PREFACE Hyaluronan (HA) is a normal component of human extracellular matrices that modulates tissue hydration, elasticity, and cellular fate. Excessive accumulation of HA is observed in a number of pathological conditions, including inflammation, wound healing, and cancer. The underlying mechanisms of HA accumulation in solid tumors, and the increased level of circulating HA in some blood borne malignancies, are still not fully understood. Steadystate HA levels are not static but are impacted by the dynamic interplay of the HA synthase (HAS) enzymes that synthesize and secrete HA at the plasma membrane, the hyaluronidase (Hyal) enzymes that hydrolyze HA, and the cell surface receptors that mediate internalization and processing of HA. In this volume of Advances in Cancer Research, we focused on the latest research in regulation of HA synthesis and turnover, and the consequences of excess HA as a differential trigger of intracellular signaling pathways. Hyaluronidase activity is associated with enhanced permeability of tissue, interstitium, or vasculature. Several significant new directions pursued in recent characterizations of these enzymes are discussed in Chapters 1 and 2. In particular, the activity of hyaluronidases, Hyal1 and Hyal2, was found to be essential for the aggressive progression of tumors and could be targeted by systemically applied small-molecule inhibitors to reduce tumor growth. In addition, it has been demonstrated that HA accumulation does not initiate or promote tumor progression, but rather protects against tumor initiation and blocks progression, unless hyaluronidase activity is also upregulated. These studies were especially conclusive when examined in the collective picture of clinical association studies, functional manipulation of human tumor cells tested by preclinical outcomes, and characterization of tumorigenesis in the naked mole rat model, which is cancer impervious until its HA production is inhibited or its hyaluronidase-mediated removal of HA is elevated. Recently, successful clinical trials using controlled application of hyaluronidase to sensitize cancer to chemotherapy are also discussed. HAS enzymes were first cloned, sequenced, and characterized in the 1990s. Numerous studies of HAS gene expression subsequently showed that HA production is significantly elevated by growth factor and cytokineinduced increases in HAS transcript levels. Chapters 3–5 discuss recent advances that reveal additional complexity in the control of HAS activity. Novel posttranscriptional and posttranslational mechanisms controlling xv

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HA production include alternative splicing, ubiquitination, and reversible phosphorylation or O-linked N-acetylglucosaminylation. These studies define a central connection between HA production and cellular metabolic status. The newly identified presence of HA and HAS3 in exocytosed vesicles called exosomes is also described and summarized with respect to its possible implications for cellular transformation, tumor or stromal cell–cell communication, and metastasis. The information content of HA as a signal in tumorigenesis is extensively discussed in Chapters 6–13. It is well accepted that HA polymers versus HA oligomers or fragments elicit different responses downstream of ligation by cell surface receptors such as CD44. Chapters 6 and 7 describe the impact of HA signaling on the microenvironment of bone, differentiation of mesenchymal stem cells, and endothelial integrity. The cooperativity of between HA, CD44, and growth factor receptors is detailed in Chapters 8–11, with a particular focus on tumor cell invasion, tumorigenesis, cancer stem cell proliferation, and TGFβ-mediated epithelial-to-mesenchymal transition as a prerequisite for the metastatic spread of cancer cells. Further attention is given to the targeting of these mechanisms for pharmacologic interventions in tumor progression. Chapters 12 and 13 examine additional therapeutic implications of HA cell surface interactions with the receptor for HA-mediated motility (RHAMM) and the extracellular matrix metalloproteinase inducer (EMMPRIN, or CD147). Melanie A. Simpson Paraskevi Heldin

Hyaluronan signaling and turnover. Preface.

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