Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Hyaluronic acid in digestive cancers



Hyaluronan (HA), an extracellular and peri-cellular glycosaminoglycan with a large molecular weight, plays an important role in cancer growth and metastasis. The aim of this study was to summarize the biological roles and regulation of HA and small HA fragments, and their metabolismn enzymes and receptors in human digestive cancers.


A systematic literature search mainly focusing on the biological roles of HA in the development and progression of human digestive cancers was performed using electronic databases.


The correlation between HA accumulation and tumor progression has been shown in various digestive cancers. HA and HA fragment-tumor cell interaction could activate the downstream signaling pathways, promoting cell proliferation, adhesion, migration and invasion, and inducing angiogenesis, lymphangiogenesis, epithelial-mesenchymal transition, stem cell-like property, and chemoradioresistance in digestive cancers.


A better insight into the mechanism of HA and HA fragment involvement in digestive cancer progression might be useful for the development of novel biomarkers and therapeutic strategies.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. Abetamann V, Kern HF, Elsasser HP (1996) Differential expression of the hyaluronan receptors CD44 and RHAMM in human pancreatic cancer cells. Clin Cancer Res Off J Am Assoc Cancer Res 2:1607–1618

  2. Abruzzo A et al (2016) Chitosan nanoparticles for lipophilic anticancer drug delivery: development, characterization and in vitro studies on HT29 cancer cells. Colloids Surf B Biointerfaces 145:362–372. doi:10.1016/j.colsurfb.2016.05.023

  3. Agren UM, Tammi RH, Tammi MI (1997) Reactive oxygen species contribute to epidermal hyaluronan catabolism in human skin organ culture. Free Radic Biol Med 23:996–1001

  4. Alaniz L et al (2004) Modulation of matrix metalloproteinase-9 activity by hyaluronan is dependent on NF-kappaB activity in lymphoma cell lines with dissimilar invasive behavior. Biochem Biophys Res Commun 324:736–743. doi:10.1016/j.bbrc.2004.09.120

  5. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–1313

  6. Banerji S et al (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801

  7. Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP (2007) Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 24:587–597. doi:10.1007/s10585-007-9114-6

  8. Bouga H et al (2010) Involvement of hyaluronidases in colorectal cancer BMC cancer 10:499. doi:10.1186/1471-2407-10-499

  9. Bourguignon LY, Singleton PA, Zhu H, Diedrich F (2003) Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J Biol Chem 278:29420–29434. doi:10.1074/jbc.M301885200

  10. Bullard KM, Kim HR, Wheeler MA, Wilson CM, Neudauer CL, Simpson MA, McCarthy JB (2003) Hyaluronan synthase-3 is upregulated in metastatic colon carcinoma cells and manipulation of expression alters matrix retention and cellular growth International journal of cancer. J Int Cancer 107:739–746. doi:10.1002/ijc.11475

  11. Cance WG et al (2000) Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes Clinical cancer research: an official journal of the American Association for. Cancer Res 6:2417–2423

  12. Carreira CM, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 61:8079–8084

  13. Cheng XB, Sato N, Kohi S, Yamaguchi K (2013) Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma. PloS One 8:e80765. doi:10.1371/journal.pone.0080765

  14. Choi KY et al (2012) Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer. Biomaterials 33:6186–6193. doi:10.1016/j.biomaterials.2012.05.029

  15. Chow G, Tauler J, Mulshine JL (2010) Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer. J Biomed Biotechnol 2010:485468. doi:10.1155/2010/485468

  16. David-Raoudi M, Tranchepain F, Deschrevel B, Vincent JC, Bogdanowicz P, Boumediene K, Pujol JP (2008) Wound Repair Regen Off Publ Wound Healing Soc Eur Tissue Repair Soc. Wound repair and regeneration 16:274–287. doi:10.1111/j.1524-475X.2007.00342.x

  17. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284. doi:10.1038/nrc1590

  18. Du YC, Chou CK, Klimstra DS, Varmus H (2011) Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis. Proc Natl Acad Sci USA 108:16753–16758. doi:10.1073/pnas.1114022108

  19. Dunn KM, Lee PK, Wilson CM, Iida J, Wasiluk KR, Hugger M, McCarthy JB (2009) Inhibition of hyaluronan synthases decreases matrix metalloproteinase-7 (MMP-7) expression and activity. Surgery 145:322–329. doi:10.1016/j.surg.2008.11.008

  20. Endo K, Terada T (2000) Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival. J Hepatol 32:78–84

  21. Fieber C et al (2004) Hyaluronan-oligosaccharide-induced transcription of metalloproteases. J Cell Sci 117:359–367. doi:10.1242/jcs.00831

  22. Fink SP et al (2015) Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. Oncotarget 6:30500–30515. doi:10.18632/oncotarget.5921

  23. Frost GI, Csoka AB, Wong T, Stern R (1997) Purification, cloning, and expression of human plasma hyaluronidase. Biochem Biophys Res Commun 236:10–15

  24. Fuchs K, Hippe A, Schmaus A, Homey B, Sleeman JP, Orian-Rousseau V (2013) Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44. Cell Death Dis 4:e819. doi:10.1038/cddis.2013.364

  25. Gao F et al (2005) Hypoxia-induced alterations in hyaluronan and hyaluronidase. Adv Exp Med Biol 566:249–256. doi:10.1007/0-387-26206-7_33

  26. Gao F, Lu YM, Cao ML, Liu YW, He YQ, Wang Y (2006) Expression and quantification of LYVE-1 in human colorectal cancer. Clin Exp Med 6:65–71. doi:10.1007/s10238-006-0097-4

  27. Gao F, Liu Y, He Y, Yang C, Wang Y, Shi X, Wei G (2010) Hyaluronan oligosaccharides promote excisional wound healing through enhanced angiogenesis. Matrix Biol J Int Soc Matrix Biol 29:107–116. doi:10.1016/j.matbio.2009.11.002

  28. Gately CL et al (1984) In vitro studies on the cell-mediated immune response to human brain tumors. II. Leukocyte-induced coats of glycosaminoglycan increase the resistance of glioma cells to cellular immune attack. J Immunol 133:3387–3395

  29. Ghatak S, Misra S, Toole BP (2002) Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J Biol Chem 277:38013–38020. doi:10.1074/jbc.M202404200

  30. Ghatak S, Misra S, Toole BP (2005) Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells. J Biol Chem 280:8875–8883. doi:10.1074/jbc.M410882200

  31. Go SI et al (2016) CD44 variant 9 serves as a poor prognostic marker in early gastric cancer, but not in advanced gastric cancer. Cancer Res Treat Off J Korean Cancer Assoc 48:142–152. doi:10.4143/crt.2014.227

  32. Gotoda T et al (2000) Expression of CD44 variants and prognosis in oesophageal squamous cell carcinoma. Gut 46:14–19

  33. Gunthert U et al (1991) A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65:13–24

  34. Guo LX, Zou K, Ju JH, Xie H (2005) Hyaluronan promotes tumor lymphangiogenesis and intralymphantic tumor growth in xenografts. Acta Biochim Biophys Sin 37:601–606

  35. Gurski LA et al (2012) Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels. PLoS One 7:e50075. doi:10.1371/journal.pone.0050075

  36. Hajime M et al (2007) Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. Int J Cancer 120:2704–2709. doi:10.1002/ijc.22349

  37. Hall CL et al (1995) Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82:19–26

  38. Hardwick C et al (1992) Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol 117:1343–1350

  39. Heffler M, Golubovskaya VM, Conroy J, Liu S, Wang D, Cance WG, Dunn KB (2013) FAK and HAS inhibition synergistically decrease colon cancer cell viability and affect expression of critical genes. Anti-cancer Agents Med Chem 13:584–594

  40. Herrera-Gayol A, Jothy S (2001) Effects of hyaluronan on the invasive properties of human breast cancer cells in vitro. Int J Exp Pathol 82:193–200

  41. Hobarth K, Maier U, Marberger M (1992) Topical chemoprophylaxis of superficial bladder cancer with mitomycin C and adjuvant hyaluronidase. Eur Urol 21:206–210

  42. Ishigami S et al (2011) Prognostic impact of CD168 expression in gastric cancer. BMC Cancer 11:106. doi:10.1186/1471-2407-11-106

  43. Itano N et al (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274:25085–25092

  44. Itano N et al (2002) Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration. Proc Natl Acad Sci USA 99:3609–3614. doi:10.1073/pnas.052026799

  45. Jacobetz MA et al (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62:112–120. doi:10.1136/gutjnl-2012-302529

  46. Jain A, Jain SK, Ganesh N, Barve J, Beg AM (2010) Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomed Nanotechnol Biol Med 6:179–190. doi:10.1016/j.nano.2009.03.002

  47. Jiang G, Park K, Kim J, Kim KS, Hahn SK (2009) Target specific intracellular delivery of siRNA/PEI-HA complex by receptor mediated endocytosis. Mol Pharm 6:727–737. doi:10.1021/mp800176t

  48. Jojovic M, Delpech B, Prehm P, Schumacher U (2002) Expression of hyaluronate and hyaluronate synthase in human primary tumours and their metastases in scid mice. Cancer Lett 188:181–189

  49. Ju SY, Chiou SH, Su Y (2014) Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression. Stem Cell Res 12:86–100. doi:10.1016/j.scr.2013.09.011

  50. Kakehashi A, Ishii N, Sugihara E, Gi M, Saya H, Wanibuchi H (2016) CD44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus-positive patients with resected hepatocellular carcinoma. Cancer Sci 107:609–618. doi:10.1111/cas.12908

  51. Katoh S et al (2015) Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer. Anticancer Res 35:239–244

  52. Kawano Y, Okamoto I, Murakami D, Itoh H, Yoshida M, Ueda S, Saya H (2000) Ras oncoprotein induces CD44 cleavage through phosphoinositide 3-OH kinase and the rho family of small G proteins. J Biol Chem 275:29628–29635. doi:10.1074/jbc.M002440200

  53. Khurana SS et al (2013) The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation. J Biol Chem 288:16085–16097. doi:10.1074/jbc.M112.445551

  54. Kim HR et al (2004) Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD44. Cancer Res 64:4569–4576. doi:10.1158/0008-5472.CAN-04-0202

  55. Kim MS et al (2005) Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Int J Oncol 27:839–846

  56. Kobel M, Weichert W, Cruwell K, Schmitt WD, Lautenschlager C, Hauptmann S (2004) Epithelial hyaluronic acid and CD44v6 are mutually involved in invasion of colorectal adenocarcinomas and linked to patient prognosis. Virchows Arch Int J Pathol 445:456–464. doi:10.1007/s00428-004-1095-0

  57. Kohno N, Ohnuma T, Truog P (1994) Effects of hyaluronidase on doxorubicin penetration into squamous carcinoma multicellular tumor spheroids and its cell lethality. J Cancer Res Clin Oncol 120:293–297

  58. Kolliopoulos C, Bounias D, Bouga H, Kyriakopoulou D, Stavropoulos M, Vynios DH (2013) Hyaluronidases and their inhibitors in the serum of colorectal carcinoma patients. J Pharm Biomed Anal 83:299–304. doi:10.1016/j.jpba.2013.05.037

  59. Kosaki R, Watanabe K, Yamaguchi Y (1999) Overproduction of hyaluronan by expression of the hyaluronan synthase Has2 enhances anchorage-independent growth and tumorigenicity. Cancer Res 59:1141–1145

  60. Kouvidi K et al (2011) Role of receptor for hyaluronic acid-mediated motility (RHAMM) in low molecular weight hyaluronan (LMWHA)-mediated fibrosarcoma cell adhesion. J Biol Chem 286:38509–38520. doi:10.1074/jbc.M111.275875

  61. Kultti A et al (2009) 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 315:1914–1923. doi:10.1016/j.yexcr.2009.03.002

  62. Kultti A et al (2014) Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. BioMed Res Int 2014:817613. doi:10.1155/2014/817613

  63. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068. doi:10.1002/stem.154

  64. Lai E et al (2010) Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth in mice. Dis Colon Rectum 53:475–482. doi:10.1007/DCR.0b013e3181c87084

  65. Lau WM et al (2014) CD44v8-10 is a cancer-specific marker for gastric cancer stem cells. Cancer Res 74:2630–2641. doi:10.1158/0008-5472.CAN-13-2309

  66. Laurich C, Wheeler MA, Iida J, Neudauer CL, McCarthy JB, Bullard KM (2004) Hyaluronan mediates adhesion of metastatic colon carcinoma cells. J Surg Res 122:70–74. doi:10.1016/j.jss.2004.05.018

  67. Lee H, Mok H, Lee S, Oh YK, Park TG (2007) Target-specific intracellular delivery of siRNA using degradable hyaluronic acid nanogels. J Control Rel Off J Control Rel Soc 119:245–252. doi:10.1016/j.jconrel.2007.02.011

  68. Li C et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037. doi:10.1158/0008-5472.CAN-06-2030

  69. Liu D et al (1996) Expression of hyaluronidase by tumor cells induces angiogenesis in vivo. Proc Natl Acad Sci USA 93:7832–7837

  70. Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA (2005) CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res 65:6755–6763. doi:10.1158/0008-5472.CAN-05-0863

  71. Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715. doi:10.1016/j.cell.2008.03.027

  72. Matou-Nasri S, Gaffney J, Kumar S, Slevin M (2009) Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and gamma-adducin. Int J Oncol 35:761–773

  73. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, Noble PW (1996) Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Investig 98:2403–2413. doi:10.1172/JCI119054

  74. Mezghrani O et al (2015) Hepatocellular carcinoma dually-targeted nanoparticles for reduction triggered intracellular delivery of doxorubicin. Int J Pharm 478:553–568. doi:10.1016/j.ijpharm.2014.10.041

  75. Mima K et al (2014) Preoperative serum hyaluronic acid level as a prognostic factor in patients undergoing hepatic resection for hepatocellular carcinoma. Br J Surg 101:269–276. doi:10.1002/bjs.9343

  76. Misra S, Ghatak S, Zoltan-Jones A, Toole BP (2003) Regulation of multidrug resistance in cancer cells by hyaluronan. J Biol Chem 278:25285–25288. doi:10.1074/jbc.C300173200

  77. Misra S et al (2008) Hyaluronan constitutively regulates activation of COX-2-mediated cell survival activity in intestinal epithelial and colon carcinoma cells. J Biol Chem 283:14335–14344. doi:10.1074/jbc.M703811200

  78. Morohashi H et al (2006) Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL). Biochem Biophys Res Commun 345:1454–1459. doi:10.1016/j.bbrc.2006.05.037

  79. Mueller BM, Schraufstatter IU, Goncharova V, Povaliy T, DiScipio R, Khaldoyanidi SK (2010) Hyaluronan inhibits postchemotherapy tumor regrowth in a colon carcinoma xenograft model. Mol Cancer Ther 9:3024–3032. doi:10.1158/1535-7163.MCT-10-0529

  80. Murray D, Morrin M, McDonnell S (2004) Increased invasion and expression of MMP-9 in human colorectal cell lines by a CD44-dependent mechanism. Anticancer Res 24:489–494

  81. Nagaoka A et al (2015) Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts. J Biol Chem 290:30910–30923. doi:10.1074/jbc.M115.673566

  82. Nakazawa H et al (2006) 4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells. Cancer Chemother Pharmacol 57:165–170. doi:10.1007/s00280-005-0016-5

  83. Nobumoto A et al (2008) Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices. Glycobiology 18:735–744. doi:10.1093/glycob/cwn062

  84. Olofsson B, Porsch H, Heldin P (2014) Knock-down of CD44 regulates endothelial cell differentiation via NFkappaB-mediated chemokine production. PLoS One 9:e90921. doi:10.1371/journal.pone.0090921

  85. Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074–3086. doi:10.1101/gad.242602

  86. Pares A et al (1996) Serum hyaluronate reflects hepatic fibrogenesis in alcoholic liver disease and is useful as a marker of fibrosis. Hepatology 24:1399–1403. doi:10.1002/hep.510240615

  87. Park MJ et al (2002) PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res 62:6318–6322

  88. Peterson RS et al (2004) CD44 modulates Smad1 activation in the BMP-7 signaling pathway. J Cell Biol 166:1081–1091. doi:10.1083/jcb.200402138

  89. Piccioni F et al (2012) Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice. Glycobiology 22:400–410. doi:10.1093/glycob/cwr158

  90. Porsch H, Bernert B, Mehic M, Theocharis AD, Heldin CH, Heldin P (2013) Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene 32:4355–4365. doi:10.1038/onc.2012.475

  91. Prehm P (1984) Hyaluronate is synthesized at plasma membranes. Biochem J 220:597–600

  92. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–429. doi:10.1016/j.ccr.2012.01.007

  93. Roden L, Campbell P, Fraser JR, Laurent TC, Pertoft H, Thompson JN (1989) Enzymic pathways of hyaluronan catabolism. Ciba Found Symp 143:60–76 (discussion 76–86, 281–285)

  94. Rooney P, Kumar S, Ponting J, Wang M (1995) The role of hyaluronan in tumour neovascularization (review). Int J Cancer J Int Cancer 60:632–636

  95. Ropponen K et al (1998) Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res 58:342–347

  96. Sato N, Maehara N, Goggins M (2004) Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 64:6950–6956. doi:10.1158/0008-5472.CAN-04-0677

  97. Scaife CL, Shea JE, Dai Q, Firpo MA, Prestwich GD, Mulvihill SJ (2008) Synthetic extracellular matrix enhances tumor growth and metastasis in an orthotopic mouse model of pancreatic adenocarcinoma. J Gastrointest Surg Off J Soc Surg Aliment Tract 12:1074–1080. doi:10.1007/s11605-007-0425-3

  98. Schmaus A et al (2014) Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis. Br J Cancer 111:559–567. doi:10.1038/bjc.2014.332

  99. Setala LP et al (1999) Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. Br J Cancer 79:1133–1138. doi:10.1038/sj.bjc.6690180

  100. Shen YN et al (2014) Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage. Biochem Biophys Res Commun 443:796–801. doi:10.1016/j.bbrc.2013.12.026

  101. Simpson MA, Wilson CM, Furcht LT, Spicer AP, Oegema TR Jr, McCarthy JB (2002) Manipulation of hyaluronan synthase expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells. J Biol Chem 277:10050–10057. doi:10.1074/jbc.M110069200

  102. Sleeman JP, Thiery JP (2011) SnapShot: the epithelial-mesenchymal transition. Cell 145(162):e161. doi:10.1016/j.cell.2011.03.029

  103. Sohr S, Engeland K (2008) RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle 7:3448–3460

  104. Stern R, Asari AA, Sugahara KN (2006) Hyaluronan fragments: an information-rich system. Eur J Cell Biol 85:699–715. doi:10.1016/j.ejcb.2006.05.009

  105. Stern R, Kogan G, Jedrzejas MJ, Soltes L (2007) The many ways to cleave hyaluronan. Biotechnol Adv 25:537–557. doi:10.1016/j.biotechadv.2007.07.001

  106. Subramaniam V, Gardner H, Jothy S (2007a) Soluble CD44 secretion contributes to the acquisition of aggressive tumor phenotype in human colon cancer cells. Exp Mol Pathol 83:341–346. doi:10.1016/j.yexmp.2007.08.007

  107. Subramaniam V, Vincent IR, Gilakjan M, Jothy S (2007b) Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy. Exp Mol Pathol 83:332–340. doi:10.1016/j.yexmp.2007.08.013

  108. Sugahara KN, Murai T, Nishinakamura H, Kawashima H, Saya H, Miyasaka M (2003) Hyaluronan oligosaccharides induce CD44 cleavage and promote cell migration in CD44-expressing tumor cells. J Biol Chem 278:32259–32265. doi:10.1074/jbc.M300347200

  109. Sugahara KN, Hirata T, Hayasaka H, Stern R, Murai T, Miyasaka M (2006) Tumor cells enhance their own CD44 cleavage and motility by generating hyaluronan fragments. J Biol Chem 281:5861–5868. doi:10.1074/jbc.M506740200

  110. Takahashi Y, Li L, Kamiryo M, Asteriou T, Moustakas A, Yamashita H, Heldin P (2005) Hyaluronan fragments induce endothelial cell differentiation in a CD44- and CXCL1/GRO1-dependent manner. J Biol Chem 280:24195–24204. doi:10.1074/jbc.M411913200

  111. Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL (2004) Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 279:17079–17084. doi:10.1074/jbc.M310859200

  112. Teng BP, Heffler MD, Lai EC, Zhao YL, LeVea CM, Golubovskaya VM, Bullarddunn KM (2011) Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth by increasing apoptosis. Anti-Cancer Agents Med Chem 11:620–628

  113. Teranishi F, Takahashi N, Gao N, Akamo Y, Takeyama H, Manabe T, Okamoto T (2009) Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Sci 100:770–777

  114. Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, Simon JC (2000) Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 165:1863–1870

  115. Termeer C et al (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195:99–111

  116. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142. doi:10.1038/nrm1835

  117. Tolg C et al (2012) A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis in excisional skin wounds. Am J Pathol 181:1250–1270. doi:10.1016/j.ajpath.2012.06.036

  118. Toole BP (1990) Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol 2:839–844

  119. Twarock S, Tammi MI, Savani RC, Fischer JW (2010) Hyaluronan stabilizes focal adhesions, filopodia, and the proliferative phenotype in esophageal squamous carcinoma cells. J Biol Chem 285:23276–23284. doi:10.1074/jbc.M109.093146

  120. Vizoso FJ, del Casar JM, Corte MD, Garcia I, Corte MG, Alvarez A, Garcia-Muniz JL (2004) Significance of cytosolic hyaluronan levels in gastric cancer. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 30:318–324. doi:10.1016/j.ejso.2003.11.007

  121. Wang SJ, Bourguignon LY (2006) Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch Otolaryngol Head Neck Surg 132:771–778. doi:10.1001/archotol.132.7.771

  122. Wang C, Tammi M, Guo H, Tammi R (1996) Hyaluronan distribution in the normal epithelium of esophagus, stomach, and colon and their cancers. Am J Pathol 148:1861–1869

  123. Wang YZ, Cao ML, Liu YW, He YQ, Yang CX, Gao F (2011) CD44 mediates oligosaccharides of hyaluronan-induced proliferation, tube formation and signal transduction in endothelial cells. Exp Biol Med 236:84–90. doi:10.1258/ebm.2010.010206

  124. West DC, Hampson IN, Arnold F, Kumar S (1985) Angiogenesis induced by degradation products of hyaluronic acid. Science 228:1324–1326

  125. Wu Y, Zhao Q, Peng C, Sun L, Li XF, Kuang DM (2011) Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop. J Pathol 225:438–447. doi:10.1002/path.2947

  126. Wu M, Du Y, Liu Y, He Y, Yang C, Wang W, Gao F (2014) Low molecular weight hyaluronan induces lymphangiogenesis through LYVE-1-mediated signaling pathways. PLoS One 9:e92857. doi:10.1371/journal.pone.0092857

  127. Xin Y, Grace A, Gallagher MM, Curran BT, Leader MB, Kay EW (2001) CD44V6 in gastric carcinoma: a marker of tumor progression. Appl Immunohistochem Mol Morphol AIMM/Off Publ Soc Appl Immunohistochem 9:138–142

  128. Yang CW et al (2005) Integrative genomics based identification of potential human hepatocarcinogenesis-associated cell cycle regulators: RHAMM as an example. Biochem Biophys Res Commun 330:489–497. doi:10.1016/j.bbrc.2005.03.005

  129. Yoshida H et al (2013) KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Sci USA 110:5612–5617. doi:10.1073/pnas.1215432110

  130. Yoshida H, Nagaoka A, Nakamura S, Tobiishi M, Sugiyama Y, Inoue S (2014) N-terminal signal sequence is required for cellular trafficking and hyaluronan-depolymerization of KIAA1199. FEBS Lett 588:111–116. doi:10.1016/j.febslet.2013.11.017

  131. Yoshihara S et al (2005) A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. FEBS Lett 579:2722–2726. doi:10.1016/j.febslet.2005.03.079

  132. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176

  133. Zhang L et al (2013a) Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor-1 alpha in hepatocellular carcinoma. BMC Cancer 13:108. doi:10.1186/1471-2407-13-108

  134. Zhang L, Yao J, Zhou J, Wang T, Zhang Q (2013b) Glycyrrhetinic acid-graft-hyaluronic acid conjugate as a carrier for synergistic targeted delivery of antitumor drugs. Int J Pharm 441:654–664. doi:10.1016/j.ijpharm.2012.10.030

  135. Zlobec I, Baker K, Terracciano LM, Lugli A (2008) RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis. Clin Cancer Res Off J Am Assoc Cancer Res 14:3798–3806. doi:10.1158/1078-0432.CCR-07-5103

  136. Zoltan-Jones A, Huang L, Ghatak S, Toole BP (2003) Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem 278:45801–45810. doi:10.1074/jbc.M308168200

Download references


The authors would sincerely thank the reviewers and editors for critically reviewing this paper and for the constructive and thoughtful comments and suggestions. This work was supported by the Medical Scientific Research Foundation of Anhui Province (No.: 2010A009). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Wu RL, Huang L, Zhao HC, and Geng XP designed the research; Wu RL and Huang L performed the research and wrote the paper; Zhao HC and Geng XP critically reviewed the paper.

Author information

Correspondence to Xiao-Ping Geng.

Ethics declarations

Conflict of interest


Additional information

Ruo-Lin Wu and Lei Huang have contributed equally to this paper.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, R., Huang, L., Zhao, H. et al. Hyaluronic acid in digestive cancers. J Cancer Res Clin Oncol 143, 1–16 (2017). https://doi.org/10.1007/s00432-016-2213-5

Download citation


  • Hyaluronan
  • Receptor
  • Digestive cancer
  • Tumor growth
  • Epithelial–mesenchymal transition
  • Metastasis
  • Prognosis