Hyaluronan in Cancer Biology

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Hyaluronan biology is being recognized as an important regulator of cancer progression. Paradoxically, both hyaluronan (HA) and hyaluronidases, the enzymes that eliminate HA, have also been correlated with cancer progression. Hyaluronan, a long-chain polymer of the extracellular matrix, opens up tissue spaces through which cancer cells move and metastasize. It also confers motility upon cells through interactions of cell-surface HA with the cytoskeleton. Embryonic cells in the process of movement and proliferation use the same strategy. It is an example of how cancer cells have commandeered normal cellular processes for their own survival and spread. There are also parallels between cancer and wound healing, cancer occasionally being defined as a wound that does not heal.

The growing body of literature regarding this topic has recently progressed from describing the association of hyaluronan and hyaluronidase expression associated with different cancers, to understanding the mechanisms that drive tumor cell activation, proliferation, drug resistance, etc. No one source, however, discusses hyaluronan synthesis and catabolism, as well as the factors that regulate the balance. This book offers a comprehensive summary and cutting-edge insight into Hyaluronan biology, the role of the HA receptors, the hyaluronidase enzymes that degrade HA, as well as HA synthesis enzymes and their relationship to cancer.

• Offers a comprehensive summary and cutting-edge insight into Hyaluronan biology, the role of the HA receptors, the hyaluronidase enzymes that degrade HA, as well as HA synthesis enzymes and their relationship to cancer

• Chapters are written by the leading international authorities on this subject, from laboratories that focus on the investigation of hyaluronan in cancer initiation, progression, and dissemination

• Focuses on understanding the mechanisms that drive tumor cell activation, proliferation, and drug resistance

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Editorial Reviews

From the Publisher
"For decades, hyaluronan researchers have followed with growing interest the slowly developing story of how cancer progression and metastasis are correlated with or regulated by hyaluronan and its catabolic degradation products. Initially trying to understand the role of hyaluronan metabolism in prostate, breast, melanoma and other carcinomas was a bit like the story of the blind men touching and describing an elephant, each with a different impression of what they found. Now, however, our understanding of how hyaluronan is related to cancer biology has come into much clearer focus and this is captured nicely in Hyaluronan in Cancer - a collection of well written research perspectives and summaries from 20 research groups around the world. The timing of this volume edited by Dr. Stern is excellent - readers can now get an overview and understand the importance of hyaluronan in multiple cancers. The book provides the first state-of-the-field summary and should be a highly useful and cited source for cancer biologists and hyaluronan researchers for many years."

—Paul H. Weigel, Ph.D., Professor, Chairman George Lynn Cross Research Professor, Ed Miller Endowed Chair Biochemistry & Molecular Biology, The University of Oklahoma Health Sciences Center, College of Medicine, Oklahoma City, OK, USA

"Hyaluronan is a major component of the fluid extracellular matrix that surrounds cells and fills the intercellular spaces of tissue. Long known for its fundamental role in tissue development and physiology, hyaluronan’s involvement in cancer progression and metastasis has more recently become the subject of intense multidisciplinary efforts.

This volume provides a state-of-the-art review of hyaluronan’s role in the cell biology of cancer, its diagnostic and prognostic value, and its potential as a target for therapeutic intervention. Authored by leading researchers in the field, the chapters help bridge the gap between basic science and clinical oncology, providing background and context that will prove valuable to both cancer and hyaluronan researchers for years to come."

— Philip A. Band, PhD, NYU Hospital for Joint Diseases, Department of Pharmacology, Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, USA

"The link between the polysaccharide hyaluronan and cancer is well established. This excellent and comprehensive book brings together expert opinion for a thorough and up-to-date review of the topic. It covers the cell biology of hyaluronan in cancer, the role of hyaluronan receptors and signal transduction pathways and the clinical uses of hyaluronan-related biomaterials as anti-cancer agents. This book is a must read for those interested in the role of hyaluronan and its receptors in cancer biology and therapy."

—Anthony J. Day, Faculty of Life Sciences, University of Manchester, UK

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Product Details

  • ISBN-13: 9780123741783
  • Publisher: Elsevier Science
  • Publication date: 4/1/2009
  • Pages: 468
  • Product dimensions: 6.20 (w) x 9.10 (h) x 1.20 (d)

Meet the Author

Robert Stern, MD, is Emeritus Professor, Department of Pathology, School of Medicine, University of California, San Francisco. Robert Stern left Germany in 1938 for Seattle, Washington. He graduated from Harvard College in 1957, and obtained the M.D. degree from the University of Washington (Seattle) in 1962, followed by a rotating internship at King County Hospital (Seattle). While a medical student, he worked in the laboratories of Drs. Krebs and Fisher, who became Nobel laureates. He received his resident training in Anatomic Pathology at the NCI, and was a research scientist at the NIH for 10 years. Since 1977, he has been a member of the Pathology Department at the University of California, San Francisco. He is a board-certified Anatomic Pathologist, participating in the research, teaching, administrative, and diagnostic activities of the Department. He directed the Ph.D. program in Experimental Pathology for ten years. For the past decade, his research has focused on hyaluronan and the hyaluronidases, an outgrowth of an interest in malignancies of connective tissue, stromal-epithelial interactions in cancer, and biology of the tumor extracellular matrix. His laboratory was the first to identify the family of six hyaluronidase sequences in the human genome. These enzymes were then sequenced, expressed, and characterized in his laboratory. Subsequent work has identified a catabolic pathway for hyaluronan.

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Read an Excerpt


Academic Press

Copyright © 2009 Elsevier Inc.
All right reserved.

ISBN: 978-0-08-092108-2

Chapter One

Association Between Cancer and "Acid Mucopolysaccharides": An Old Concept Comes of Age, Finally

Robert Stern


Introduction 4 Hyaluronan 4 Historical Perspective 4 Overview 5 Hyaluronan Can Influence Cell Fate: Studies from Embryology 6 Cancer Is a Price Paid for Metazoan Evolution 7

Stromal–Epithelial Interaction in Cancer 7 Extracellular Matrix of Normal Cells 7 The Stroma Around Tumors Is Highly Abnormal, but Tends to Resemble Embryonic Mesenchyme 8 Mechanisms for Peritumor Stromal Abnormalities 8

Hyaluronan in Cancer 9 Malignancies Have Increased Hyaluronan 9 Mechanisms for the Increased Hyaluronan in Malignancies 10 Cancers Are Resilient in Utilizing Hyaluronan Metabolism for Their Own Promotion 10 Anomalously, Hyaluronan Oligomers Can Inhibit Tumor Growth 11

Abnormalities in Other Glycosaminoglycans Occur in Malignancy 11 Conclusions 12


The influence of hyaluronan (HA) on cancer progression has been exceedingly well described (Toole, 2002; Toole et al., 2002; Toole and Hascall, 2002; Stern, 2005). However, recognition of this important phenomenon has lagged, and inexplicably, continues to be neglected by most cancer biologists. Knowledge in this area has advanced extremely rapidly, and has taken on additional significance, now that it is documented that the major receptor for HA, CD44, is expressed on the surface of virtually all stem cells, including cancer stem cells (e.g., Al Hajj et al., 2003). This volume aims to bring attention to the field of HA and its role in cancer initiation, progression, and spread.

Assembly of these reviews is now particularly timely. It is the first volume ever to appear dedicated entirely to the role of HA in cancer biology. A recent textbook on basic oncology, widely recognized to be of superior quality, does not have a single citation in the index for HA (Weinberg, 2006). CD44 is given one citation, without mentioning that it is the predominant receptor for HA. Ironically, even the Weinberg laboratory has since then become aware of the significance of HA and CD44 in cancer progression (Godar et al., 2008).

Our purpose here is to draw attention to a critical molecule that that has been neglected, and up until now, poorly understood by most cancer scientists. The time has come, finally, to bring HA, previously known as hyaluronic acid (Balazs et al., 1986), and before that, as simply an acid mucopolysaccharide, to the attention of a wider audience.


Historical Perspective

The term "ground substance" was first applied to the amorphous material between cells by the German anatomist, Henle, in 1841 (Henle, 1841). It is a mistranslation of the German "Grundsubstanz," which would be better translated as "basic," "fundamental," or "primordial" substance. By 1852, sufficient information had accrued for the inclusion of "Grundsubstanz" in a textbook of human histology (Koellicker, 1852).

The modern era of ground substance research began in 1928 with the discovery of a "spreading factor" by Francisco Duran-Reynals. Testicular extracts stimulated rapid spread of materials injected subcutaneously on the backs of shaved rabbits, while simultaneously causing dissolution of the ground substance (Duran-Reynals, 1928; 1929; Duran-Reynals and Suner Pi, 1929; Duran-Reynals and Stewart, 1933). The active principal of these extracts was later shown to be the enzyme, hyaluronidase (Chain and Duthrie, 1940; Hobby et al., 1941), the class of enzymes that degrade HA. Interestingly, in one of the studies by Duran-Reynals, hyaluronidase-like activity was demonstrated in extracts of human malignancies, particularly from breast cancers and malignant melanoma (Duran-Reynals et al., 1929).

"Ground substance" was subsequently renamed "acid mucopolysaccharides," a term first proposed by Karl Meyer (1938), who first described HA (Meyer and Palmer, 1934; 1936). This was the term to designate the hexosamine-containing sugar polymers that occurred in animal tissues alone, as well as when bound to proteins. Chondroitin sulfate is the major GAG of the matrix of such tissues as cartilage, tendon, and scar. However, it is now well established that HA is by far the predominant "acid mucopolysaccharide" that constitutes true "ground substance," though heparan sulfate is the most abundant GAG at the cell surface.


Hyaluronan is a high-molar-mass linear glycosaminoglycan (GAG) found intracellularly, on the surface of cells, but predominantly in the extracellular matrix (ECM) between cells. This linear polysaccharide can reach a size of 6 to 8 MDa. It is a ubiquitous polymer with the repeating disaccharide structure of (-β1,3-N-acetyl-D-glucosamine-β1,4-D-glucuronic acid-)n. It has one carboxyl group per disaccharide repeating unit, and is therefore a polyelectrolyte with a negative charge at neutral pH. It is near perfect in chemical repeats, with no known deviations in its simple disaccharide structure with the possible exception of occasional deacetylated glucosamine residues.

Hyaluronan, at low concentrations, is ubiquitous. However, it is found in high concentrations during embryogenesis, and whenever rapid tissue turnover and repair are occurring. It occurs in particularly high concentrations in fetal tissues, in amniotic fluid, is the major constituent of fetal structures such as Wharton's jelly of the umbilical cord, but also in malignancies. Over 50% of total body HA occurs in the skin (Reed et al., 1988).

At the cellular level, a burst of HA synthesis occurs just prior to mitosis, enabling some cells to become dissociated from neighboring cells and to lose the adhesion from their surrounding ECM in preparation for division (Toole et al., 1972; Tomida et al., 1974; Mian, 1986; Brecht et al., 1986). It is during this short period within the cell cycle that normal cells most closely resemble transformed cells. The deposition of HA preceding mitosis promotes detachment, and also confers motility directly upon cells (Turley and Torrance, 1984; Turley et al., 1985), correlating possibly with the movement of metastatic tumor cells.

Cancer cells do not do unusual things, but do usual things at unusual times. The formulation can be posited that cancer cells emulate that point in the cell cycle when cells synthesize increased levels of HA, round up, detach from their substratum, and leave temporarily the social contract in order to divide. Normal cells then degrade that HA in order to reattach to the substratum and to carry on the business of being normal tissue components. Cancer cells have learned to eliminate this step, to retain their HA coat, enabling them instead, to continue to divide endlessly (Itano et al., 2002).

Hyaluronan Can Influence Cell Fate: Studies from Embryology

Classical studies in embryogenesis document that HA is ubiquitous in developmental processes and in tissue modeling. Hyaluronan is particularly prevalent when undifferentiated cells are proliferating rapidly and move from their stem cell niche to the site of organ development. This stage of cell proliferation and movement ends when cells commit to a program of differentiation. In fact, the HA environment actively inhibits differentiation, creating instead an environment that promotes proliferation (Ozzello et al., 1960). Cells must lose their HA-rich environment in order for that commitment to differentiation to occur (Toole, 1991). Such a series of events were demonstrated for limb development, as well as cornea, the neural tube, cartilage and muscle development, and branching morphogenesis of parenchymal organs (Bernfield and Banerjee, 1972; Gakunga et al., 1997). Neuroectoderm pinches off to become neural crest elements, which then wander through the vertebrate body in an HA-rich environment. Such movement ceases just as HA becomes degraded (Pratt et al., 1975).

Again, parallels can be drawn between this window of normal tissue development and the onset of tumor growth, when cancer cells move and proliferate. Normal proliferating cells shed their HA through hyaluronidase activity. In most cases, it may be the failure to remove the HA coat, or the continuous turnover and replacement that promotes, malignant cell growth and the development of cancer.

Early studies of the influence of an HA environment on cell fate were from the laboratory of Arnold Caplan (Kujawa et al., 1986b). Primitive myoblasts derived from chick embryo skeletal muscle plated on plastic will proliferate, fuse to form a syncytium, and will begin to synthesize actin and myosin, and even begin to have contractile activity. However, the same cells grown on an HA-covered dish will grow and proliferate, but will not fuse, will not express skeletal muscle actin or myosin, nor show contractile behavior.


Excerpted from HYALURONAN IN CANCER BIOLOGY Copyright © 2009 by Elsevier Inc.. Excerpted by permission of Academic Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

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Table of Contents

Each contributor will be asked to provide a historic perspective, followed by new research, followed by glimpses and extrapolation into the possible future. The editor will write a general introduction and he will introduce each "section" to place it in a larger context, within the context of oncology and within the context of hyaluronan, from both the basic science as well as the clinical perspectives.

Introduction and history of HA in cancer biology
Robert Stern, UC San Francisco, USA

Overview of the HA-cancer field
Bryan Toole, University of South Carolina, USA

Section on HA receptors
Lilly Bourguignon, UC San Francisco, USA — (CD44)
Eva Turley, London Regional Cancer Center, Canada — (RHAMM)
David Naor, Hebrew University, Israel — (CD44 and HA in murine lymphoma)

Section on the hyaluronidase enzymes that degrade HA
Gregory Frost, Halozyme Corporation, USA — (hyaluronidase in new treatment modalities)
Gerhard Baumgartner, Ludwig Boltzmann Institute, Vienna, Austria — (hyaluronidase, an adjunct in cancer treatments)
Antonei Csoka, University of Pittsburgh, USA — (history of the 3p21.3 tumor suppressor gene locus)
Robert Stern, UC San Francisco, USA — (hyaluronidase and paradoxes in cancer biology)
Kazuki Sugahara, Burham Institute, USA — (biology of HA fragments)

Section on stem cells, fetal cells and mesenchymal-epithelial transitions
Seth L. Schor, University of Dundee, UK
Ana M Schor, University of Dundee, UK
Bryan Toole, University of South Carolina, USA

Section on the HA synthesis enzymes and their relationship to cancer
Koji Kimata, Aichi Medical University, Japan
Naoki Itano, Shinshu University, Japan
Andrew Spicer, UC Davis, USA

Section on site-specific malignancies
Malignant melanoma
Jan C. Simon, University of Leipzig, Germany

Genito-urinary cancers
Melanie Simpson, University of Nebraska, USA — (prostate cancer)
Vinata Lokeshwar, University of Miami, USA — (prostate and bladder cancer)
James McCarthy, University of Minnesota, USA — (prostate cancer)

Breast cancer
Tracey Brown, Monash University, Australia
Paraskevi Heldin, Upsalla University, Sweden
Lurong Zhang, University of Rochester, USA

Stromal HA and its Influcence on Malignancies
Raija Tammi, University of Kuopio, Finland
Marku Tammi, University of Kuopio, Finland

Section on new approaches to diagnosis and treatments that are HA-based
Frank Szoka, UC San Francisco, USA — (HA, CD44 in liposomes, and new drug delivery systems
Michal Neeman, Weizmann Institute, Israel — (HA, hyaluronidase diagnostics using NMR)
Kasturi Datta, Nehru University, India — (HA-binding protein-1 in cancer)
Bertrand Delpech, Centre Henri-Becquerel, Rouen, France — (hyaluronectin and tumors of the CNS)

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