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HYALURONAN IN CANCER BIOLOGY
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
OUTLINE
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
INTRODUCTION
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.
HYALURONAN
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.
Overview
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.
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