[Frontiers in Bioscience 11, 2106-2112, September 1, 2006] 2106 WNT signaling in malignant mesothelioma Simon Fox 1 and Arun Dharmarajan 2 1 Pharmacogenetics Laboratory, School of Pharmacy, Curtin University of Technology and West Australian Biomedical Research Institute,; Bentley, WA, Australia, 2 School of Anatomy and Human Biology, The University of Western Australia; Crawley, WA, Australia TABLE OF CONTENTS 1. Abstract 2. Introduction 3. The mesothelium 4. Mesothelial and mesothelioma cell plasticity 5. Wnt/Frizzled signaling in mesothelioma 5.1. Beta-catenin function and signaling 5.2. Secreted regulators of Wnt/Frizzled signaling in mesothelioma 5.3. Non-canonical signaling in malignant mesothelioma 6. Perspective 7. Acknowledgements 8. References 1. ABSTRACT Neoplastic transformation of mesothelium is commonly associated with exposure to asbestos and gives rise to malignant mesothelioma, an aggressive disease that has proved particularly refractory to conventional anti- cancer therapies. The Wnt signaling pathways play key roles in fundamental processes, which include both development and homeostasis. The importance of these pathways in tumorigenesis is emphasized by the many cancers which show aberrations in Wnt signaling. In this review we examine the current evidence for activation of Wnt signaling and the abnormal expression of specific molecules in malignant mesothelioma. 2. INTRODUCTION Malignant mesothelioma (MM) is a particularly aggressive cancer that is characterized by rapid progression, late metastases and poor prognosis [reviewed in (1)]. Although this tumor is relatively uncommon, the incidence is expected to continue to rise at least over the next decade as a consequence of high past asbestos use and the long latency period between exposure to asbestos and tumor development. MM is highly resistant to conventional forms of anti-cancer therapy and both radiotherapy and chemotherapy have limited effect. Despite the exploration of a variety of new therapeutic approaches with some success, treatment remains palliative at best (2). The