RESEARCH ON MELANOMA – A GLIMPSE INTO CURRENT DIRECTIONS AND FUTURE TRENDS Edited by Mandi Murph Research on Melanoma – A Glimpse into Current Directions and Future Trends Edited by Mandi Murph Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access articles distributed under the Creative Commons Non Commercial Share Alike Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published articles. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Petra Nenadic Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright dean bertoncelj, 2011. Used under license from Shutterstock.com First published August, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Research on Melanoma – A Glimpse into Current Directions and Future Trends, Edited by Mandi Murph p. cm. ISBN 978-953-307-293-7 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part 1 Epigenetics 1 Chapter 1 Predictive Capacity and Functional Significance of MicroRNA in Human Melanoma 3 Xiaobo Li and Yaguang Xi Chapter 2 Epigenetic Changes in Melanoma and the Development of Epigenetic Therapy for Melanoma 19 Duc P. Do and Syed A.A. Rizvi Chapter 3 Genetic, Epigenetic and Molecular Changes in Melanoma: A New Paradigm for Biological Classification 35 Stefania Staibano, Massimo Mascolo, Maria Siano, Gennaro Ilardi and Gaetano De Rosa Part 2 Therapeutics 69 Chapter 4 A Bromophosphonate Analogue of Lysophosphatidic Acid Surpasses Dacarbazine in Reducing Cell Proliferation and Viability of MeWo Melanoma Cells 71 Duy Nguyen, Oanh Nguyen, Honglu Zhang, Glenn D. Prestwich and Mandi M. Murph Chapter 5 Low-Anticoagulant Heparins in the Treatment of Metastasis 81 Narayanam V. Rao, Glenn D. Prestwich, John R. Hoidal and Thomas P. Kennedy Chapter 6 Novel Antifolates as Produgs for the Treatment of Melanoma 101 Jose Neptuno Rodriguez-Lopez, Luis Sanchez-del-Campo, Magali Saez-Ayala, Maria F. Montenegro and Juan Cabezas-Herrera VI Contents Chapter 7 The Potential of Triterpenoids in the Treatment of Melanoma 125 J. Sarek, M. Kvasnica, M. Vlk, M. Urban, P. Dzubak and M. Hajduch Part 3 Molecular Signaling 159 Chapter 8 New Molecular Targets for the Systemic Therapy of Melanoma 161 Kausar Begam Riaz Ahmed and Michael A. Davies Chapter 9 BRAF V600E Mutated Gene Variant as a Circulating Molecular Marker in Metastatic Melanoma Patients 181 Viviana Vallacchi, Licia Rivoltini and Monica Rodolfo Chapter 10 Ultraviolet Light as a Modulator of Melanoma Development 197 Graeme Walker and Elke Hacker Chapter 11 Dual Roles of the Melanoma CAM (MelCAM/METCAM) in Malignant Progression of Melanoma 229 Guang-Jer Wu Chapter 12 Dual Function of Wnts in Human Cutaneous Melanoma 243 Ksenia Kulikova, Alexey Kibardin, Nikolay Gnuchev, Georgii Georgiev and Sergey Larin Chapter 13 A POU3F2-MITF-SHC4 Axis in Phenotype Switching of Melanoma Cells 269 Thomas Strub, Dominique Kobi, Dana Koludrovic and Irwin Davidson Chapter 14 The Role of Cellular Differentiation and Cell Fate in Malignant Melanoma 287 Paul Kuzel and Andy J. Chien Part 4 Tumor Progression and the Microenvironment 309 Chapter 15 Role of Angiogenesis and Microenvironment in Melanoma Progression 311 Roberto Ria, Antonia Reale and Angelo Vacca Chapter 16 Stromal Microenvironment Alterations in Malignant Melanoma 335 Svetlana Brychtova, Michala Bezdekova, Jaroslav Hirnak, Eva Sedlakova, Martin Tichy and Tomas Brychta Contents VII Chapter 17 Current Insight Into the Metastatic Process and Melanoma Cell Dissemination 361 Isabelle Bourgault-Villada, Michelle Hong, Karen Khoo, Muly Tham, Benjamin Toh,Lu-En Wai and Jean-Pierre Abastado Chapter 18 Increased Resistance of Vasculogenic Mimicry-Forming Uveal Melanoma Cells against Cytotoxic Agents in Three-Dimensional Cultures 377 Klara Valyi-Nagy, Andras Voros, Eva Gagyi and Tibor Valyi-Nagy Chapter 19 The Role of Adhesion Receptors in Melanoma Metastasis and Therapeutic Intervention Thereof 393 Michael Alexander and Gerd Bendas Preface This is an exciting time for the field of melanoma research. So far in 2011 the FDA has approved two new immunotherapies against this malignancy and is likely to vote on a targeted therapeutic soon. The clinical trials evaluating BRAF inhibitors are being discussed at major symposia and appearing in popular news media. There hasn’t been this much activity on melanoma therapeutics since 1998. For researchers it is particularly exciting to see years of studying aberrant molecular mechanisms in the laboratory translate into the clinic. The goal of scientists who tirelessly study mechanisms of disease is this – to contribute to developing lifesaving interventions. Now is the time when this dream is coming to fruition. Although the ability to cure every melanoma patient may still be elusive, exploiting melanoma’s molecular weaknesses and observing dramatic effects provides hope and confidence to researchers that it can be done. Thus, this book on melanoma research provides a glimpse of many diverse scientific aspects that are currently underway in melanoma research laboratories around the world. Although the topics are different they all have the same goals, to develop better understandings of malignancy and treatment methods. The sections of this book are organized to reflect emerging trends in research, starting with epigenetics. The role of epigenetics is under investigation in melanoma as well as other types of cancers. There is much progress to be made in this complex area to help explain the etiology of disease, a topic that patients always ask when attempting to pinpoint the source of their cancer. In addition, a subsequent section contains work discussing emerging, promising and much‐needed therapeutics. Although newer drugs have an enhanced ability for treatment, they also suffer from chemoresistance development, a huge clinical problem among other cancer types. Thus, there is still much work to be done in the area of melanoma therapeutics. In the section on Molecular Signaling, the manuscripts cover a broad range of areas. The classical pathways are discussed, including BRAF, along with some emerging proteins that are likely highly relevant to melanoma. This theme is continued with the final section on Tumor Progression and the Microenvironment. Manuscripts organized in this section are focused on angiogenesis, the tumor microenvironment and metastasis. All of these reflect clinical problems in need of additional research, whereby contributions aimed towards melanoma are likely to be translatable to numerous cancer types. X Preface This book would not have been possible without the help of several wonderful people. These include Ana Pantar, Petra Nenadic, Juliet Eneh and Molly Altman. I would also like to thank my spouse, Gary Rollie, who has always been incredibly supportive of my career and dealt with me this past year as I worked on this project. I think he knew when I said, “This will only take a few more minutes”, that it wasn’t true, but he patiently understood that at some point I would finish. Sincerely, Mandi Murph, Ph.D. Assistant Professor Department of Pharmaceutical and Biomedical Sciences University of Georgia College of Pharmacy Athens, GA, USA [...]... normal cells, acetylation and deacetylation exist in equilibrium Acetylation is a reaction that is catalyzed by histone acetyltransferases (HATs), and the deacetylation reaction is catalyzed by histone deacetylases (HDACs) These two families of enzymes regulate the delicate balance needed for maintaining the states of chromatin and chromatin dynamics (Figure 1) Acetylation is a reversible reaction occurring... histone modifications and chromatin remodeling Histones can be modified by methylation, acetylation, phosphorylation, biotinylation, ubiquitination, sumoylation, and ADP-ribosylation Lysine residues in the histone tails can be acetylated or methylated Arginine residues can be methylated (Howell et al., 2009) Among all of the posttranslational modifications on histone tails, histone acetylation is among... miR-13 3a miR-17-5p miR-1 8a miR-1 9a/ b miRc-Kit, p27 PLZF 221/222 miR-532-5p RUNX3 miR-2 0a miR-9 2a Table 1 MicroRNAs in melanoma progression ↓Invasion ↑ Proliferation, invasion; ↓ differentiation ↑Invasion 14 Research on Melanoma – A Glimpse into Current Directions and Future Trends 6 Summary There were approximately 40 publications from the past year and a half that reported the involvement of miRNA in melanoma. .. amino acid positions 9, 14, 18, and 23 for histone H3 and at amino acid positions 5, 8, 12, 16 for histone H4 are frequent targets for acetylation These histone modifications facilitate access and binding of transcription factors Histone deacetylation is associated with an inactive (closed) state of chromatin and transcriptional repression (Kouzarides, 2007; Strahl & Allis, 2000) Deacetylation is catalyzed... melanoma research from both laboratory and clinical settings, which evidences the perspective of miRNA as one of the most valuable biomarkers and therapeutic targets in current melanoma research We are pleased to find the that research trend of miRNA and melanoma has changed from solely searching altered specific miRNAs to exploring molecular networks and connections between miRNAs and signaling pathways... expression patterns in predicting metastatic risk in uveal melanoma They found the most significant discriminator to classify low and high metastatic risk was let-7b and miR-19 9a expression A classifier system that included the top six miRNA discriminators accurately distinguished melanoma patient tissues with high 12 Research on Melanoma – A Glimpse into Current Directions and Future Trends metastatic... A, Dadras SS Profiling and discovery of novel miRNAs from formalin-fixed, paraffin-embedded melanoma and nodal specimens J Mol Diagn 2009;11:420-9 [65] Radhakrishnan A, Badhrinarayanan N, Biswas J, Krishnakumar S Analysis of chromosomal aberration (1, 3, and 8) and association of microRNAs in uveal melanoma Mol Vis 2009;15:2146-54 [66] Leidinger P, Keller A, Borries A, Reichrath J, Rass K, Jager SU,... PTEN and TIMP3 downregulation Cancer Cell 2009;16:498-509 [61] Godshalk SE, Paranjape T, Nallur S, Speed W, Chan E, Molinaro AM, Bacchiocchi A, Hoyt K, Tworkoski K, Stern DF, Sznol M, Ariyan S, et al A Variant in a MicroRNA complementary site in the 3' UTR of the KIT oncogene increases risk of acral melanoma Oncogene 2010 18 Research on Melanoma – A Glimpse into Current Directions and Future Trends. .. deacetylase non- 22 Research on Melanoma – A Glimpse into Current Directions and Future Trends histone proteins, such as tumor suppressors (e.g., p53), and signaling molecules (e.g., STAT1 and STAT3) (Minucci & Pelicci, 2006) Example of Biological Functions HDAC Tissue Distribution Localization HDAC1 HDAC2 Class I essential in cell survival and ubiquitous proliferation nucleus HDAC3 HDAC8 HDAC4 heart; brain;... time-to-progession was comparable in both arms of the study MS-275 was well tolearted, with nausea, diarrhea, and hypophosphatemia as the most frequently reported adverse events (Hauschild et al., 2008) 24 Research on Melanoma – A Glimpse into Current Directions and Future Trends Compound Chemical Group [Range] HDAC Specificity Sodium butyrate Short-chain fatty acid mM Class I, IIa Valproic acid (VPA) Short-chain . RESEARCH ON MELANOMA – A GLIMPSE INTO CURRENT DIRECTIONS AND FUTURE TRENDS Edited by Mandi Murph Research on Melanoma – A Glimpse into Current Directions and. Roberto Ria, Antonia Reale and Angelo Vacca Chapter 16 Stromal Microenvironment Alterations in Malignant Melanoma 335 Svetlana Brychtova, Michala Bezdekova, Jaroslav Hirnak, Eva Sedlakova, Martin. Klara Valyi-Nagy, Andras Voros, Eva Gagyi and Tibor Valyi-Nagy Chapter 19 The Role of Adhesion Receptors in Melanoma Metastasis and Therapeutic Intervention Thereof 393 Michael Alexander and