{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:27:06Z","timestamp":1777498026354,"version":"3.51.4"},"reference-count":62,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T00:00:00Z","timestamp":1553212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["#276426 #284520 and #312519"],"award-info":[{"award-number":["#276426 #284520 and #312519"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>CD44 is a multifunctional adhesion molecule typically upregulated in malignant, inflamed and injured tissues. Due to its ability to bind multiple ligands present in the tumor microenvironment, it promotes multiple cellular functions related to tumorigenesis. Recent data has shown that CD44 and its principal ligand hyaluronan (HA) are carried by extracellular vesicles (EV) derived from stem and tumor cells, but the role of CD44 in EV shedding has not been studied so far. To answer this question, we utilized CD44-negative human gastric carcinoma cell line MKN74 manipulated to stably express CD44 standard form (CD44s). The effect of CD44s expression on HA metabolism, EV secretion, morphology and growth of these cells was studied. Interestingly, HAS2 and HYAL2 expression levels were significantly upregulated in CD44s-expressing cells. Cell-associated HA levels were significantly increased, while HA levels in the culture medium of CD44s-positive cells was lower compared to CD44s-negative MOCK cells. CD44s expression had no significant effect on the proliferation capacity of cells, but cells showed diminished contact inhibition. Superresolution imaging revealed that CD44s and HA were accumulated on filopodia and EVs secreted from CD44s-positive cells, but no differences in total numbers of secreted EV between CD44s-negative and -positive cells was detected. In 3D cultures, CD44s-expressing cells had an enhanced invasion capacity in BME gel and increased spheroidal growth when cultured in collagen I gel. No significant differences in mitotic activity, tumor size or morphology were detected in CAM assays. However, a significant increase in HA staining coverage was detected in CD44s-positive tumors. Interestingly, CD44s-positive EVs embedded in HA-rich matrix were detected in the stromal areas of tumors. The results indicate that CD44s expression significantly increases the HA binding capacity of gastric cancer cells, while the secreted HA is downregulated. CD44s is also carried by EVs secreted by CD44s-expressing cells. These findings highlight the potential usefulness of CD44s and its ligands as multipurpose EV biomarkers, because they are upregulated in inflammatory, injured, and cancer cells and accumulate on the surface of EVs secreted in these situations.<\/jats:p>","DOI":"10.3390\/cells8030276","type":"journal-article","created":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T05:03:12Z","timestamp":1553662992000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["CD44s Assembles Hyaluronan Coat on Filopodia and Extracellular Vesicles and Induces Tumorigenicity of MKN74 Gastric Carcinoma Cells"],"prefix":"10.3390","volume":"8","author":[{"given":"Kai","family":"H\u00e4rk\u00f6nen","sequence":"first","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"given":"Sanna","family":"Oikari","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"given":"Heikki","family":"Kyykallio","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8446-2357","authenticated-orcid":false,"given":"Janne","family":"Capra","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"given":"Sini","family":"Hakkola","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"given":"Kirsi","family":"Ketola","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5211-1007","authenticated-orcid":false,"given":"Uma","family":"Thanigai Arasu","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"given":"George","family":"Daaboul","sequence":"additional","affiliation":[{"name":"Nanoview Nanosciences, Boston, MA 02135, USA"}]},{"given":"Andrew","family":"Malloy","sequence":"additional","affiliation":[{"name":"Nanoview Nanosciences, Boston, MA 02135, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8340-2264","authenticated-orcid":false,"given":"Carla","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, 4099-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology, University of Porto, 4099-135 Porto, Portugal"},{"name":"Department of Pathology and Oncology, Faculty of Medicine, University of Porto, 4099-319 Porto, Portugal"}]},{"given":"Otto","family":"Jokelainen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland"},{"name":"Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland"},{"name":"Cancer Center of Eastern Finland, University of Kuopio, 70211 Kuopio, Finland"}]},{"given":"Reijo","family":"Sironen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland"},{"name":"Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland"},{"name":"Cancer Center of Eastern Finland, University of Kuopio, 70211 Kuopio, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8267-1905","authenticated-orcid":false,"given":"Jaana M.","family":"Hartikainen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland"},{"name":"Translational Cancer Research Area, University of Eastern Finland, 70211 Kuopio, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7862-5727","authenticated-orcid":false,"given":"Kirsi","family":"Rilla","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/0092-8674(89)90639-9","article-title":"A human lymphocyte homing receptor, the hermes antigen, is related to cartilage proteoglycan core and link proteins","volume":"56","author":"Goldstein","year":"1989","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/0092-8674(90)90694-A","article-title":"CD44 is the principal cell surface receptor for hyaluronate","volume":"61","author":"Aruffo","year":"1990","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.biocel.2016.09.009","article-title":"CD44: More than a mere stem cell marker","volume":"81","author":"Morath","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1083\/jcb.140.4.885","article-title":"Ezrin\/radixin\/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2","volume":"140","author":"Yonemura","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S0960-9822(98)70277-5","article-title":"Identification and functional analysis of the ezrin-binding site in the hyaluronan receptor, CD44","volume":"8","author":"Legg","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8875","DOI":"10.1074\/jbc.M410882200","article-title":"Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells","volume":"280","author":"Ghatak","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_7","first-page":"211","article-title":"CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion","volume":"41","author":"Cho","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13045-018-0605-5","article-title":"The biology and role of CD44 in cancer progression: Therapeutic implications","volume":"11","author":"Chen","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.yexcr.2010.11.017","article-title":"Hyaluronan in human malignancies","volume":"317","author":"Sironen","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1080\/10408360290795574","article-title":"CD44 in Cancer","volume":"39","author":"Naor","year":"2002","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00418-013-1143-4","article-title":"Tissue distribution and subcellular localization of hyaluronan synthase isoenzymes","volume":"141","author":"Nikunen","year":"2014","journal-title":"Histochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1369\/jhc.2008.951665","article-title":"Pericellular hyaluronan coat visualized in live cells with a fluorescent probe is scaffolded by plasma membrane protrusions","volume":"56","author":"Rilla","year":"2008","journal-title":"J. Histochem. Cytochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1369\/jhc.2009.953802","article-title":"Organization of hyaluronan and versican in the extracellular matrix of human fibroblasts treated with the viral mimetic poly I:C","volume":"57","author":"Evanko","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/wrr.12022","article-title":"Mannose reduces hyaluronan and leukocytes in wound granulation tissue and inhibits migration and hyaluronan-dependent monocyte binding","volume":"21","author":"Jokela","year":"2013","journal-title":"Wound Repair Regen."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1177\/002215549704500813","article-title":"Patterns of hyaluronan staining are modified by fixation techniques","volume":"45","author":"Lin","year":"1997","journal-title":"J. Histochem. Cytochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.drudis.2016.12.009","article-title":"Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy","volume":"22","author":"Wickens","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: Exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pokharel, D., Padula, M., Lu, J., Jaiswal, R., Djordjevic, S., and Bebawy, M. (2016). The role of CD44 and ERM proteins in expression and functionality of P-glycoprotein in breast cancer cells. Molecules, 21.","DOI":"10.3390\/molecules21030290"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.matbio.2017.05.001","article-title":"Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles","volume":"64","author":"Arasu","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12964-015-0124-8","article-title":"MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry","volume":"14","author":"Ramos","year":"2016","journal-title":"Cell Commun. Signal."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Koistinen, V., H\u00e4rk\u00f6nen, K., K\u00e4rn\u00e4, R., Arasu, U.T., Oikari, S., and Rilla, K. (2017). EMT induced by EGF and wounding activates hyaluronan synthesis machinery and EV shedding in rat primary mesothelial cells. Matrix Biol., 63.","DOI":"10.1016\/j.matbio.2016.12.007"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1016\/j.yexcr.2013.05.021","article-title":"Hyaluronan production enhances shedding of plasma membrane-derived microvesicles","volume":"319","author":"Rilla","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/B978-0-12-800092-2.00005-8","article-title":"Hyaluronan-coated extracellular vesicles- A novel link between hyaluronan and cancer","volume":"123","author":"Rilla","year":"2004","journal-title":"Adv. Cancer Res."},{"key":"ref_24","first-page":"6410","article-title":"Elevated hyaluronan concentration without hyaluronidase activation in malignant epithelial ovarian tumors","volume":"62","author":"Hiltunen","year":"2002","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35111","DOI":"10.1074\/jbc.M103481200","article-title":"Hyaluronan enters keratinocytes by a novel endocytic route for catabolism","volume":"276","author":"Tammi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1242\/jcs.106.1.365","article-title":"Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis","volume":"106","author":"Hua","year":"1993","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31890","DOI":"10.1074\/jbc.M504736200","article-title":"Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity","volume":"280","author":"Rilla","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Karalis, T.T., Heldin, P., Vynios, D.H., Neill, T., Buraschi, S., Iozzo, R.V., Karamanos, N.K., and Skandalis, S.S. (2018). Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status: Regulation of hyaluronan\/HAS2\/CD44 and specific matrix effectors. Matrix Biol.","DOI":"10.1016\/j.matbio.2018.04.007"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1046\/j.1523-1747.2001.00236.x","article-title":"CD44 is the Principal mediator of hyaluronic-acid-induced melanoma cell proliferation","volume":"116","author":"Assmann","year":"2001","journal-title":"J. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Heldin, P., Lin, C.-Y., Kolliopoulos, C., Chen, Y.-H., and Skandalis, S.S. (2018). Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production. Matrix Biol.","DOI":"10.1016\/j.matbio.2018.01.017"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34176","DOI":"10.1038\/srep34176","article-title":"A single molecule assay to probe monovalent and multivalent bonds between hyaluronan and its key leukocyte receptor CD44 under force","volume":"6","author":"Bano","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1006\/excr.1993.1264","article-title":"Synthesis and assembly of the hyaluronan-containing coats around normal human mesothelial cells","volume":"208","author":"Heldin","year":"1993","journal-title":"Exp. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.yexcr.2013.09.021","article-title":"Hyaluronan synthase 1 (HAS1) produces a cytokine-and glucose-inducible, CD44-dependent cell surface coat","volume":"320","author":"Siiskonen","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fimmu.2015.00043","article-title":"Hyaluronan synthase 1: A mysterious enzyme with unexpected functions","volume":"6","author":"Siiskonen","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Knudson, W., Ishizuka, S., Terabe, K., Askew, E.B., and Knudson, C.B. (2018). The pericellular hyaluronan of articular chondrocytes. Matrix Biol.","DOI":"10.1016\/j.matbio.2018.02.005"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23276","DOI":"10.1074\/jbc.M109.093146","article-title":"Hyaluronan stabilizes focal adhesions, filopodia, and the proliferative phenotype in esophageal squamous carcinoma cells","volume":"285","author":"Twarock","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15821","DOI":"10.1074\/jbc.M512840200","article-title":"Hyaluronan synthesis induces microvillus-like cell surface protrusions","volume":"281","author":"Kultti","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Melero-Fernandez de Mera, R.M., Arasu, U.T., K\u00e4rn\u00e4, R., Oikari, S., Rilla, K., Vigetti, D., Passi, A., Heldin, P., Tammi, M.I., and Deen, A.J. (2018). Effects of mutations in the post-translational modification sites on the trafficking of hyaluronan synthase 2 (HAS2). Matrix Biol.","DOI":"10.1016\/j.matbio.2018.10.004"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1158\/1541-7786.MCR-16-0191","article-title":"Exosomes promote ovarian cancer cell invasion through transfer of CD44 to peritoneal mesothelial cells","volume":"15","author":"Nakamura","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fimmu.2015.00068","article-title":"Interactions between CD44 and hyaluronan in leukocyte trafficking","volume":"6","author":"McDonald","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1182\/blood-2003-10-3611","article-title":"CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem\/progenitor cells to bone marrow","volume":"103","author":"Avigdor","year":"2004","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00418-012-0916-5","article-title":"The interaction between CD44 on tumour cells and hyaluronan under physiologic flow conditions: Implications for metastasis formation","volume":"137","author":"Richter","year":"2012","journal-title":"Histochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14939","DOI":"10.1074\/jbc.275.20.14939","article-title":"Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44","volume":"275","author":"Nandi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00418-016-1405-z","article-title":"Hyaluronan-positive plasma membrane protrusions exist on mesothelial cells in vivo","volume":"145","author":"Koistinen","year":"2016","journal-title":"Histochem. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1021\/mp2000428","article-title":"Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes","volume":"8","author":"Qhattal","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5043","DOI":"10.1016\/j.bmc.2005.04.084","article-title":"Recent advances in tumor-targeting anticancer drug conjugates","volume":"13","author":"Jaracz","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20614","DOI":"10.1021\/acsami.6b06823","article-title":"Multifunctional hyaluronic acid and chondroitin sulfate nanoparticles: Impact of glycosaminoglycan presentation on receptor mediated cellular uptake and immune activation","volume":"8","author":"Oommen","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1440-1827.2011.02760.x","article-title":"Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer","volume":"62","author":"Wakamatsu","year":"2012","journal-title":"Pathol. Int."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cao, X., Cao, D., Jin, M., Jia, Z., Kong, F., Ma, H., Wang, Y., and Jiang, J. (2014). CD44 but not CD24 expression is related to poor prognosis in non-cardia adenocarcinoma of the stomach. BMC Gastroenterol., 14.","DOI":"10.1186\/1471-230X-14-157"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1007\/s00432-015-1964-8","article-title":"Evaluation of the prognostic value and functional roles of CD44v6 in gastric cancer","volume":"141","author":"Xie","year":"2015","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/bjc.2016.401","article-title":"Prognostic impact of CD44-positive cancer stem-like cells at the invasive front of gastric cancer","volume":"116","author":"Kodama","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1053\/j.gastro.2015.05.059","article-title":"Genetics and molecular pathogenesis of gastric adenocarcinoma","volume":"149","author":"Tan","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.semcancer.2008.03.005","article-title":"Hyaluronan in human tumors: Pathobiological and prognostic messages from cell-associated and stromal hyaluronan","volume":"18","author":"Tammi","year":"2008","journal-title":"Semin. Cancer Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/ijc.27707","article-title":"Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer","volume":"132","author":"Auvinen","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"811","DOI":"10.3892\/etm.2012.505","article-title":"CD44 is associated with tumor recurrence and is an independent poor prognostic factor for patients with localized clear cell renal cell carcinoma after nephrectomy","volume":"3","author":"Jeong","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_56","first-page":"5318","article-title":"CD44 expression indicates favorable prognosis in epithelial ovarian cancer","volume":"9","author":"Anttila","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_57","first-page":"717","article-title":"Low expression of CD44 is an independent factor of poor prognosis in ovarian mucinous carcinoma","volume":"38","author":"Matuura","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1182\/blood.V90.6.2217","article-title":"CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity","volume":"90","author":"Schmits","year":"1997","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2018.03.023","article-title":"Extracellular matrix: The driving force of mammalian diseases","volume":"71\u201372","author":"Iozzo","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"45538","DOI":"10.18632\/oncotarget.9998","article-title":"Prognostic significance of CD44 in human colon cancer and gastric cancer: Evidence from bioinformatic analyses","volume":"7","author":"Xia","year":"2016","journal-title":"Oncotarget"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tammi, M.I., Oikari, S., Pasonen-Sepp\u00e4nen, S., Rilla, K., Auvinen, P., and Tammi, R.H. (2018). Activated hyaluronan metabolism in the tumor matrix\u2014Causes and consequences. Matrix Biol.","DOI":"10.1016\/j.matbio.2018.04.012"},{"key":"ref_62","first-page":"201","article-title":"Extracellular vesicles are integral and functional components of the extracellular matrix","volume":"75\u201376","author":"Rilla","year":"2017","journal-title":"Matrix Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/3\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:40:04Z","timestamp":1760186404000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/3\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,22]]},"references-count":62,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["cells8030276"],"URL":"https:\/\/doi.org\/10.3390\/cells8030276","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,22]]}}}