Location of Repository

Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis

By Miranda P. Ween, Martin K. Oehler and Carmela Ricciardelli


There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer

Topics: Review
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier: oai:pubmedcentral.nih.gov:3083686
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles



    1. A novel intralymphatic nanocarrier delivery system for cisplatin therapy in breast cancer with improved tumor efficacy and lower systemic toxicity in vivo.
    2. (2008). A paclitaxel-hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity. Clin. Cancer Res.
    3. (2006). A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro.
    4. (2009). Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides. Cancer Res.
    5. (2008). An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor.
    6. Ankyrin-Tiam1 interaction promotes Rac1 signaling and metastatic breast tumor cell invasion and migration.
    7. Assembly of a chondrocyte-like pericellular matrix on non-chondrogenic cells. Role of the cell surface hyaluronan receptors in the assembly of a pericellular matrix.
    8. (1993). Assembly of pericellular matrices by COS-7 cells transfected with CD44 lymphocyte-homing receptor genes.
    9. (1995). Association of versican with dermal matrices and its potential role in hair follicle development and cycling.
    10. (1999). Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro.
    11. (1997). Binding of ovarian cancer cells to immobilized hyaluronic acid.
    12. (1993). Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H. Cancer Res.
    13. (1995). CD-44 is not involved in the metastatic spread of ovarian cancer in vivo. Anticancer Res.
    14. CD44 and beta1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells.
    15. (2000). CD44 and beta1 integrins mediate ovarian carcinoma cell migration toward extracellular matrix proteins.
    16. (1999). CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression.
    17. (2011). CD44 expression indicates favorable prognosis in epithelial ovarian cancer.
    18. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration.
    19. (1990). CD44 is the principal cell surface receptor for hyaluronate. Cell
    20. (1998). CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression.
    21. (1999). CD44 modulates Hs578T human breast cancer cell adhesion, migration, and invasiveness.
    22. (2004). CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res.
    23. (2009). CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts.
    24. (1995). CD44 variant expression is a common feature of epithelial ovarian cancer: lack of association with standard prognostic factors.
    25. CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2.
    26. (2009). CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.
    27. (2010). CD44, a therapeutic target for metastasising tumours.
    28. (2004). CD44s expression, in benign, borderline and malignant tumors of ovarian surface epithelium. Correlation with p53, steroid receptor status, proliferative indices (PCNA, MIB1) and survival. Anticancer Res.
    29. CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer.
    30. (2003). Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells.
    31. (1994). Characterization of the complete genomic structure of the human versican gene and functional analysis of its promoter.
    32. Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer.
    33. (2009). Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression.
    34. Decreased CD44 standard form expression correlates with prognostic variables in ovarian carcinomas.
    35. (2008). DNA vaccination with CD44 variant isoform reduces mammary tumor local growth and lung metastasis. Mol. Cancer Ther.
    36. (2002). Elevated hyaluronan concentration without hyaluronidase activation in malignant epithelial ovarian tumors. Cancer Res.
    37. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models.
    38. (2003). Establishment of an in vitro assay to measure the invasion of ovarian carcinoma cells through mesothelial cell monolayers.
    39. (2003). Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Res.
    40. (1997). Expression of CD44 standard and variant isoforms v5, v6 and v7 in human ovarian cancer cell lines. Anticancer Res.
    41. Expression of CD44S and CD44v5 is more common in stage III than in stage I serous ovarian carcinomas.
    42. (2004). Expression of CD44v6 and E-cadherin in prostate carcinoma and metastasis of prostate carcinoma. Zhonghua Nan Ke Xue
    43. (1995). Expression of cell adhesion molecules on ovarian tumour cell lines and mesothelial cells, in relation to ovarian cancer metastasis. Cancer Lett.
    44. (2004). Expression of E-cadherin, and CD44s and CD44v6 and its association with prognosis in head and neck cancer. Auris Nasus Larynx
    45. (2004). Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer. Clin. Cancer Res.
    46. (2011). Expression of hyaluronan in human tumor progression.
    47. (2009). Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.
    48. (2002). Expression of hyaluronate and hyaluronate synthase in human primary tumours and their metastases in scid mice. Cancer Lett.
    49. (1999). Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival. Clin. Cancer Res.
    50. (2006). Extracellular matrix of ovarian tumors.
    51. Formation of hyaluronan- and versican-rich pericellular matrix by prostate cancer cells promotes cell motility.
    52. (1999). Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells.
    53. Genistein selectively inhibits platelet-derived growth factor-stimulated versican biosynthesis in monkey arterial smooth muscle cells.
    54. (1992). Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.
    55. Glioma invasiveness responds variably to irradiation in a co-culture model.
    56. Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration.
    57. (2000). High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res.
    58. (2001). High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer.
    59. Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds.
    60. (2011). Homepage of Halozyme. Available online: http://www.halozyme.com/products_oncology.php (accessed on 25
    61. (1996). Human ovarian tumour cells can bind hyaluronic acid via membrane CD44: a possible step in peritoneal metastasis.
    62. Hyaluronan and homeostasis: a balancing act.
    63. Hyaluronan binding to link module of TSG-6 and to G1 domain of aggrecan is differently regulated by pH.
    64. (2000). Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts
    65. Hyaluronan oligosaccharides inhibit tumorigenicity of osteosarcoma cell lines MG-63 and LM-8 in vitro and in vivo via perturbation of hyaluronan-rich pericellular matrix of the cells.
    66. (2004). Hyaluronan synthase expression in ovarian cancer.
    67. (1997). Hyaluronan synthases.
    68. (1993). Hyaluronan-binding proteins in development, tissue homeostasis, and disease.
    69. Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.
    70. Hyaluronan-CD44 interaction with neural Wiskott-Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to beta-catenin nuclear translocation, transcriptional up-regulation, and cell migration in ovarian tumor cells.
    71. (2004). Hyaluronan: from extracellular glue to pericellular cue.
    72. (1995). Hyaluronic acid secreted by mesothelial cells: a natural barrier to ovarian cancer cell adhesion.
    73. (2008). Hyaluronic acid-paclitaxel conjugate micelles: synthesis, characterization, and antitumor activity.
    74. (2007). Hyaluronic acid-paclitaxel: antitumor efficacy against CD44(+) human ovarian carcinoma xenografts. Neoplasia
    75. (1997). Hyaluronidase activity in gynaecological cancer tissues with different metastatic forms.
    76. (2010). Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth.
    77. (2006). Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.
    78. (1997). In vivo inhibition of CD44 limits intra-abdominal spread of a human ovarian cancer xenograft in nude mice: a novel role for CD44 in the process of peritoneal implantation. Cancer Res.
    79. (1996). Increased hyaluronan at sites of attachment to mesentery by CD44-positive mouse ovarian and breast tumor cells.
    80. (2008). Induction of apoptosis by antiCD44 antibody in human chondrosarcoma cell line SW1353.
    81. (2008). Inhibition of CD44 expression by small interfering RNA to suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo. Folia Biol.
    82. (2008). Inhibition of CD44 expression in hepatocellular carcinoma cells enhances apoptosis, chemosensitivity, and reduces tumorigenesis and invasion. Cancer Chemother. Pharmacol.
    83. (2009). Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides. Clin. Cancer Res.
    84. (1994). Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody. Cancer Res.
    85. (1998). Inhibition of tumor growth in vivo by hyaluronan oligomers.
    86. Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration.
    87. Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation.
    88. (2009). Low molecular weight hyaluronan inhibits colorectal carcinoma growth by decreasing tumor cell proliferation and stimulating immune response. Cancer Lett.
    89. (2006). Lung fibroblast proteoglycan production induced by serum is inhibited by budesonide and formoterol.
    90. (1989). Metaphylactic effect of mitomycin C with and without hyaluronidase after transurethral resection of bladder cancer: randomized
    91. (2008). Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model. Mol. Cancer Ther.
    92. Modulation of Hyaluronan production by CD44 positive Glioma cells.
    93. (1989). Multiple domains of the large fibroblast proteoglycan, versican.
    94. (1997). Ovarian cancer: natural history and metastatic pattern.
    95. (2010). Peritoneal adhesion and angiogenesis in ovarian carcinoma are inversely regulated by hyaluronan: the role of gonadotropins. Neoplasia
    96. Peritoneal inflammation—A microenvironment for Epithelial Ovarian Cancer (EOC).
    97. (2009). Positive hyaluronan/PEI/DNA complexes as a target-specific intracellular delivery to malignant breast cancer. Drug Deliv.
    98. (2008). Prognostic significance of CD44s expression in biliary tract cancers.
    99. (1995). Prognostic value of CD44 splice variant expression in ovarian cancer. Oncology
    100. (2001). Prognostic value of hyaluronan expression in non-small-cell lung cancer: Increased stromal expression indicates unfavorable outcome in patients with adenocarcinoma.
    101. (1999). Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity. Biochimie
    102. Regulation of proteoglycan synthesis by leukotriene d4 and epidermal growth factor in bronchial smooth muscle cells.
    103. (2002). Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer. Clin. Cancer Res.
    104. (2009). Reversal effects of hyaluronan oligosaccharides on adriamycin resistance of K562/A02 cells. Anticancer Drugs
    105. Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion.
    106. Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters.
    107. Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators.
    108. Silibinin suppresses CD44 expression in prostate cancer cells.
    109. (2009). Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol. Cancer Ther.
    110. Silibinin suppresses PMAinduced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells.
    111. (2007). SPARC inhibits LPA-mediated mesothelial-ovarian cancer cell crosstalk. Neoplasia
    112. Splice variant expression of CD44 in patients with breast and ovarian cancer.
    113. (2007). Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy.
    114. (2009). Target specific intracellular delivery of siRNA/PEI-HA complex by receptor mediated endocytosis.
    115. (2006). Targeting of CD44 eradicates human acute myeloid leukemic stem cells.
    116. (1999). Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings.
    117. (2009). The biological role and regulation of versican levels in cancer. Cancer Metastasis Rev.
    118. The CD44 receptor is a molecular predictor of survival in ovarian cancer.
    119. (1998). The impact of extracellular matrix on the chemoresistance of solid tumors—experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy. Cancer Lett.
    120. (2008). The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and
    121. (2005). The interaction of versican with its binding partners. Cell Res.
    122. (2001). The microenvironment of the tumour-host interface.
    123. (2003). The role of hyaluronan in mesothelium-induced motility of ovarian carcinoma cells. Anticancer Res.
    124. (2007). The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2.
    125. (2010). Transforming growth factor beta-induced protein (TGFBIp) secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells.
    126. (1998). Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res.
    127. (2009). Tumor-endothelial interaction links the CD44(+)/CD24(−) phenotype with poor prognosis in early-stage breast cancer. Neoplasia
    128. (2005). Tumor-stroma interactions: their role in the control of tumor cell invasion. Biochimie
    129. Up-regulation of stromal versican expression in advanced stage serous ovarian cancer.
    130. (2001). Versican accumulation in human prostatic fibroblast cultures is enhanced by prostate cancer cell-derived transforming growth factor beta1. Cancer Res.
    131. (2003). Versican in epithelial ovarian cancer: Relation to hyaluronan, clinicopathologic factors and prognosis.
    132. (2010). Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides.
    133. Versican overexpression in human breast cancer lesions: known and new isoforms for stromal tumor targeting.
    134. (2008). Vitronectin and its receptors partly mediate adhesion of ovarian cancer cells to peritoneal mesothelium in vitro. Tumour Biol.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.