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CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors

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Abstract

Elevated serum levels of a glycoprotein known as chitinase-3-like protein 1 (CHI3L1) have been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in cancer have not yet been completely elucidated. In this review, we describe the role of CHI3L1 in inducing pro-inflammatory/pro-tumorigenic and angiogenic factors that could promote tumor growth and metastasis.

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References

  1. Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993;268(34):25803–10.

    CAS  PubMed  Google Scholar 

  2. Morrison BW, Leder P. neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene. 1994;9(12):3417–26.

    CAS  PubMed  Google Scholar 

  3. Shackelton LM, Mann DM, Millis AJ. Identification of a 38-kDa heparin-binding glycoprotein (gp38 k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling. J Biol Chem. 1995;270(22):13076–83.

    Article  CAS  PubMed  Google Scholar 

  4. Rehli M, Krause SW, Andreesen R. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics. 1997;43(2):221–5.

    Article  CAS  PubMed  Google Scholar 

  5. Renkema GH, et al. Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem. 1998;251(1–2):504–9.

    Article  CAS  PubMed  Google Scholar 

  6. Fusetti F, et al. Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem. 2003;278(39):37753–60.

    Article  CAS  PubMed  Google Scholar 

  7. Shibata Y, et al. Oral administration of chitin down-regulates serum IgE levels and lung eosinophilia in the allergic mouse. J Immunol. 2000;164(3):1314–21.

    Article  CAS  PubMed  Google Scholar 

  8. Boot RG, et al. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem. 2001;276(9):6770–8.

    Article  CAS  PubMed  Google Scholar 

  9. Araujo AC, Souto-Padron T, de Souza W. Cytochemical localization of carbohydrate residues in microfilariae of Wuchereria bancrofti and Brugia malayi. J Histochem Cytochem. 1993;41(4):571–8.

    Article  CAS  PubMed  Google Scholar 

  10. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol. 1994;48:471–97.

    Article  CAS  PubMed  Google Scholar 

  11. Fuhrman JA, Piessens WF. Chitin synthesis and sheath morphogenesis in Brugia malayi microfilariae. Mol Biochem Parasitol. 1985;17(1):93–104.

    Article  CAS  PubMed  Google Scholar 

  12. Neville AC, Parry DA, Woodhead-Galloway J. The chitin crystallite in arthropod cuticle. J Cell Sci. 1976;21(1):73–82.

    CAS  PubMed  Google Scholar 

  13. Shahabuddin M, Vinetz JM. Chitinases of human parasites and their implications as antiparasitic targets. EXS. 1999;87:223–34.

    CAS  PubMed  Google Scholar 

  14. Coffman FD. Chitinase 3-Like-1 (CHI3L1): a putative disease marker at the interface of proteomics and glycomics. Crit Rev Clin Lab Sci. 2008;45(6):531–62.

    Article  CAS  PubMed  Google Scholar 

  15. Houston DR, et al. Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes. J Biol Chem. 2003;278(32):30206–12.

    Article  CAS  PubMed  Google Scholar 

  16. Bigg HF, et al. The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation. J Biol Chem. 2006;281(30):21082–95.

    Article  CAS  PubMed  Google Scholar 

  17. Nyirkos P, Golds EE. Human synovial cells secrete a 39 kDa protein similar to a bovine mammary protein expressed during the non-lactating period. Biochem J. 1990;269(1):265–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Kzhyshkowska J, Gratchev A, Goerdt S. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomark Insights. 2007;2:128–46.

    PubMed Central  PubMed  Google Scholar 

  19. Johansen JS, et al. High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival. Breast Cancer Res Treat. 2003;80(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  20. Cintin C, et al. Serum YKL-40 and colorectal cancer. Br J Cancer. 1999;79(9–10):1494–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Johansen JS. Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull. 2006;53(2):172–209.

    CAS  PubMed  Google Scholar 

  22. Johansen JS, et al. High serum YKL-40 level in patients with small cell lung cancer is related to early death. Lung Cancer. 2004;46(3):333–40.

    Article  PubMed  Google Scholar 

  23. Hogdall EV, et al. High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival. Oncol Rep. 2003;10(5):1535–8.

    PubMed  Google Scholar 

  24. Dupont J, et al. Early detection and prognosis of ovarian cancer using serum YKL-40. J Clin Oncol. 2004;22(16):3330–9.

    Article  CAS  PubMed  Google Scholar 

  25. Brasso K, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006;66(5):503–13.

    Google Scholar 

  26. Diefenbach CS, et al. Preoperative serum YKL-40 is a marker for detection and prognosis of endometrial cancer. Gynecol Oncol. 2007;104(2):435–42.

    Article  CAS  PubMed  Google Scholar 

  27. Schmidt H, et al. Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma. Cancer. 2006;106(5):1130–9.

    Article  CAS  PubMed  Google Scholar 

  28. Biggar RJ, et al. Serum YKL-40 and interleukin 6 levels in Hodgkin lymphoma. Clin Cancer Res. 2008;14(21):6974–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Bergmann OJ, et al. High serum concentration of YKL-40 is associated with short survival in patients with acute myeloid leukemia. Clin Cancer Res. 2005;11(24 Pt 1):8644–52.

    Article  CAS  PubMed  Google Scholar 

  30. Pelloski CE, et al. YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res. 2005;11(9):3326–34.

    Article  CAS  PubMed  Google Scholar 

  31. Mitsuhashi A, et al. Serum YKL-40 as a marker for cervical adenocarcinoma. Ann Oncol. 2009;20(1):71–7.

    Article  CAS  PubMed  Google Scholar 

  32. Mizoguchi A, Mizoguchi E. Inflammatory bowel disease, past, present and future: lessons from animal models. J Gastroenterol. 2008;43(1):1–17.

    Article  PubMed  Google Scholar 

  33. He CH, et al. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor alpha2. Cell Rep. 2013;4(4):830–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Libreros S, et al. Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: Decreased tumor metastasis in a breast cancer model. Int J Cancer. 2011;131(2):377–86.

    Google Scholar 

  35. Recklies AD, White C, Ling H. The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. Biochem J. 2002;365(Pt 1):119–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Johansen JS, Jensen HS, Price PA. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol. 1993;32(11):949–55.

    Article  CAS  PubMed  Google Scholar 

  37. Scully S, et al. Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution. PLoS ONE. 2011;6(10):e25819.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Malinda KM, et al. Gp38 k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Exp Cell Res. 1999;250(1):168–73.

    Article  CAS  PubMed  Google Scholar 

  39. De Ceuninck F, et al. YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun. 2001;285(4):926–31.

    Article  PubMed  Google Scholar 

  40. Shao R, et al. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009;28(50):4456–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Kawada M, et al. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012;31(26):3111–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Jensen BV, Johansen JS, Price PA. High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. Clin Cancer Res. 2003;9(12):4423–34.

    CAS  PubMed  Google Scholar 

  43. Hottinger AF, et al. YKL-40 and MMP-9 as serum markers for patients with primary central nervous system lymphoma. Ann Neurol. 2011;70(1):163–9.

    Article  CAS  PubMed  Google Scholar 

  44. Brasso K, Iversen P. Prostatic cancer 2006–status and new challenges. The Danish society of urology. Ugeskr Laeger. 2006;168(12):1243.

    PubMed  Google Scholar 

  45. Shao R, et al. Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers. Br J Cancer. 2011;105(8):1203–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Kang EJ, et al. YKL-40 expression could be a poor prognostic marker in the breast cancer tissue. Tumour Biol. 2013. doi:10.1007/s13277-013-1036-0.

  47. Johansen JS, et al. Serum YKL-40: a new potential marker of prognosis and location of metastases of patients with recurrent breast cancer. Eur J Cancer. 1995;31A(9):1437–42.

    Article  CAS  PubMed  Google Scholar 

  48. Coskun U, et al. Locally advanced breast carcinoma treated with neoadjuvant chemotherapy: are the changes in serum levels of YKL-40, MMP-2 and MMP-9 correlated with tumor response? Neoplasma. 2007;54(4):348–52.

    CAS  PubMed  Google Scholar 

  49. Faibish M, et al. A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther. 2011;10(5):742–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Francescone RA, et al. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem. 2011;286(17):15332–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Krause SW, et al. Differential screening identifies genetic markers of monocyte to macrophage maturation. J Leukoc Biol. 1996;60(4):540–5.

    CAS  PubMed  Google Scholar 

  52. Nigro JM, et al. Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res. 2005;65(5):1678–86.

    Article  CAS  PubMed  Google Scholar 

  53. Lee CG, et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med. 2009;206(5):1149–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Mizoguchi E. Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology. 2006;130(2):398–411.

    Article  CAS  PubMed  Google Scholar 

  55. Pearson G, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.

    CAS  PubMed  Google Scholar 

  56. Johansen JS, et al. Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity. Rheumatology (Oxford). 1999;38(7):618–26.

    Article  CAS  Google Scholar 

  57. Vind I, et al. Serum YKL-40, a potential new marker of disease activity in patients with inflammatory bowel disease. Scand J Gastroenterol. 2003;38(6):599–605.

    Article  CAS  PubMed  Google Scholar 

  58. Johansen JS, et al. Increased serum YKL-40 in patients with pulmonary sarcoidosis–a potential marker of disease activity? Respir Med. 2005;99(4):396–402.

    Article  PubMed  Google Scholar 

  59. Sakazaki Y, et al. Overexpression of chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic mice, smokers and COPD. PLoS One. 2011;6(9):e24177.

    Google Scholar 

  60. Elias JA, et al. Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. J Allergy Clin Immunol. 2005;116(3):497–500.

    Article  CAS  PubMed  Google Scholar 

  61. Rathcke CN, Vestergaard H. YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. Inflamm Res. 2006;55(6):221–7.

    Article  CAS  PubMed  Google Scholar 

  62. Johansen JS, et al. Plasma YKL-40: a new potential marker of fibrosis in patients with alcoholic cirrhosis? Scand J Gastroenterol. 1997;32(6):582–90.

    Article  CAS  PubMed  Google Scholar 

  63. Johansen JS, et al. Serum YKL-40 is increased in patients with hepatic fibrosis. J Hepatol. 2000;32(6):911–20.

    Article  CAS  PubMed  Google Scholar 

  64. Bonneh-Barkay D, et al. YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor. Am J Pathol. 2008;173(1):130–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Chupp GL, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007;357(20):2016–27.

    Article  CAS  PubMed  Google Scholar 

  66. Ober C, et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med. 2008;358(16):1682–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Johansen JS, et al. Serum YKL-40, a new prognostic biomarker in cancer patients? Cancer Epidemiol Biomarkers Prev. 2006;15(2):194–202.

    Article  CAS  PubMed  Google Scholar 

  68. Eurich K, et al. Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells. World J Gastroenterol. 2009;15(42):5249–59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Tang H, et al. YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-kappaB pathways, causing bronchial smooth muscle proliferation and migration. J Immunol. 2013;190(1):438–46.

    Article  CAS  PubMed  Google Scholar 

  71. Qin W, et al. Increased expression of the inflammatory protein YKL-40 in precancers of the breast. Int J Cancer. 2007;121(7):1536–42.

    Article  CAS  PubMed  Google Scholar 

  72. Kawada M, et al. Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein. Lab Invest. 2008;88(8):883–95.

    Article  CAS  PubMed  Google Scholar 

  73. Owen JL, et al. Expression of the inflammatory chemokines CCL2, CCL5 and CXCL2 and the receptors CCR1-3 and CXCR2 in T lymphocytes from mammary tumor-bearing mice. Cell Immunol. 2011;270(2):172–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010;16(3):133–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Letuve S, et al. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol. 2008;181(7):5167–73.

    Article  CAS  PubMed  Google Scholar 

  76. Aguilera B, et al. Transglycosidase activity of chitotriosidase: improved enzymatic assay for the human macrophage chitinase. J Biol Chem. 2003;278(42):40911–6.

    Article  CAS  PubMed  Google Scholar 

  77. Saidi A, et al. Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma. Int J Cancer. 2008;122(10):2187–98.

    Article  CAS  PubMed  Google Scholar 

  78. Hughes K, et al. Conditional deletion of Stat3 in mammary epithelium impairs the acute phase response and modulates immune cell numbers during post-lactational regression. J Pathol. 2012;227(1):106–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Werb Z, et al. Matrix-degrading proteases and angiogenesis during development and tumor formation. Apmis. 1999;107(1):11–8.

    Article  CAS  PubMed  Google Scholar 

  80. Coussens LM, et al. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103(3):481–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295(5564):2387–92.

    Article  CAS  PubMed  Google Scholar 

  82. Owen JL, et al. Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor. J Immunol. 2003;171(8):4340–51.

    Article  CAS  PubMed  Google Scholar 

  83. Shibata Y, Metzger WJ, Myrvik QN. Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: mannose receptor-mediated phagocytosis initiates IL-12 production. J Immunol. 1997;159(5):2462–7.

    CAS  PubMed  Google Scholar 

  84. Nagatani K, et al. Chitin microparticles for the control of intestinal inflammation. Inflamm Bowel Dis. 2012;18(9):1698–710.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Yoshimi Shibata for providing us the chitin microparticles used in these studies. This work was supported by different National Institutes of Health grants NIH R15 CA135513-01 and R15 CA135513-01-OS1.

Conflict of interest

The authors declare that they have no conflict of interest.

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  1. Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA

    Stephania Libreros, Ramon Garcia-Areas & Vijaya Iragavarapu-Charyulu

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  1. Stephania Libreros
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  2. Ramon Garcia-Areas
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  3. Vijaya Iragavarapu-Charyulu
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Correspondence to Vijaya Iragavarapu-Charyulu.

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Libreros, S., Garcia-Areas, R. & Iragavarapu-Charyulu, V. CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors. Immunol Res 57, 99–105 (2013). https://doi.org/10.1007/s12026-013-8459-y

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