DOI QR코드

DOI QR Code

Role of Gremlin-1 in Cancer

  • Park, Sin-Aye (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
  • Received : 2018.10.22
  • Accepted : 2018.12.04
  • Published : 2018.12.31

Abstract

Gremlin-1 (GREM1) has been defined as an antagonist of bone morphogenetic proteins (BMPs), particularly during embryonic development and tissue differentiation. However, recent studies have shown that GREM1 has BMPs-dependent or -independent functions in diverse human diseases. GREM1 plays a key role in the process of organ fibrosis, including lungs, kidneys, and so on. The GREM1-induced fibrosis typically promotes the development of other diseases, such as pulmonary hypertension, renal inflammation, and diabetic nephropathy. More recently, considerable evidence has been reported showing that GREM1 is involved in the promotion and/or progression of tumors in vitro and in vivo. It also performs an oncogenic role in the maintenance of cancer stem cells. Although GREM1 is known to function in a variety of diseases, here we focus on the role of GREM1 in cancer, and suggest GREM1 as a potential therapeutic target in certain types of cancer.

Keywords

References

  1. Ali IH, Brazil DP. Bone morphogenetic proteins and their antagonists: Current and emerging clinical uses. Br J Pharmacol. 2014. 171: 3620-3632. https://doi.org/10.1111/bph.12724
  2. Allison SJ. Fibrosis: Targeting emt to reverse renal fibrosis. Nat Rev Nephrol. 2015. 11: 565. https://doi.org/10.1038/nrneph.2015.133
  3. Boers W, Aarrass S, Linthorst C, Pinzani M, Elferink RO, Bosma P. Transcriptional profiling reveals novel markers of liver fibrogenesis: Gremlin and insulin-like growth factor-binding proteins. J Biol Chem. 2006. 281: 16289-16295. https://doi.org/10.1074/jbc.M600711200
  4. Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A. Bone morphogenetic proteins: A critical review. Cell Signal. 2011. 23: 609-620. https://doi.org/10.1016/j.cellsig.2010.10.003
  5. Buijs JT, van der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J, Petersen M, van Overveld PG, Pelger RC, van der Pluijm G. The bmp2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene. 2012. 31: 2164-2174. https://doi.org/10.1038/onc.2011.400
  6. Cahill E, Costello CM, Rowan SC, Harkin S, Howell K, Leonard MO, Southwood M, Cummins EP, Fitzpatrick SF, Taylor CT, Morrell NW, Martin F, McLoughlin P. Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation. 2012. 125: 920-930. https://doi.org/10.1161/CIRCULATIONAHA.111.038125
  7. Cai X, Yang X, Jin C, Li L, Cui Q, Guo Y, Dong Y, Yang X, Guo L, Zhang M. Identification and verification of differentially expressed micrornas and their target genes for the diagnosis of esophageal cancer. Oncol Lett. 2018. 16: 3642-3650.
  8. Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev. 2003. 24: 218-235. https://doi.org/10.1210/er.2002-0023
  9. Chang JC. Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance. Medicine (Baltimore). 2016. 95: S20-25. https://doi.org/10.1097/MD.0000000000004766
  10. Chen MH, Yeh YC, Shyr YM, Jan YH, Chao Y, Li CP, Wang SE, Tzeng CH, Chang PM, Liu CY, Chen MH, Hsiao M, Huang CY. Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors. J Gastroenterol. 2013. 48: 101-108. https://doi.org/10.1007/s00535-012-0614-z
  11. Church RH, Ali I, Tate M, Lavin D, Krishnakumar A, Kok HM, Hombrebueno JR, Dunne PD, Bingham V, Goldschmeding R, Martin F, Brazil DP. Gremlin1 plays a key role in kidney development and renal fibrosis. Am J Physiol Renal Physiol. 2017. 312: F1141-F1157. https://doi.org/10.1152/ajprenal.00344.2016
  12. Ciuclan L, Sheppard K, Dong L, Sutton D, Duggan N, Hussey M, Simmons J, Morrell NW, Jarai G, Edwards M, Dubois G, Thomas M, Van Heeke G, England K. Treatment with antigremlin 1 antibody ameliorates chronic hypoxia/su5416-induced pulmonary arterial hypertension in mice. Am J Pathol. 2013. 183: 1461-1473. https://doi.org/10.1016/j.ajpath.2013.07.017
  13. Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Giner FC, Rodenas-Cuadrado P, Mallappa S, Clark S, Thomas H, Jeffery R, Poulsom R, Rodriguez-Justo M, Novelli M, Chetty R, Silver A, et al. Aberrant epithelial grem1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med. 2015. 21: 62-70. https://doi.org/10.1038/nm.3750
  14. Erdmann R, Ozden C, Weidmann J, Schultze A. Targeting the gremlin-vegfr2 axis - a promising strategy for multiple diseases? J Pathol. 2015. 236: 403-406. https://doi.org/10.1002/path.4544
  15. Farkas L, Farkas D, Gauldie J, Warburton D, Shi W, Kolb M. Transient overexpression of gremlin results in epithelial activation and reversible fibrosis in rat lungs. Am J Respir Cell Mol Biol. 2011. 44: 870-878. https://doi.org/10.1165/rcmb.2010-0070OC
  16. Galamb O, Wichmann B, Sipos F, Spisak S, Krenacs T, Toth K, Leiszter K, Kalmar A, Tulassay Z, Molnar B. Dysplasiacarcinoma transition specific transcripts in colonic biopsy samples. PLoS One. 2012. 7: e48547. https://doi.org/10.1371/journal.pone.0048547
  17. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG. The bmp inhibitor coco reactivates breast cancer cells at lung metastatic sites. Cell. 2012. 150: 764-779. https://doi.org/10.1016/j.cell.2012.06.035
  18. Gazzerro E, Pereira RC, Jorgetti V, Olson S, Economides AN, Canalis E. Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology. 2005. 146: 655-665. https://doi.org/10.1210/en.2004-0766
  19. Gazzerro E, Smerdel-Ramoya A, Zanotti S, Stadmeyer L, Durant D, Economides AN, Canalis E. Conditional deletion of gremlin causes a transient increase in bone formation and bone mass. J Biol Chem. 2007. 282: 31549-31557. https://doi.org/10.1074/jbc.M701317200
  20. Graham JR, Williams CM, Yang Z. Microrna-27b targets gremlin 1 to modulate fibrotic responses in pulmonary cells. J Cell Biochem. 2014. 115: 1539-1548. https://doi.org/10.1002/jcb.24809
  21. Guan Y, Cheng W, Zou C, Wang T, Cao Z. Gremlin1 promotes carcinogenesis of glioma in vitro. Clin Exp Pharmacol Physiol. 2017. 44: 244-256. https://doi.org/10.1111/1440-1681.12697
  22. Guimei M, Baddour N, Elkaffash D, Abdou L, Taher Y. Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis c: An immunohistochemical and pcr study of human liver biopsies. BMC Res Notes. 2012. 5: 390. https://doi.org/10.1186/1756-0500-5-390
  23. Han EJ, Yoo SA, Kim GM, Hwang D, Cho CS, You S, Kim WU. Grem1 is a key regulator of synoviocyte hyperplasia and invasiveness. J Rheumatol. 2016. 43: 474-485. https://doi.org/10.3899/jrheum.150523
  24. Heron M, van Moorsel CH, Grutters JC, Huizinga TW, van der Helm-van Mil AH, Nagtegaal MM, Ruven HJ, van den Bosch JM. Genetic variation in grem1 is a risk factor for fibrosis in pulmonary sarcoidosis. Tissue Antigens. 2011. 77: 112-117. https://doi.org/10.1111/j.1399-0039.2010.01590.x
  25. Hong D, Liu T, Huang W, Liao Y, Wang L, Zhang Z, Chen H, Zhang X, Xiang Q. Gremlin1 delivered by mesenchymal stromal cells promoted epithelial-mesenchymal transition in human esophageal squamous cell carcinoma. Cell Physiol Biochem. 2018. 47: 1785-1799. https://doi.org/10.1159/000491060
  26. Jang BG, Kim HS, Chang WY, Bae JM, Oh HJ, Wen X, Jeong S, Cho NY, Kim WH, Kang GH. Prognostic significance of stromal grem1 expression in colorectal cancer. Hum Pathol. 2017. 62: 56-65. https://doi.org/10.1016/j.humpath.2016.12.018
  27. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003. 112: 1776-1784. https://doi.org/10.1172/JCI200320530
  28. Karagiannis GS, Berk A, Dimitromanolakis A, Diamandis EP. Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1. Mol Oncol. 2013. 7: 826-839. https://doi.org/10.1016/j.molonc.2013.04.002
  29. Karagiannis GS, Musrap N, Saraon P, Treacy A, Schaeffer DF, Kirsch R, Riddell RH, Diamandis EP. Bone morphogenetic pro tein antagonist gremlin-1 regulates colon cancer progression. Biol Chem. 2015. 396: 163-183.
  30. Karagiannis GS, Treacy A, Messenger D, Grin A, Kirsch R, Riddell RH, Diamandis EP. Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts. Mol Oncol. 2014. 8: 1240-1252. https://doi.org/10.1016/j.molonc.2014.04.004
  31. Kim HS, Shin MS, Cheon MS, Kim JW, Lee C, Kim WH, Kim YS, Jang BG. Grem1 is expressed in the cancer-associated myofibroblasts of basal cell carcinomas. PLoS One. 2017. 12: e0174565. https://doi.org/10.1371/journal.pone.0174565
  32. Kim M, Yoon S, Lee S, Ha SA, Kim HK, Kim JW, Chung J. Gremlin-1 induces bmp-independent tumor cell proliferation, migration, and invasion. PLoS One. 2012. 7: e35100. https://doi.org/10.1371/journal.pone.0035100
  33. Lavoz C, Alique M, Rodrigues-Diez R, Pato J, Keri G, Mezzano S, Egido J, Ruiz-Ortega M. Gremlin regulates renal inflammation via the vascular endothelial growth factor receptor 2 pathway. J Pathol. 2015. 236: 407-420. https://doi.org/10.1002/path.4537
  34. Lee H, O'Meara SJ, O'Brien C, Kane R. The role of gremlin, a bmp antagonist, and epithelial-to-mesenchymal transition in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2007. 48: 4291-4299. https://doi.org/10.1167/iovs.07-0086
  35. Lewis A, Freeman-Mills L, de la Calle-Mustienes E, Giraldez-Perez RM, Davis H, Jaeger E, Becker M, Hubner NC, Nguyen LN, Zeron-Medina J, Bond G, Stunnenberg HG, Carvajal JJ, Gomez-Skarmeta JL, Leedham S, Tomlinson I. A polymorphic enhancer near grem1 influences bowel cancer risk through differential cdx2 and tcf7l2 binding. Cell Rep. 2014. 8: 983-990. https://doi.org/10.1016/j.celrep.2014.07.020
  36. Li J, Liu H, Zou L, Ke J, Zhang Y, Zhu Y, Yang Y, Gong Y, Tian J, Zou D, Peng X, Gong J, Zhong R, Huang K, Chang J, Miao X. A functional variant in grem1 confers risk for colorectal cancer by disrupting a hsa-mir-185-3p binding site. Oncotarget. 2017. 8: 61318-61326.
  37. Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer-Hofer K, Zammataro L, Presta M. Gremlin is a novel agonist of the major proangiogenic receptor vegfr2. Blood. 2010. 116: 3677-3680. https://doi.org/10.1182/blood-2010-06-291930
  38. Mulvihill MS, Kwon YW, Lee S, Fang LT, Choi H, Ray R, Kang HC, Mao JH, Jablons D, Kim IJ. Gremlin is overexpressed in lung adenocarcinoma and increases cell growth and proliferation in normal lung cells. PLoS One. 2012. 7: e42264. https://doi.org/10.1371/journal.pone.0042264
  39. Myllarniemi M, Lindholm P, Ryynanen MJ, Kliment CR, Salmenkivi K, Keski-Oja J, Kinnula VL, Oury TD, Koli K. Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis. Am J Respir Crit Care Med. 2008. 177: 321-329. https://doi.org/10.1164/rccm.200706-945OC
  40. Namkoong H, Shin SM, Kim HK, Ha SA, Cho GW, Hur SY, Kim TE, Kim JW. The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with ywhah protein. BMC Cancer. 2006. 6: 74. https://doi.org/10.1186/1471-2407-6-74
  41. Pelli A, Vayrynen JP, Klintrup K, Makela J, Makinen MJ, Tuomisto A, Karttunen TJ. Gremlin1 expression associates with serrated pathway and favourable prognosis in colorectal cancer. Histopathology. 2016. 69: 831-838. https://doi.org/10.1111/his.13006
  42. Rodrigues-Diez R, Lavoz C, Carvajal G, Rayego-Mateos S, Rodrigues Diez RR, Ortiz A, Egido J, Mezzano S, Ruiz-Ortega M. Gremlin is a downstream profibrotic mediator of transforming growth factor-beta in cultured renal cells. Nephron Exp Nephrol. 2012. 122: 62-74. https://doi.org/10.1159/000346575
  43. Rodrigues-Diez R, Rodrigues-Diez RR, Lavoz C, Carvajal G, Droguett A, Garcia-Redondo AB, Rodriguez I, Ortiz A, Egido J, Mezzano S, Ruiz-Ortega M. Gremlin activates the smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells. Biomed Res Int. 2014. 2014:802841.
  44. Sato M, Kawana K, Fujimoto A, Yoshida M, Nakamura H, Nishida H, Inoue T, Taguchi A, Takahashi J, Adachi K, Nagasaka K, Matsumoto Y, Wada-Hiraike O, Oda K, Osuga Y, Fujii T. Clinical significance of gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance. Oncol Rep. 2016. 35: 391-397. https://doi.org/10.3892/or.2015.4367
  45. Savagner P. The epithelial-mesenchymal transition (emt) phenomenon. Ann Oncol. 2010. 21 Suppl 7: vii89-92.
  46. Schuetz CS, Bonin M, Clare SE, Nieselt K, Sotlar K, Walter M, Fehm T, Solomayer E, Riess O, Wallwiener D, Kurek R, Neubauer HJ. Progression-specific genes identified by expression profiling of matched ductal carcinomas in situ and invasive breast tumors, combining laser capture microdissection and oligonucleotide microarray analysis. Cancer Res. 2006. 66: 5278-5286. https://doi.org/10.1158/0008-5472.CAN-05-4610
  47. Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE, Brown PO. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A. 2006. 103: 14842-14847. https://doi.org/10.1073/pnas.0606857103
  48. Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, Peri F, Pessi A, Orsatti L, Talamo F, Castronovo V, Waltregny D, Cotelli F, Ribatti D, Presta M. Bone morphogenic protein antagonist drm/gremlin is a novel proangiogenic factor. Blood. 2007. 109: 1834-1840. https://doi.org/10.1182/blood-2006-06-032276
  49. Staloch D, Gao X, Liu K, Xu M, Feng X, Aronson JF, Falzon M, Greeley GH, Rastellini C, Chao C, Hellmich MR, Cao Y, Ko TC. Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. J Mol Med (Berl). 2015. 93: 1085-1093. https://doi.org/10.1007/s00109-015-1308-9
  50. Tamminen JA, Parviainen V, Ronty M, Wohl AP, Murray L, Joenvaara S, Varjosalo M, Lepparanta O, Ritvos O, Sengle G, Renkonen R, Myllarniemi M, Koli K. Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug. Oncogenesis. 2013. 2: e66. https://doi.org/10.1038/oncsis.2013.29
  51. Wang DJ, Zhi XY, Zhang SC, Jiang M, Liu P, Han XP, Li J, Chen Z, Wang CL. The bone morphogenetic protein antagonist gremlin is overexpressed in human malignant mesothelioma. Oncol Rep. 2012. 27: 58-64.
  52. Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O, Li M, Shen C, Hu A, Haydon RC, Kang R, Mok J, Lee MJ, Luu HL, Shi LL. Bone morphogenetic protein (bmp) signaling in development and human diseases. Genes Dis. 2014. 1: 87-105. https://doi.org/10.1016/j.gendis.2014.07.005
  53. Yamasaki Y, Ishigami S, Arigami T, Kita Y, Uchikado Y, Kurahara H, Kijima Y, Maemura K, Natsugoe S. Expression of gremlin1 in gastric cancer and its clinical significance. Med Oncol. 2018. 35: 30. https://doi.org/10.1007/s12032-017-1073-4
  54. Yan K, Wu Q, Yan DH, Lee CH, Rahim N, Tritschler I, DeVecchio J, Kalady MF, Hjelmeland AB, Rich JN. Glioma cancer stem cells secrete gremlin1 to promote their maintenance within the tumor hierarchy. Genes Dev. 2014. 28: 1085-1100. https://doi.org/10.1101/gad.235515.113
  55. Yin M, Tissari M, Tamminen J, Ylivinkka I, Ronty M, von Nandelstadh P, Lehti K, Hyytiainen M, Myllarniemi M, Koli K. Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma. Oncotarget. 2017. 8: 98280-98297.