Review
Hyaluronan: A constitutive regulator of chemoresistance and malignancy in cancer cells

https://doi.org/10.1016/j.semcancer.2008.03.009Get rights and content

Abstract

Hyaluronan not only is an important structural component of extracellular matrices but also interacts instructively with cells during embryonic development, healing processes, inflammation, and cancer. It binds to several different types of cell surface receptors, including CD44, thus leading to co-regulation of important signaling pathways, notably those induced by activation of receptor tyrosine kinases. Consequently, interactions of both stromal and tumor cell-derived hyaluronan with tumor cells play important cooperative roles in several aspects of malignancy. This review focuses on cell autonomous hyaluronan–tumor cell interactions that lead to activation of receptor tyrosine kinases and enhanced drug resistance. Particular emphasis is placed on the role of hyaluronan–CD44 interactions in drug transporter expression and activity, especially in cancer stem-like cells that are highly malignant and resistant to chemotherapy. Antagonists of hyaluronan–CD44 interaction, especially small hyaluronan oligomers, may be useful in therapeutic strategies aimed at preventing tumor recurrence from these therapy-resistant sub-populations within malignant cancers.

Section snippets

Introduction: the relationships between drug resistance, malignancy and cancer stem-like cells

Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of morbidity and mortality from cancer. Recently, sub-populations of stem-like cells have been characterized within a variety of cancers. These cells are highly malignant in that they can rapidly regenerate a fully grown tumor when implanted in small numbers in an animal host [1], [2], [3] and they may be responsible for tumor metastasis [4], [5]. In addition, these cells

Hyaluronan in tumor progression

Hyaluronan is a large, linear glycosaminoglycan composed of 2000–25,000 disaccharides of glucuronic acid and N-acetylglucosamine: [β1,4-GlcUA-β1,3-GlcNAc-]n, with molecular weights usually ranging from 105 to 107 Da. Hyaluronan is distributed ubiquitously in vertebrate tissues. In adult tissues such as the vitreous, synovial fluid and dermis, it clearly plays an extracellular, structural role that depends on its unique hydrodynamic properties as well as its interactions with other extracellular

Cell autonomous regulation of receptor tyrosine kinase activation and anti-apoptotic signaling pathways by endogenously produced hyaluronan

Receptor tyrosine kinases are a class of plasma membrane receptors that bind various regulatory factors, such as EGF, IGF, HGF and PDGF, and activate several intracellular signaling pathways, such as the MAP kinase and phosphoinositide 3-kinase/AKT pathways. Aberrant activities of these receptors, especially members of the ERBB family, have been implicated in the progression of numerous types of human cancers. Increased activity of receptor tyrosine kinases can arise from gene amplification,

Regulation of multidrug resistance by hyaluronan

Drug resistance can arise in numerous ways, e.g. decreased uptake of drugs due to cell and tissue barriers, activation of repair and detoxification mechanisms, increased activities of anti-apoptotic signaling pathways, or enhanced drug efflux via cell membrane transporters [59], [60], [61], [62]. Drug efflux from cancer cells is commonly mediated by ATP-dependent efflux pumps such as members of the MDR, MRP and other ABC transporter subgroups, and expression of these transporters is frequently

Hyaluronan–CD44 interactions, cancer stem cells and resistance to chemotherapy

Of particular relevance to the relationship of malignant cell properties to chemoresistance are the properties of a small sub-population of stem-like cells that has now been characterized within many cancers. These cells have been variously named: “cancer stem cells”, “cancer progenitor cells” and “tumor-initiating cells”. These cells are highly malignant in that a very small number can rapidly regenerate a fully grown tumor when implanted in an animal host [1], [2], [3] and they may include

Acknowledgements

Recent work from our lab that is described herein was supported by grants to B.P.T. from the National Institutes of Health (CA073839 and CA082867), the Department of Defense (OC050368) and The Charlotte Geyer Foundation.

References (105)

  • S. Ghatak et al.

    Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway

    J Biol Chem

    (2002)
  • C.B. Underhill et al.

    Effects of detergent solubilization on the hyaluronate-binding protein from membranes of simian virus 40-transformed 3T3 cells

    J Biol Chem

    (1983)
  • J. Lesley et al.

    Hyaluronan binding by cell surface CD44

    J Biol Chem

    (2000)
  • M. Rahmanian et al.

    Hyaluronan oligosaccharides induce tube formation of a brain endothelial cell line in vitro

    Exp Cell Res

    (1997)
  • N. Itano et al.

    Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic malignant transformation

    J Biol Chem

    (2004)
  • M.A. Simpson

    Concurrent expression of hyaluronan biosynthetic and processing enzymes promotes growth and vascularization of prostate tumors in mice

    Am J Pathol

    (2006)
  • J. Condeelis et al.

    Macrophages: obligate partners for tumor cell migration, invasion, and metastasis

    Cell

    (2006)
  • A. Zoltan-Jones et al.

    Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells

    J Biol Chem

    (2003)
  • S. Ghatak et al.

    Hyaluronan regulates constitutive ErbB2 phosphorylation and signal complex formation in carcinoma cells

    J Biol Chem

    (2005)
  • S. Misra et al.

    Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells

    J Biol Chem

    (2006)
  • S. Misra et al.

    Regulation of multi-drug resistance in cancer cells by hyaluronan

    J Biol Chem

    (2003)
  • M. Mogi et al.

    Akt signaling regulates side population cell phenotype via Bcrp1 translocation

    J Biol Chem

    (2003)
  • J. Neuzil et al.

    Tumour-initiating cells vs. cancer 'stem’ cells and CD133: what's in the name?

    Biochem Biophys Res Commun

    (2007)
  • Z.W. Li et al.

    Tumor microenvironment and drug resistance in hematologic malignancies

    Blood Rev

    (2006)
  • B. St Croix et al.

    Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors

    Cancer Lett

    (1998)
  • B. Desoize et al.

    Multicellular resistance: a paradigm for clinical resistance?

    Crit Rev Oncol Hematol

    (2000)
  • C.B. Underhill et al.

    Receptors for hyaluronate on the surface of parent and virus-transformed cell lines: binding and aggregation studies

    Exp Cell Res

    (1981)
  • R. Ohashi et al.

    Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell

    Cancer Lett

    (2007)
  • P.A. Singleton et al.

    CD44 interaction with ankyrin and IP(3) receptor in lipid rafts promotes hyaluronan-mediated Ca(2+) signaling leading to nitric oxide production and endothelial cell adhesion and proliferation

    Exp Cell Res

    (2004)
  • T. Schulz et al.

    Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP

    J Biol Chem

    (2007)
  • M. Crainie et al.

    Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants

    Blood

    (1999)
  • C.A. Maxwell et al.

    RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma

    Blood

    (2004)
  • L.M. Pilarski et al.

    Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells

    Blood

    (1999)
  • S.K. Nilsson et al.

    Hyaluronan is synthesized by primitive hemopoietic cells, participates in their lodgment at the endosteum following transplantation, and is involved in the regulation of their proliferation and differentiation in vitro

    Blood

    (2003)
  • A. Avigdor et al.

    CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow

    Blood

    (2004)
  • A. Calabro et al.

    Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients

    Blood

    (2002)
  • S. Adamia et al.

    Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma

    Blood

    (2005)
  • M. Shipitsin et al.

    Molecular definition of breast tumor heterogeneity

    Cancer Cell

    (2007)
  • P. Dalerba et al.

    Cancer stem cells: models and concepts

    Annu Rev Med

    (2007)
  • R.P. Hill et al.

    “Destemming” cancer stem cells

    J Natl Cancer Inst

    (2007)
  • A.L. Vescovi et al.

    Brain tumour stem cells

    Nat Rev Cancer

    (2006)
  • T. Brabletz et al.

    Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression

    Nat Rev Cancer

    (2005)
  • F. Li et al.

    Beyond tumorigenesis: cancer stem cells in metastasis

    Cell Res

    (2007)
  • M. Dean et al.

    Tumour stem cells and drug resistance

    Nat Rev Cancer

    (2005)
  • K.E. Miletti-Gonzalez et al.

    The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer

    Cancer Res

    (2005)
  • B.P. Toole

    Hyaluronan: from extracellular glue to pericellular cue

    Nat Rev Cancer

    (2004)
  • R.S. Kerbel et al.

    Multicellular resistance: a new paradigm to explain aspects of acquired drug resistance of solid tumors

    Cold Spring Harb Symp Quant Biol

    (1994)
  • D. Jiang et al.

    Hyaluronan in tissue injury and repair

    Annu Rev Cell Dev Biol

    (2007)
  • R. Kosaki et al.

    Overproduction of hyaluronan by expression of the hyaluronan synthase Has2 enhances anchorage-independent growth and tumorigenicity

    Cancer Res

    (1999)
  • N. Liu et al.

    Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells

    Cancer Res

    (2001)
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