Lumican, a Small Leucine-Rich Proteoglycan, and Its Biological Function in Tumor Progression

  • Michael Pratt
  • Ya’an Kang
  • Xinqun Li
  • Jason B. FlemingEmail author
Part of the Biology of Extracellular Matrix book series (BEM)


Lumican is a member of the small leucine-rich proteoglycan (SLRP) family that was originally discovered in the chick cornea and is found in many other tissues throughout the human body. The SLRP family includes decorin, lumican, biglycan, and fibromodulin and constitutes an abundant component of the extracellular matrix (ECM). Lumican plays a significant role in the ECM as an organizer of collagen, although recent studies demonstrate that lumican also modulates numerous cellular functions including proliferation, migration, and differentiation. The contribution of lumican to cancer progression has been noted in several cancers including breast, colorectal, and pancreatic; however, its precise biologic function is still being uncovered. In cancer, lumican appears to play a context-specific role, where high levels of lumican are associated with a poor prognosis in some cancers and a better prognosis in others. This chapter focuses on the function of lumican in cell biology and the ECM of solid tumors and is aimed at providing insights into molecular mechanisms surrounding lumican and tumor biology.


  1. Albig AR, Roy TG, Becenti DJ, Schiemann WP (2007) Transcriptome analysis of endothelial cell gene expression induced by growth on matrigel matrices: identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis 10:197–216CrossRefPubMedGoogle Scholar
  2. Baba H, Ishiwata T, Takashi E, Xu G, Asano G (2001) Expression and localization of lumican in the ischemic and reperfused rat heart. Jpn Circ J 65:445–450CrossRefPubMedGoogle Scholar
  3. Baghy K, Horvath Z, Regos E, Kiss K, Schaff Z, Iozzo RV, Kovalszky I (2013) Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis. FEBS J 280:2150–2164CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bates DO, Curry FE (1996) Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol 271:H2520–H2528PubMedGoogle Scholar
  5. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337CrossRefPubMedPubMedCentralGoogle Scholar
  6. Blochberger TC, Cornuet PK, Hassell JR (1992a) Isolation and partial characterization of lumican and decorin from adult chicken corneas. A keratan sulfate-containing isoform of decorin is developmentally regulated. J Biol Chem 267:20613–20619PubMedGoogle Scholar
  7. Blochberger TC, Vergnes JP, Hempel J, Hassell JR (1992b) cDNA to chick lumican (corneal keratan sulfate proteoglycan) reveals homology to the small interstitial proteoglycan gene family and expression in muscle and intestine. J Biol Chem 267:347–352PubMedGoogle Scholar
  8. Brezillon S, Radwanska A, Zeltz C, Malkowski A, Ploton D, Bobichon H, Perreau C, Malicka-Blaszkiewicz M, Maquart FX, Wegrowski Y (2009) Lumican core protein inhibits melanoma cell migration via alterations of focal adhesion complexes. Cancer Lett 283:92–100CrossRefPubMedGoogle Scholar
  9. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257CrossRefPubMedGoogle Scholar
  10. Chakravarti S, Stallings RL, Sundarraj N, Cornuet PK, Hassell JR (1995) Primary structure of human lumican (keratan sulfate proteoglycan) and localization of the gene (LUM) to chromosome 12q21.3-q22. Genomics 27:481–488CrossRefPubMedGoogle Scholar
  11. Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, Lamantia C, Carroll H (1998) Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican. J Cell Biol 141:1277–1286CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cole GJ, Mccabe CF (1991) Identification of a developmentally regulated keratan sulfate proteoglycan that inhibits cell adhesion and neurite outgrowth. Neuron 7:1007–1018CrossRefPubMedGoogle Scholar
  13. Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Andrade de Paula CA, Carneiro CR, Ortiz V, Toma L, Kao WW, Nader HB (2013) Lumican expression, localization and antitumor activity in prostate cancer. Exp Cell Res 319:967–981CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dolhnikoff M, Morin J, Roughley PJ, Ludwig MS (1998) Expression of lumican in human lungs. Am J Respir Cell Mol Biol 19:582–587CrossRefPubMedGoogle Scholar
  15. D’Onofrio MF, Brezillon S, Baranek T, Perreau C, Roughley PJ, Maquart FX, Wegrowski Y (2008) Identification of beta1 integrin as mediator of melanoma cell adhesion to lumican. Biochem Biophys Res Commun 365:266–272CrossRefPubMedGoogle Scholar
  16. Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61CrossRefPubMedGoogle Scholar
  17. Fullwood NJ, Davies Y, Nieduszynski IA, Marcyniuk B, Ridgway AE, Quantock AJ (1996) Cell surface-associated keratan sulfate on normal and migrating corneal endothelium. Invest Ophthalmol Vis Sci 37:1256–1270PubMedGoogle Scholar
  18. Funderburgh JL, Mitschler RR, Funderburgh ML, Roth MR, Chapes SK, Conrad GW (1997) Macrophage receptors for lumican. A corneal keratan sulfate proteoglycan. Invest Ophthalmol Vis Sci 38:1159–1167PubMedGoogle Scholar
  19. Geng Y, Mcquillan D, Roughley PJ (2006) SLRP interaction can protect collagen fibrils from cleavage by collagenases. Matrix Biol 25:484–491CrossRefPubMedGoogle Scholar
  20. Goodman TT, Olive PL, Pun SH (2007) Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int J Nanomedicine 2:265–274CrossRefPubMedPubMedCentralGoogle Scholar
  21. Grover J, Chen XN, Korenberg JR, Roughley PJ (1995) The human lumican gene. Organization, chromosomal location, and expression in articular cartilage. J Biol Chem 270:21942–21949CrossRefPubMedGoogle Scholar
  22. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefPubMedGoogle Scholar
  23. Harhaj NS, Barber AJ, Antonetti DA (2002) Platelet-derived growth factor mediates tight junction redistribution and increases permeability in MDCK cells. J Cell Physiol 193:349–364CrossRefPubMedGoogle Scholar
  24. Iozzo RV (1997) The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol 32:141–174CrossRefPubMedGoogle Scholar
  25. Ishiwata T, Fujii T, Ishiwata S, Ikegawa S, Naito Z (2004) Effect of morpholino antisense oligonucleotide against lumican mRNA in human embryonic kidney (HEK) 293 cells. Pathol Int 54:77–81CrossRefPubMedGoogle Scholar
  26. Ishiwata T, Cho K, Kawahara K, Yamamoto T, Fujiwara Y, Uchida E, Tajiri T, Naito Z (2007) Role of lumican in cancer cells and adjacent stromal tissues in human pancreatic cancer. Oncol Rep 18:537–543PubMedGoogle Scholar
  27. Ishiwata T, Yamamoto T, Kawahara K, Kawamoto Y, Matsuda Y, Ishiwata S, Naito Z (2010) Enhanced expression of lumican inhibited the attachment and growth of human embryonic kidney 293 cells. Exp Mol Pathol 88:363–370CrossRefPubMedGoogle Scholar
  28. Kajava AV (1998) Structural diversity of leucine-rich repeat proteins. J Mol Biol 277:519–527CrossRefPubMedGoogle Scholar
  29. Kalamajski S, Oldberg A (2009) Homologous sequence in lumican and fibromodulin leucine-rich repeat 5-7 competes for collagen binding. J Biol Chem 284:534–539CrossRefPubMedGoogle Scholar
  30. Kannagi R, Izawa M, Koike T, Miyazaki K, Kimura N (2004) Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci 95:377–384CrossRefPubMedGoogle Scholar
  31. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lee S, Bowrin K, Hamad AR, Chakravarti S (2009) Extracellular matrix lumican deposited on the surface of neutrophils promotes migration by binding to beta2 integrin. J Biol Chem 284:23662–23669CrossRefPubMedPubMedCentralGoogle Scholar
  33. Leygue E, Snell L, Dotzlaw H, Hole K, Hiller-Hitchcock T, Roughley PJ, Watson PH, Murphy LC (1998) Expression of lumican in human breast carcinoma. Cancer Res 58:1348–1352PubMedGoogle Scholar
  34. Li X, Truty MA, Kang Y, Chopin-Laly X, Zhang R, Roife D, Chatterjee D, Lin E, Thomas RM, Wang H, Katz MH, Fleming JB (2014) Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery. Clin Cancer Res 20:6529–6540CrossRefPubMedPubMedCentralGoogle Scholar
  35. Li X, Roife D, Kang Y, Dai B, Pratt M, Fleming JB (2016) Extracellular lumican augments cytotoxicity of chemotherapy in pancreatic ductal adenocarcinoma cells via autophagy inhibition. Oncogene 35:4881–9035CrossRefPubMedGoogle Scholar
  36. Liu CY, Kao WW (2012) Lumican promotes corneal epithelial wound healing. Methods Mol Biol 836:285–290CrossRefPubMedGoogle Scholar
  37. Lu YP, Ishiwata T, Kawahara K, Watanabe M, Naito Z, Moriyama Y, Sugisaki Y, Asano G (2002) Expression of lumican in human colorectal cancer cells. Pathol Int 52:519–526CrossRefPubMedGoogle Scholar
  38. Lu P, Wang Y, Graham L, Mchale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150:1264–1273CrossRefPubMedPubMedCentralGoogle Scholar
  39. Matsuda Y, Yamamoto T, Kudo M, Kawahara K, Kawamoto M, Nakajima Y, Koizumi K, Nakazawa N, Ishiwata T, Naito Z (2008) Expression and roles of lumican in lung adenocarcinoma and squamous cell carcinoma. Int J Oncol 33:1177–1185PubMedGoogle Scholar
  40. Naito Z (2005) Role of the small leucine-rich proteoglycan (SLRP) family in pathological lesions and cancer cell growth. J Nippon Med Sch 72:137–145CrossRefPubMedGoogle Scholar
  41. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60:2497–2503PubMedGoogle Scholar
  42. Niewiarowska J, Brezillon S, Sacewicz-Hofman I, Bednarek R, Maquart FX, Malinowski M, Wiktorska M, Wegrowski Y, Cierniewski CS (2011) Lumican inhibits angiogenesis by interfering with alpha2beta1 receptor activity and downregulating MMP-14 expression. Thromb Res 128:452–457CrossRefPubMedGoogle Scholar
  43. Nikitovic D, Berdiaki A, Zafiropoulos A, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN (2008a) Lumican expression is positively correlated with the differentiation and negatively with the growth of human osteosarcoma cells. FEBS J 275:350–361CrossRefPubMedGoogle Scholar
  44. Nikitovic D, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN (2008b) Lumican, a small leucine-rich proteoglycan. IUBMB Life 60:818–823CrossRefPubMedGoogle Scholar
  45. Nikitovic D, Papoutsidakis A, Karamanos NK, Tzanakakis GN (2014) Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response. Matrix Biol 35:206–214CrossRefPubMedGoogle Scholar
  46. Onda M, Ishiwata T, Kawahara K, Wang R, Naito Z, Sugisaki Y (2002) Expression of lumican in thickened intima and smooth muscle cells in human coronary atherosclerosis. Exp Mol Pathol 72:142–149CrossRefPubMedGoogle Scholar
  47. Panis C, Pizzatti L, Herrera AC, Cecchini R, Abdelhay E (2013) Putative circulating markers of the early and advanced stages of breast cancer identified by high-resolution label-free proteomics. Cancer Lett 330:57–66CrossRefPubMedGoogle Scholar
  48. Pietraszek K, Brezillon S, Perreau C, Malicka-Blaszkiewicz M, Maquart FX, Wegrowski Y (2013) Lumican – derived peptides inhibit melanoma cell growth and migration. PLoS One 8:e76232CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pietraszek K, Chatron-Colliet A, Brezillon S, Perreau C, Jakubiak-Augustyn A, Krotkiewski H, Maquart FX, Wegrowski Y (2014) Lumican: a new inhibitor of matrix metalloproteinase-14 activity. FEBS Lett 588:4319–4324CrossRefPubMedGoogle Scholar
  50. Ping Lu Y, Ishiwata T, Asano G (2002) Lumican expression in alpha cells of islets in pancreas and pancreatic cancer cells. J Pathol 196:324–330CrossRefPubMedGoogle Scholar
  51. Qin H, Ishiwata T, Asano G (2001) Effects of the extracellular matrix on lumican expression in rat aortic smooth muscle cells in vitro. J Pathol 195:604–608CrossRefPubMedGoogle Scholar
  52. Schafer M, Werner S (2008) Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9:628–638CrossRefPubMedGoogle Scholar
  53. Seya T, Tanaka N, Shinji S, Yokoi K, Koizumi M, Teranishi N, Yamashita K, Tajiri T, Ishiwata T, Naito Z (2006) Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis. Oncol Rep 16:1225–1230PubMedGoogle Scholar
  54. Sharma B, Ramus MD, Kirkwood CT, Sperry EE, Chu PH, Kao WW, Albig AR (2013) Lumican exhibits anti-angiogenic activity in a context specific manner. Cancer Microenviron 6:263–271CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sriraman SK, Aryasomayajula B, Torchilin VP (2014) Barriers to drug delivery in solid tumors. Tissue Barriers 2:e29528CrossRefPubMedPubMedCentralGoogle Scholar
  56. Stetler-Stevenson WG, Yu AE (2001) Proteases in invasion: matrix metalloproteinases. Semin Cancer Biol 11:143–152CrossRefPubMedGoogle Scholar
  57. Suhovskih AV, Mostovich LA, Kunin IS, Boboev MM, Nepomnyashchikh GI, Aidagulova SV, Grigorieva EV (2013) Proteoglycan expression in normal human prostate tissue and prostate cancer. ISRN Oncol 2013:680136PubMedPubMedCentralGoogle Scholar
  58. Sun X, Gao X, Zhou L, Sun L, Lu C (2013) PDGF-BB-induced MT1-MMP expression regulates proliferation and invasion of mesenchymal stem cells in 3-dimensional collagen via MEK/ERK1/2 and PI3K/AKT signaling. Cell Signal 25:1279–1287CrossRefPubMedGoogle Scholar
  59. Suzuki H, Chikada M, Yokoyama MK, Kurokawa MS, Ando T, Furukawa H, Arito M, Miyairi T, Kato T (2016) Aberrant glycosylation of lumican in aortic valve stenosis revealed by proteomic analysis. Int Heart J 57:104–111CrossRefPubMedGoogle Scholar
  60. Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562CrossRefPubMedGoogle Scholar
  61. Weber IT, Harrison RW, Iozzo RV (1996) Model structure of decorin and implications for collagen fibrillogenesis. J Biol Chem 271:31767–31770CrossRefPubMedGoogle Scholar
  62. Wight TN, Kinsella MG, Qwarnstrom EE (1992) The role of proteoglycans in cell adhesion, migration and proliferation. Curr Opin Cell Biol 4:793–801CrossRefPubMedGoogle Scholar
  63. Yang ZX, Lu CY, Yang YL, Dou KF, Tao KS (2013) Lumican expression in pancreatic ductal adenocarcinoma. Hepatogastroenterology 60:349–353PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Michael Pratt
    • 1
  • Ya’an Kang
    • 1
  • Xinqun Li
    • 1
  • Jason B. Fleming
    • 1
    Email author
  1. 1.Department of Surgical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations