Amino Acids

, Volume 44, Issue 1, pp 81–88 | Cite as

Tissue transglutaminase, inflammation, and cancer: how intimate is the relationship?

  • Santosh Kumar
  • Kapil MehtaEmail author
Invited Review


Despite significant advances in surgery and biology, cancer remains a major health problem. It is now well accepted that metastasis and cancer cells’ acquired or inherent resistance to conventional therapies are major roadblocks to successful treatment. Chronic inflammation is an important driving force that provides a favorable platform for cancer’s progression and development and suggests a link between inflammation and metastatic transformation. However, how chronic inflammation contributes to metastatic cell transformation is not well understood. According to the current theory of cancer progression, a small subpopulation of cancer stem cells (CSCs) in tumors is responsible for their metastasis, resistance, and sustenance. Whether CSCs originate from normal stem cells or from dedifferentiation of terminally differentiated cells remains unknown. Recent evidence indicates that stem cells are not unique; malignant or nonmalignant cells can reprogram and de-differentiate to acquire a stemness phenotype. Thus, phenotypic plasticity may exist between stem cells and non-stem cells, and a dynamic equilibrium may exist between the two phenotypes. Moreover, this equilibrium may shift in one direction or another on the basis of contextual signals in the microenvironment that influence the interconversion between stem and non-stem cell compartments. Whether the inflammatory microenvironment influences this interconversion and shifts the dynamic equilibrium towards stem cell compartments remains unknown. We recently found that aberrant tissue transglutaminase (TG2) expression induces the mesenchymal transition (EMT) and stem cell characteristics in epithelial cells. This finding, in conjunction with the observation that inflammatory signals (e.g., TGFβ, TNFα, and NF-κB) which induce EMT, also induce TG2 expression, suggests a possible link between TG2, inflammation, and cancer progression. In this review, we summarize TG2-driven processes in inflammation and their implications in cancer progression.


Chemoresistance Metastasis Cancer stem cells EMT Inflammation Transglutaminase 2 



Supported in part by a grant from the Susan G. Komen for the Cure Foundation ( The authors wish to thank Ms. Ann Sutton for critical reading the manuscript.


  1. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  2. Bertout J, Thomas-Tikhonenko A (2006) Infection and neoplastic growth 101: the required reading for microbial pathogens aspiring to cause cancer. Cancer Treat Res 130:167–197PubMedCrossRefGoogle Scholar
  3. Clarke DD, Mycek MJ, Neidle A, Waelsch H (1957) The incorporation of amines into proteins. Arch Biochem Biophys 79:338–354CrossRefGoogle Scholar
  4. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997) Identification of tissue transglutaminase as the autoantigen of coeliac disease. Nat Med 3:797–801PubMedCrossRefGoogle Scholar
  5. Dubin PJ, McAllister F, Kolls JK (2007) Is cystic fibrosis a TH17 disease? Inflamm Res 56:221–227PubMedCrossRefGoogle Scholar
  6. Elli L, Bergamini CM, Bardella MT, Schuppan D (2009) Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver Dis 41:541–550PubMedCrossRefGoogle Scholar
  7. Facchiano F, Facchiano A, Facchiano AM (2006) The role of transglutaminase-2 and its substrates in human diseases. Front Biosci 11:1758–1773PubMedCrossRefGoogle Scholar
  8. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885PubMedCrossRefGoogle Scholar
  9. Fok JY, Ekmekcioglu S, Mehta K (2006) Implications of tissue transglutaminase expression in malignant melanoma. Mol Cancer Ther 5:1493–1503PubMedCrossRefGoogle Scholar
  10. Frese-Schaper M, Schardt JA, Sakai T, Carboni GL, Schmid RA, Frese S (2010) Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5. FEBS Lett 584:2867–2871PubMedCrossRefGoogle Scholar
  11. Grenard P, Bresson-Hadni S, El Alaoui S, Chevallier M, Vuitton DA, Ricard-Blum S (2001) Transglutaminase-mediated cross-linking is involved in the stabilization of extracellular matrix in human liver fibrosis. J Hepatol 35:367–375PubMedCrossRefGoogle Scholar
  12. Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396PubMedCrossRefGoogle Scholar
  13. Grivennikov S, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedCrossRefGoogle Scholar
  14. Hwang JY, Mangala LS, Fok JY, Lin YG, Merritt WM, Spannuth WA, Nick AM, Fiterman DJ, Vivas-Mejia PE, Deavers MT, Coleman RL, Lopez-Berestein G, Mehta K, Sood AK (2008) Clinical and biological significance of tissue transglutaminase in ovarian carcinoma. Cancer Res 68:5849–5858PubMedCrossRefGoogle Scholar
  15. Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (2003) Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res 63:8614–8622PubMedGoogle Scholar
  16. Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 89:991–1023PubMedCrossRefGoogle Scholar
  17. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grünert S (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313PubMedCrossRefGoogle Scholar
  18. Jeanes A, Gottardi CJ, Yap AS (2008) Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27:6920–6929PubMedCrossRefGoogle Scholar
  19. Jiang D, Ying W, Lu Y, Wan J, Zhai Y, Liu W, Zhu Y, Qiu Z, Qian X, He F (2003) Identification of metastasis associated proteins by proteomic analysis and functional exploration of interleukin-18 in metastasis. Proteomics 3:724–737PubMedCrossRefGoogle Scholar
  20. Johnson TS, Griffin M, Thomas GL, Skill J, Cox A, Yang B, Nicholas B, Birckbichler PJ, Muchaneta-Kubara C, Meguid El Nahas A (1997) The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis. J Clin Invest 99:2950–2960PubMedCrossRefGoogle Scholar
  21. Johnson K, Hashimoto S, Lotz M, Pritzker K, Terkeltaub R (2001) Interleukin-1 induces pro-mineralizing activity of cartilage tissue transglutaminase and factor XIIIa. Am J Pathol 159:149–163PubMedCrossRefGoogle Scholar
  22. Johnson TS, EI-Koraie AF, Skill NJ, Baddour NM, EI Nahas AM, Njloma M, Adam AG, Griffin M (2003) Tissue transglutaminase and the progression of human renal scarring. J Am Soc Nephrol 14:2052–2062PubMedCrossRefGoogle Scholar
  23. Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119:1417–1419PubMedCrossRefGoogle Scholar
  24. Kalluri R, Neilson EG (2003) Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784PubMedGoogle Scholar
  25. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401PubMedCrossRefGoogle Scholar
  26. Kiemer AK, Takeuchi K, Quinlan MP (2001) Identification of genes involved in epithelial–mesenchymal transition and tumor progression. Oncogene 20:6679–6688PubMedCrossRefGoogle Scholar
  27. Kim SY (2006) Transglutaminase 2 in inflammation. Front Biosci 11:3026–3035PubMedCrossRefGoogle Scholar
  28. Kumar A, Xu J, Brady S, Gao H, Yu D, Reuben J, Mehta K (2010) Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PLoS One 5:e13390PubMedCrossRefGoogle Scholar
  29. Kumar A, Gao H, Xu J, Reuben J, Yu D, Mehta K (2011) Evidence that aberrant expression of tissue transglutaminase promotes stem cell characteristics in mammary epithelial cells. PLoS One 6:e20701PubMedCrossRefGoogle Scholar
  30. Kuncio GS, Tsyganskaya M, Zhu J, Liu S-L, Nagy L, Thomazy V, Davies PJ, Zern MA (1998) TNF alpha modulates expression of the tissue transglutaminase gene in liver cells. Am J Physiol 274:G240–G245PubMedGoogle Scholar
  31. Lee KN, Birckbichler PJ, Patterson MK Jr (1989) GTP hydrolysis by guinea pig liver transglutaminase. Biochem Biophys Res Commun 162:1370–1375PubMedCrossRefGoogle Scholar
  32. Lee J, Kim YS, Choi DH, Bang MS, Han TR, Joh TH, Kim SY (2004) Transglutaminase 2 induces nuclear factor-κB activation via a novel pathway in BV-2 microglia. J Biol Chem 279:53725–53735PubMedCrossRefGoogle Scholar
  33. Lesort M, Tucholski J, Miller ML, Johnson GV (2000) Tissue transglutaminase: a possible role in neurodegenerative diseases. Prog Neurobiol 61:439–463PubMedCrossRefGoogle Scholar
  34. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906PubMedCrossRefGoogle Scholar
  35. Maiuri L, Luciani A, Giardino I, Raia V, Villella VR, D’Apolito M, Pettoello-Mantovani M, Guido S, Ciacci C, Cimmino M, Cexus ON, Londei M, Quaratino S (2008) Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation. J Immunol 180:7697–7705PubMedGoogle Scholar
  36. Mangala LS, Fok JY, Zorrilla-Calancha IR, Verma A, Mehta K (2007) Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26:2459–2470PubMedCrossRefGoogle Scholar
  37. Mann AP, Verma A, Sethi G, Manavathi B, Wang H, Fok JY, Kunnumakkara AB, Kumar R, Aggarwal BB, Mehta K (2006) Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-κB in cancer cells: delineation of a novel pathway. Cancer Res 66:8788–8795PubMedCrossRefGoogle Scholar
  38. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer related inflammation. Nature 454:436–444PubMedCrossRefGoogle Scholar
  39. Mehta K, Eckert R (2005) Transglutaminases—family of enzymes with diverse functions. Prog Exp Tumor Res 38:1–247PubMedCrossRefGoogle Scholar
  40. Mehta K, Fok J, Miller FR, Koul D, Sahin AA (2004) Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res 10:8068–8076PubMedCrossRefGoogle Scholar
  41. Mehta K, Kumar A, Kim HI (2010) Transglutaminase 2: A multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol 80:1921–1929PubMedCrossRefGoogle Scholar
  42. Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono K, Im MJ, Graham RM (1994) Gh: a GTPbinding protein with transglutaminase activity and receptor signaling function. Science 264:1593–1596PubMedCrossRefGoogle Scholar
  43. Osika E, Cavaillon JM, Chadelat K, Boule M, Fitting C, Tournier G, Clement A (1999) Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway disease. Eur Respir J 14:339–346PubMedCrossRefGoogle Scholar
  44. Park KS, Kim HK, Lee JH, Choi YB, Park SY, Yang SH, Kim SY, Hong KM (2010) Transglutaminase 2 as a cisplatin resistance marker in non-small cell lung cancer. J Cancer Res Clin Oncol 136:493–502PubMedCrossRefGoogle Scholar
  45. Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5:e327PubMedCrossRefGoogle Scholar
  46. Quan G, Choi JY, Lee DS, Lee SC (2005) TGF-beta1 upregulates transglutaminase 2 and fibronectin in dermal fibroblasts: a possible mechanism for the stabilization of tissue inflammation. Arch Dermatol Res 297:84–90PubMedCrossRefGoogle Scholar
  47. Richards RJ, Masek LC, Brown RF (1991) Biochemical and cellular mechanisms of pulmonary fibrosis. Toxicol Pathol 19:526–539PubMedCrossRefGoogle Scholar
  48. Shao M, Cao L, Shen C, Satpathy M, Chelladurai B, Bigsby RM, Nakshatri H, Matei D (2009) Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. Cancer Res 69:9192–9201PubMedCrossRefGoogle Scholar
  49. Shweke N, Boulos N, Jouanneau C, Vandermeersch S, Melino G, Dussaule JC, Chatziantoniou C, Ronco P, Boffa JJ (2008) Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am J Pathol 173:631–642PubMedCrossRefGoogle Scholar
  50. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751PubMedCrossRefGoogle Scholar
  51. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  52. Verderio EA, Johnson T, Griffin M (2004) Tissue transglutaminase in normal and abnormal wound healing: review article. Amino Acids 26:387–404PubMedCrossRefGoogle Scholar
  53. Verderio EA, Johnson TS, Griffin M (2005) Transglutaminases in wound healing and inflammation. Prog Exp Tumor Res 38:89–114PubMedCrossRefGoogle Scholar
  54. Verma A, Mehta K (2007a) Tissue transglutaminase-mediated chemoresistance in cancer cells. Drug Resist Updat 10:144–151PubMedCrossRefGoogle Scholar
  55. Verma A, Mehta K (2007b) Transglutaminase-mediated activation of nuclear transcription factor-kappaB in cancer cells: a new therapeutic opportunity. Curr Cancer Drug Targets 7:559–565PubMedCrossRefGoogle Scholar
  56. Verma A, Wang H, Manavathi B, Fok JY, Mann AP, Kumar R, Mehta K (2006) Increased expression of tissue transglutaminase in pancreatic ductal adenocarcinoma and its implications in drug resistance and metastasis. Cancer Res 66:10525–10533PubMedCrossRefGoogle Scholar
  57. Verma A, Guha S, Diagaradjane P, Kunnumakkara AB, Sanguino AM, Lopez-Berestein G, Sood AK, Aggarwal BB, Krishnan S, Gelovani JG, Mehta K (2008) Therapeutic significance of elevated tissue transglutaminase expression in pancreatic cancer. Clin Cancer Res 14:2476–2483PubMedCrossRefGoogle Scholar
  58. Vincent-Salomon A, Thiery JP (2003) Host microenvironment in breast cancer development: epithelial–mesenchymal transition in breast cancer development. Breast Cancer Res 5:101–106PubMedCrossRefGoogle Scholar
  59. Yuan L, Choi K, Khosla C, Zheng X, Higashikubo R, Chicoine MR, Rich KM (2005) Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas. Mol Cancer Ther 4:1293–1302PubMedCrossRefGoogle Scholar
  60. Yuan L, Siegel M, Choi K, Khosla C, Miller CR, Jackson EN, Rich KM (2007) Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. Oncogene 26:2563–2573PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Experimental Therapeutics, Unit 1950The University of Texas MD Anderson Cancer CenterHoustonUSA

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