[Frontiers in Bioscience 13, 4361-4372, May 1, 2008] 4361 Osteopontin as a target for cancer therapy Nicholas IF Johnston 1 , Vignesh Kumar Gunasekharan 1 , Amod Ravindranath 1 , Ciara O’Connell 2 , Patrick G Johnston 1 , Mohamed K. El-Tanani 1 1 Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, United Kingdom, 2 School of Medicine and Dentistry, Queen’s University, Belfast, United Kingdom TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Osteopontin 3.1. Osteopontin gene structure 3.2. Regulation of osteopontin transcription 3.3. Osteopontin protein structure 4. Cell surface receptors of osteopontin 4.1. The integrin family of receptors 4.1.1. Osteopontin/integrin binding 4.2. The CD44 family of receptors 5. Osteopontin function 5.1. Cell migration and adhesion 5.2. Tissue remodelling and wound healing 5.3. Bone homeostasis 5.4. Inflammation 5.5. Cell survival and proliferation 6. Osteopontin function in cancer 6.1. Self-sufficiency in growth signals 6.2. Evasion of apoptosis 6.3. Sustained angiogenesis 6.4. Tissue invasion and metastasis 7. Osteopontin and clinical cancer - expression in tumors 8. Osteopontin as a tool in clinical cancer 8.1. OPN as a prognostic marker 8.2. Inhibition of osteopontin 8.2.1. Suppression of osteopontin message 8.2.2. Inhibition of osteopontin signaling 8.2.3. Modulation of post-translational modifications 8.2.4. Protein engineering 8.2.5. Small molecules 8.3. CD44 receptor as a target in cancer therapy 8.4. The integrin α V β 3 receptor as a target in cancer therapy 9. Perspective 10. Acknowledgements 11. References 1. ABSTRACT Osteopontin (OPN) is a glycophosphoprotein cytokine that has multiple functions. OPN is expressed and secreted by various cells, and has a role in cell adhesion, chemotaxis, prevention of apoptosis, invasion, migration and anchorage-independent growth of tumor cells. Extensive research has demonstrated the pivotal participation of OPN in the regulation of cell signaling which controls neoplastic and malignant transformation. The elevated expression of OPN has been observed in a variety of cancers. OPN has been linked with tumor metastasis and signifies a poor prognosis for the patient. This review details the mechanisms by which OPN facilitates these pathological events. It will also show that gaining an understanding of the mechanism of OPN’s action at a cellular level has led to the development of a number of therapeutic strategies against the cytokine. These include inhibiting its expression, antagonizing cell surface receptor activation and blocking downstream cell signaling pathways. In addition to the potential of these therapies, serum levels of OPN could be used as a diagnostic and prognostic marker. The authors propose that with further research and development, osteopontin directed treatment could greatly enhance outcomes for cancer patients.