Irradiation
Citrin, D. E., & Mitchell, J. B. (2017) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2017.04.001 · Cited by 125 · see citing works
TGFβ, smooth muscle cells and coronary artery disease: a review
Low, E. L., Baker, A. H., & Bradshaw, A. C. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.09.004 · Cited by 122 · see citing works
Liu, N., Feng, J., Lu, X., Yao, Z., Liu, Q. H., Lv, Y., Han, Y., Deng, J., & Zhou, Y. (2019) · Mediators of Inflammation · doi:10.1155/2019/6175091 · Cited by 121 · see citing works
Takasaka, N., Seed, R. I., Cormier, A., Bondesson, A. J., Lou, J., Elattma, A., Ito, S., Yanagisawa, H., Hashimoto, M., Ma, R., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.122591 · Cited by 119 · see citing works
Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment
Hanks, B. A., Holtzhausen, A., Evans, K. S., Jamieson, R., Gimpel, P., Campbell, O. M., Hector-Greene, M., Sun, L., Tewari, A. K., George, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65745 · Cited by 120 · see citing works
Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators
Weinmann, H. (2016) · ChemMedChem · doi:10.1002/cmdc.201500566 · Cited by 122 · see citing works
Roles of TGF-β signaling pathway in tumor microenvirionment and cancer therapy
Zhao, H., Wei, J., & Sun, J. M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107101 · Cited by 117 · see citing works
Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
Shen, Y., Lu, C., Song, Z., Qiao, C., Wang, J., Chen, J., Zhang, C., Zeng, X., Ma, Z., Chen, T., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31141-6 · Cited by 121 · see citing works
Therapeutic potential of tumor-associated neutrophils: dual role and phenotypic plasticity
Zhou, Y., Shen, G., Zhou, X., & Li, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02242-7 · Cited by 116 · see citing works
Chen, Y., Jhao, P.-Y., Hung, C., Wu, Y., Lin, S., Chiang, W., Lin, S., & Yang, K. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143645 · Cited by 114 · see citing works
Engebretsen, K. V. T., Skårdal, K., Bjørnstad, S., Marstein, H. S., Skrbic, B., Sjaastad, I., Christensen, G., Bjørnstad, J. L., & Tønnessen, T. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.08.008 · Cited by 110 · see citing works
Kovacs, R. J., Maldonado, G., Azaro, A., Fernández, M. S., Romero, F. L., Sepulveda-Sánchez, J. M., Corretti, M., Carducci, M., Dolan, M., Gueorguieva, I., et al. (2015) · Cardiovascular Toxicology · doi:10.1007/s12012-014-9297-4 · Cited by 108 · see citing works
Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse
Berridge, B. R., Mowat, V., Nagai, H., Nyska, A., Okazaki, Y., Clements, P., Rinke, M., Snyder, P. W., Boyle, M. C., & Wells, M. Y. (2016) · Journal of Toxicologic Pathology · doi:10.1293/tox.29.3s-1 · Cited by 106 · see citing works
Fujiwara, Y., Nokihara, H., Yamada, Y., Yamamoto, N., Sunami, K., Utsumi, H., Asou, H., Takahashi, O., Ogasawara, K., Gueorguieva, I., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2895-4 · Cited by 101 · see citing works
Mitra, M. S., Lancaster, K., Adedeji, A. O., Palanisamy, G. S., Dave, R. A., Zhong, F., Holdren, M. S., Turley, S. J., Liang, W., Wu, Y., et al. (2020) · Toxicological Sciences · doi:10.1093/toxsci/kfaa024 · Cited by 101 · see citing works
Transforming growth factor β and its role in heart disease
Liu, G., Ma, C., Yang, H., & Zhang, P.-Y. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4246 · Cited by 97 · see citing works
Immunotherapy for advanced hepatocellular carcinoma, where are we?
Li, Z., Ding, J., Li, H., Wang, Z., & Wu, J. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188441 · Cited by 94 · see citing works
Ariazi, J. L., Duffy, K. J., Adams, D. F., Fitch, D. M., Luo, L., Pappalardi, M. B., Biju, M. P., DiFilippo, E. H., Shaw, T., Wiggall, K., et al. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.242503 · Cited by 93 · see citing works
Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease
Minagawa, S., Lou, J., Seed, R. I., Cormier, A., Wu, S., Cheng, Y., Murray, L., Tsui, P., Connor, J., Herbst, R., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008074 · Cited by 90 · see citing works
Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges
Wu, B., Sodji, Q. H., & Oyelere, A. K. (2022) · Cancers · doi:10.3390/cancers14030552 · Cited by 90 · see citing works
Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles
Yang, Y.-S. S., Moynihan, K. D., Bekdemir, A., Dichwalkar, T., Noh, M. M., Watson, N., Melo, M. B., Ingram, J. R., Suh, H., Ploegh, H. L., et al. (2018) · Biomaterials Science · doi:10.1039/c8bm01208c · Cited by 86 · see citing works
Transforming growth factor-β receptors: versatile mechanisms of ligand activation
Chia, Z. J., Cao, Y.-N., Little, P. J., & Kamato, D. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01235-6 · Cited by 92 · see citing works
TGFβ signaling pathways in human health and disease
Chen, P., Qin, L., & Simons, M. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1113061 · Cited by 84 · see citing works
TGF-β signaling networks in the tumor microenvironment
Chan, M. K.-K., Chung, J. Y.-F., Tang, P. C.-T., Chan, A. S.-W., Ho, J. Y.-Y., Lin, T. P.-T., Chen, J., Leung, K.-T., To, K.-F., Lan, H.-Y., et al. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215925 · Cited by 90 · see citing works
Cross, M. J., Berridge, B. R., Clements, P., Cove-Smith, L., Force, T. L., Hoffmann, P., Holbrook, M., Lyon, A. R., Mellor, H. R., Norris, A. A., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12979 · Cited by 81 · see citing works
Self-citationTGFβ signaling networks in ovarian cancer progression and plasticity
Kumari, A., Shonibare, Z., Monavarian, M., Arend, R. C., Lee, N. Y., Inman, G. J., & Mythreye, K. (2021) · Clinical & Experimental Metastasis · doi:10.1007/s10585-021-10077-z · Cited by 76 · see citing works
Gueorguieva, I., Cleverly, A., Stauber, A. J., Pillay, N. S., Rodon, J. A., Miles, C., Yingling, J. M., & Lahn, M. M. F. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12256 · Cited by 77 · see citing works
Li, N., Rodriguez, J. L., Yin, Y., Logun, M. T., Zhang, L., Yu, S., Hicks, K., Zhang, J. V., Zhang, L., Xie, C., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.07.020 · Cited by 74 · see citing works
Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression
van den Bulk, J., de Miranda, N. F. C. C., & ten Dijke, P. (2021) · Clinical Science · doi:10.1042/cs20201236 · Cited by 75 · see citing works
Hou, A. J., Shih, R. M., Uy, B. R., Shafer, A. M., Chang, Z. L., Comin-Anduix, B., Güemes, M., Galić, Z., Phyu, S. M., Okada, H., et al. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae126 · Cited by 77 · see citing works
Li, T., Zhao, N., Lu, J., Zhu, Q., Liu, X., Hao, F., & Jiao, X. (2019) · Bioengineered · doi:10.1080/21655979.2019.1632669 · Cited by 71 · see citing works
Bhatia, S., Monkman, J. H., Toh, A. K. L., Nagaraj, S. H., & Thompson, E. W. (2017) · Biochemical Journal · doi:10.1042/bcj20160782 · Cited by 73 · see citing works
Scioli, M. G., Storti, G., D’Amico, F., Gentile, P., Fabbri, G., Cervelli, V., & Orlandi, A. (2019) · Cancers · doi:10.3390/cancers11071021 · Cited by 70 · see citing works
TGF ‐β superfamily co‐receptors in cancer
Pawlak, J. B., & Blobe, G. C. (2021) · Developmental Dynamics · doi:10.1002/dvdy.338 · Cited by 68 · see citing works
Maden, C. H., Fairman, D., Chalker, M., Costa, M. J., Fahy, W. A., Garman, N., Lukey, P. T., Mant, T., Parry, S., Simpson, J. K., et al. (2018) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-018-2435-3 · Cited by 65 · see citing works
Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy
Tschernia, N. P., & Gulley, J. L. (2022) · BioDrugs · doi:10.1007/s40259-022-00521-1 · Cited by 61 · see citing works
Principles of the activin receptor signaling pathway and its inhibition
Lodberg, A. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.04.001 · Cited by 62 · see citing works
Good and bad sides of TGFβ-signaling in myocardial infarction
Euler, G. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00066 · Cited by 62 · see citing works
Co-delivery nanoparticle to overcome metastasis promoted by insufficient chemotherapy
Zhou, Q., Li, Y., Zhu, Y., Yu, C., Jia, H., Bao, B., Hu, H., Xiao, C., Zhang, J., Zeng, X., et al. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.02.026 · Cited by 62 · see citing works
Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer
Suriyamurthy, S., Baker, D. A., ten Dijke, P., & Iyengar, P. V. (2019) · Cancers · doi:10.3390/cancers11050726 · Cited by 62 · see citing works
In the Shadow of Fibrosis: Innate Immune Suppression Mediated by Transforming Growth Factor-β
Thomas, B. J., Kan‐o, K., Loveland, K. L., Elias, J. A., & Bardin, P. G. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0248ps · Cited by 61 · see citing works
Fibroblasts orchestrate cellular crosstalk in the heart through the ECM
Bowers, S., Meng, Q., & Molkentin, J. D. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00043-7 · Cited by 59 · see citing works
Biological approaches for hypertrophic scars
Zhong, L.-Z., Li, M.-R., & Fu, X.-B. (2019) · International Wound Journal · doi:10.1111/iwj.13286 · Cited by 50 · see citing works
Busenhart, P., Montalban‐Arques, A., Katkeviciutė, E., Morsy, Y., Passen, C. V., Hering, L., Atrott, K., Lang, S., Garzon, J. F. G., Naschberger, E., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003465 · Cited by 58 · see citing works
Greco, R., Qu, H., Qu, H., Theilhaber, J., Shapiro, G., Gregory, R. C., Winter, C. G., Malkova, N. V., Sun, F. F., Jaworski, J. A., et al. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1811605 · Cited by 58 · see citing works
Role of IL-17A in murine models of COPD airway disease
Yanagisawa, H., Hashimoto, M., Minagawa, S., Takasaka, N., Ma, R., Moermans, C., Ito, S., Araya, J., Budelsky, A., Goodsell, A., et al. (2016) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00301.2016 · Cited by 58 · see citing works
Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy
Widjaja, A. A., Chothani, S. P., & Cook, S. A. (2020) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2020.1761203 · Cited by 54 · see citing works
MicroRNA applications for prostate, ovarian and breast cancer in the era of precision medicine
Smith, B., Agarwal, P., & Bhowmick, N. A. (2017) · Endocrine Related Cancer · doi:10.1530/erc-16-0525 · Cited by 56 · see citing works
Wang, H., Chen, M., Sang, X., You, X., Wang, Y., Paterson, I. C., Hong, W., & Yang, X. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112154 · Cited by 56 · see citing works
Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies
Harryvan, T. J., Verdegaal, E. M. E., Hardwick, J. C. H., Hawinkels, L. J. A. C., & van der Burg, S. H. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8111989 · Cited by 55 · see citing works
- Authors
- Anderton, M. J., Mellor, H. R., Bell, A., Sadler, C., Pass, M., Powell, S., Steele, S. J., Roberts, R. R. A., & Heier, A.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Heier, Annabelle
- Venue
- Toxicologic Pathology
- Publisher
- SAGE Publications
- Published
- 2011-08-22
- Volume
- 39
- Issue
- 6
- Pages
- 916-924
- ISSN
- 0192-6233 (ISSN-L)
- 1533-1601
- OpenAlex
- W2140740750
- Cited by
- 284
- References
- 55
- Citations by year
- 2026: 17 · 2025: 18 · 2024: 33 · 2023: 20 · 2022: 27 · 2021: 33 · 2020: 30 · 2019: 20 · 2018: 16 · 2017: 13 · 2016: 17 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 8
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicologic Pathology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Keywords
- ALK5 inhibitor, heart valve lesions, TGF-beta signaling, valvular interstitial cells, cardiotoxicity, preclinical toxicology, femorotibial joint, small molecule inhibitors
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Administration, Oral, Animals, Drug Evaluation, Preclinical, Female, Heart Valves, Immunohistochemistry, Signal Transduction, Transforming Growth Factor beta, Rats, Wistar, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Protein Kinase Inhibitors, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review