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Users are allowed to share and adapt the chapters for any non-commercial purposes as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. The books in their entirety are subject to copyright by the publisher. The reproduction, modification, republication and display of the books in their entirety, in any form, by anyone, for commercial purposes are strictly prohibited without the written consent of the publisher.</p> Front Matter https://exonpublications.com/index.php/exon/article/view/metastasis.Frontmatter METASTASIS Consolato M. Sergi, MD, PhD, MPH, FRCPC, FCAP Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 10.36255/exon-publications.metastasis.Frontmatter Foreword https://exonpublications.com/index.php/exon/article/view/metastasis.Foreword <p>Metastasis is an inherent characteristic of malignant tumors and designates the dissemination of cancer cells in the body with formation of secondary tumors at distant sites. Hematogenous metastasis marks the latest stage of tumor progression and in many cases is associated with poor clinical outcome. The biological mechanism of tumor metastasis is complex and requires several steps. Cancer cells have to infiltrate blood vessels or lymphatics, detach from the primary tumor, float to the next microcirculation, emigrate the vessel and proliferate in order to produce new tumor mass. This cellular behavior requires tight regulation on genetic and epigenetic levels that may vary from tumor to tumor due to heterogeneous genetic backgrounds but also activates conserved cellular pathways that are shared among different cancer entities. In this book, the authors cover several important clinical and biological aspects of cancer metastasis while at the same time highlighting different tumor entities. <a href="https://exonpublications.com/index.php/exon/article/view/metastasis.Foreword/1009">CONTINUE READING.....</a></p> Prof. Dr. med. David Horst Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 vii vii 10.36255/exon-publications.metastasis.Foreword Preface https://exonpublications.com/index.php/exon/article/view/metastasis.preface <p>Metastasis is the main cause of cancer-related deaths. In simple terms, metastasis is the spread and colonization of neoplastic cells from the place where they originate to another body part. The spread, or dissemination, of metastatic cells can be hematogenous, lymphogenous, or simple seeding into body cavities. The process of metastasis is orchestrated by a complex network of biological events, and our understanding of the processes that regulate metastasis has significantly improved. Consequently, the clinical management of metastatic cancer has also improved. The 13 chapters of this book provide an in-depth analysis of our understanding of the molecular mechanisms, and clinical management of meta-static cancer. In <em>Chapter 1</em>, Schroeder and Hall from the Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA, discuss the advantages of molecular imaging of brain metastases with positron emission tomography. Brain metastases are becoming a more frequent occurrence in the clinical setting. The chapter focuses on the usefulness of positron emission tomography to detect brain metastases while imaging for other sites of metastatic disease, discriminate treatment related changes from tumor recurrence, and identify patients for targeted radiotherapy <a href="https://exonpublications.com/index.php/exon/article/view/558/1004">CONTINUE READING.....</a></p> Consolato M. Sergi, MD, PhD, MPH, FRCPC, FCAP Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 ix xi 10.36255/exon-publications-metastasis.preface Contributors https://exonpublications.com/index.php/exon/article/view/metastasis.contributors <p><strong>AARON PERECMAN, MD</strong><br>Department of Urology, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>ADAM WIGGINS, MD</strong><br>Department of Urology, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>ALBERTO TESTORI, MD</strong><br>Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy</p> <p><strong>ANTOINE ARNAUD, MD</strong><br>Institut du Cancer Avignon-Provence, Avignon, France</p> <p><strong>BLANCA LUMBRERAS, PHD</strong><br>Department of Public Health, History of Science and Gynaecology, Miguel Hernández University, CIBER in Epidemiology and Public Health, Alicante, Spain</p> <p><strong>BUKET KOSOVA, PHD</strong><br>Ege University Faculty of Medicine, Department of Medical Biology, Izmir/Turkey</p> <p><strong>CARMEN MEJÍA, PHD</strong><br>Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. de las Ciencias s/n. Juriquilla, Querétaro CP 76230, México</p> <p><strong>CONSOLATO M. SERGI, MD, PHD, MPH, FRCPC, FCAP</strong><br>Anatomic Pathology Division, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, Ottawa, ON, Canada</p> <p><strong>DAVID WARSHAL, MD</strong><br>Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper, Cooper University Health Case, Camden, NJ, USA</p> <p><strong>DIEGO AVILES, MD</strong><br>Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper, Cooper University Health Case, Camden, NJ, USA</p> <p><strong>EDA DOGAN, MSC</strong><br>Ege University Faculty of Medicine, Department of Medical Biology, Izmir/Turkey</p> <p><strong>ELISA CHILET-ROSELL, PHD</strong><br>Department of Public Health, History of Science and Gynaecology, Miguel Hernández University, CIBER in Epidemiology and Public Health, Alicante 03550, Spain</p> <p><strong>ERLING A. HOIVIK, PHD</strong><br>Department of Clinical Science, University of Bergen, Bergen, Norway</p> <p><strong>FENG HONG, MD, PHD</strong><br>Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, USA</p> <p><strong>GIUSEPPE MANGIAMELI, MD, PHD</strong><br>Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy</p> <p><strong>HALE GULER KARA, PHD</strong><br>Ege University Faculty of Medicine, Department of Medical Biology, Izmir/Turkey</p> <p><strong>HARRY W. SCHROEDER III, MD, PHD</strong><br>Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA</p> <p><strong>JONATHAN T. XU, MD</strong><br>Department of Urology, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>KIMBERLY M. RIEGER-CHRIST, PHD</strong><br>Department of Urology and Translational Research, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>KYOKO HIDA, DDSC, PHD</strong><br>Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan</p> <p><strong>LANCE T. HALL, MD</strong><br>Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA</p> <p><strong>LÉA VAZQUEZ, DVM, MSC</strong><br>Institut du Cancer Avignon-Provence, Avignon, France</p> <p><strong>LUCY A. PARKER, PHD</strong><br>Department of Public Health, History of Science and Gynaecology, Miguel Hernández University, CIBER in Epidemiology and Public Health, Alicante, Spain</p> <p><strong>MARCO ALLOISIO, MD</strong><br>Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy</p> <p><strong>MICHELLE BUCHBINDER, PHD</strong><br>Cooper Medical School of Rowan University, Camden, NJ, USA</p> <p><strong>MING YIN, MD</strong><br>Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, USA</p> <p><strong>NAKO MAISHI, DDSC, PHD</strong><br>Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan</p> <p><strong>NIKOLAS C. ZETOUNI, MSC</strong><br>Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Walter C. Mackenzie Centre, Edmonton, AB, Canada</p> <p><strong>OLGA OSTROVSKY, PHD</strong><br>Department of Surgery, Division of Surgical Research, Cooper University Health Care, Camden, NJ, USA</p> <p><strong>QI-EN WANG, MD, PHD</strong><br>Department of Radiology, The Ohio State University Comprehensive Cancer Center, Columbus, USA</p> <p><strong>RYO TAKEDA, DDSC</strong><br>Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan</p> <p><strong>SANJNA DAS, BS</strong><br>Department of Translational Research, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>TERESA GARCÍA-GASCA, PHD</strong><br>Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. de las Ciencias s/n. Juriquilla, Querétaro CP 76230, México</p> <p><strong>THOMAS KALANTZAKOS, BA</strong><br>Department of Translational Research, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>TRAVIS SULLIVAN, MS</strong><br>Department of Translational Research, Lahey Hospital &amp; Medical Center, Burlington, MA, USA</p> <p><strong>UGO CIOFFI, MD, PHD</strong><br>Department of Surgery, University of Milan, Milan, Italy</p> <p><strong>ULISSES MORENO CELIS, PHD</strong><br>Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. de las Ciencias s/n. Juriquilla, Querétaro CP 76230, México</p> <p><strong>VILDAN BOZOK CETINTAS, PHD</strong><br>Ege University Faculty of Medicine, Department of Medical Biology, Izmir/Turkey</p> <p><strong>YASUHIRO HIDA, MD, PHD</strong><br>Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine, Sapporo, Japan</p> List of Contributors Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 xiii xvi 10.36255/exon-publications.metastasis.contributors Molecular Imaging of Brain Metastases with PET https://exonpublications.com/index.php/exon/article/view/metastasis.brain-metastases <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Molecular imaging of brain metastases with positron emission tomography with computed tomography (PET/CT) or with magnetic resonance imaging (PET/MRI) can be performed with a growing number of molecular imaging agents. The most commonly used molecular imaging agent for primary malignancies outside of the brain is a glucose analog radio-labelled with fluorine-18, 18F-fluorodeoxyglucose (18F- FDG), which can be used to identify brain metastases. Likewise, additional molecular imaging agents such as prostate specific membrane antigen (PSMA) ligands (i.e., 68Ga PSMA-11), alkylphosphocholine analogs (i.e., CLR124/CLR1404), and amino acids (i.e., 11C-MET, 18F-FET, 18F-DOPA, 18F-FACBC) can identify brain metastases. Advantages of PET in brain tumor imaging include co-registration with other imaging technologies, quantitative measurements, and significant potential for improvement in diagnostic accuracy. PET can be used to detect brain metastases while imaging for other sites of metastatic disease, discriminate treatment related changes from tumor recurrence, and identify patients for targeted radiotherapy from theranostic molecular imaging and targeted radiotherapy agents.</span></p> Harry W. Schroeder III, MD, PHD Lance T. Hall, MD Copyright (c) 2022 Harry W. Schroeder III, MD, PHD, Lance T. Hall, MD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 1 16 10.36255/exon-publications.metastasis.brain-metastases The Use of Imaging Tests for the Diagnosis and Management of Lung Nodules https://exonpublications.com/index.php/exon/article/view/metastasis.pulmonary-nodules <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Imaging tests have a central role in the diagnosis and management of lung cancer. Because of the increasing sensitivity of the current diagnostic imaging tests, and the implementation of screening programs, pulmonary nodules are more frequently detected in clinical practice. In addition, early detection of lung cancer and improvements in treatment have led to improved survival rates. As smoking was in the past more common among men, lung cancer has traditionally been considered as a male disease, particularly for older male smokers. However, this stereotype is no longer valid. A large number of studies point to a higher risk sensitivity in women than men for major lung cancer types. In this chapter, we describe the different clinical pathways in the management of solitary pulmonary nodules.</span></p> Blanca Lumbreras, PHD Elisa Chilet-Rosell, PHD Lucy A. Parker, PHD Copyright (c) 2022 Blanca Lumbreras, PHD, Elisa Chilet-Rosell, PHD, Lucy A. Parker, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 17 31 10.36255/exon-publications.metastasis.pulmonary-nodules The State of the Art in Thoracic Surgery: Treating Lung Cancer Between Tradition and Innovation https://exonpublications.com/index.php/exon/article/view/metastasis.thoracic-surgery <p><strong><span style="color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Lung cancer is the second most diagnosed cancer and was the primary cause of cancer death worldwide in 2020. Lung cancer treatment is associated with huge costs for patients and society. Consequently, there is an increasing interest on prevention, early detection with screening, and development of new treatments. Surgical management accounts for at least 90% of the activity of thoracic surgery departments. Surgery is the treatment of choice for stages I and II non small cell lung cancer. In this chapter, we discuss the state of art of thoracic surgery for surgical management of lung cancer. We start describing the milestones of lung cancer treatment, lobectomy, and lymphadenectomy, followed by a description of the traditional and innovative approaches that are currently available. Open lobectomy, and mini invasive approaches including video-assisted thoracoscopic surgery and robotic assisted thoracoscopic surgery are covered. A brief overview of the innovation and future perspective in thoracic surgery are presented.</span></p> Giuseppe Mangiameli, MD, PHD Ugo Cioffi, MD, PHD Marco Alloisio, MD Alberto Testori, MD Copyright (c) 2022 Giuseppe Mangiameli, MD, PHD, Ugo Cioffi, MD, PHD, Marco Alloisio, MD, Alberto Testori, MD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 33 48 10.36255/exon-publications.metastasis.thoracic-surgery Pulmonary Metastases: Surgical Principles, Surgical Indications, and Innovations https://exonpublications.com/index.php/exon/article/view/metastasis.pulmonary-metastases <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Pulmonary metastasectomy is an established treatment that can provide improved long-term survival for patients with metastatic tumor(s) in the lung. In this chapter, we discuss the state-of-the-art thoracic surgery in surgical management of lung metastases. The principles of pulmonary metastasectomy, followed by a comparison between thoracotomy and mini-invasive surgery are presented. Different surgical indications, and oncological outcomes according to the surgical approach (open vs mini-invasive), histological types and the number of metastatic nodules in the lung are discussed. Finally, the role of surgical margin, lymphadenectomy, and surgical resection of recurrent metastases along with a brief overview of the future perspectives in thoracic surgery in the treatment of lung metastases are presented.</span></p> Giuseppe Mangiameli, MD, PHD Ugo Cioffi, MD, PHD Marco Alloisio, MD Alberto Testori, MD Copyright (c) 2022 Giuseppe Mangiameli, MD, PHD, Ugo Cioffi, MD, PHD, Marco Alloisio, MD, Alberto Testori, MD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 49 62 10.36255/exon-publications.metastasis.pulmonary-metastases Genomic Landscapes and Tumor Evolution in Metastatic Gynecological Cancers https://exonpublications.com/index.php/exon/article/view/metastasis.gynecological-cancers <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Gynecological cancers, such as endometrial cancer, ovarian cancer, and cervical cancers affect women’s health worldwide. Metastatic and recurrent cancers are associated with poor survival, and effective treatment is lacking. A deeper understanding of the molecular mechanisms at the genomic level may help decipher the metastatic process, identify new targets, and develop personalized treatment strategies. Recent tumor evolutionary studies have provided phylogenetic interpretation of gynecological cancer metastasis. This has provided new models of metastatic development and pointed to potential targets for treatment. Moreover, cancer genome analysis of simultaneously detected tumor lesions, initially diagnosed as independent synchronous primary cancers of the endometrium and ovary, suggest that they rather represent a primary tumor-metastasis-pair relationship. This chapter provides an overview of the characterization of cancer genomes, from primary tumors to metastatic lesions of the major gynecological cancers, and how such data are interpreted in an evolutionary context.</span></p> Erling A. Hoivik, PHD Copyright (c) 2022 Erling A. Hoivik, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 63 76 10.36255/exon-publications.metastasis.gynecological-cancers Influence of Aberrant Epigenetic Changes and the Tumor Microenvironment in Ovarian Cancer Metastasis https://exonpublications.com/index.php/exon/article/view/metastasis.ovarian-cancer-epigenetics <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Metastasis in ovarian cancer is a primary driver of poor outcomes for patients because of its association with chemoresistance and low five-year survival rates. Epigenetic changes to gene expression in cancer cells are key factors that contribute to the high rates of metastasis and chemoresistance. However, ovarian cancer cells do not act alone. Once the cancer spreads to the omentum and peritoneum, it hijacks intercellular communication systems to transform neighboring cells within the tumor microenvironment into potent engines that produce critical growth factors that facilitate metastasis, chemoresistance, immune evasion, and invasion. By reversing these aberrant epigenetic modifications in cancer cells and the tumor microenvironment, novel epigenetic therapies can specifically target cancer cells while sparing healthy cells, minimizing toxicity to normal tissues. When combining these pharmaceutical agents with standard chemotherapy, metastasis and chemoresistance can be suppressed, making ovarian cancer cells newly susceptible to current cytotoxic treatments, and providing patients with hope for a cure.</span></p> Diego Aviles, MD David Warshal, MD Michelle Buchbinder, PHD Olga Ostrovsky, PHD Copyright (c) 2022 Diego Aviles, MD, David Warshal, MD, Michelle Buchbinder, PHD, Olga Ostrovsky, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 77 89 10.36255/exon-publications.metastasis.ovarian-cancer-epigenetics MetastamiRs: The Role of MicroRNAs in the Metastatic Phenotype of Prostate Cancer https://exonpublications.com/index.php/exon/article/view/metastasis.metastamirs-prostate-cancer <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate protein expression. The human genome encodes more than 2,500 miRNAs, with each being able to modulate several targets, act along a variety of cellular pathways, and affect various tissues. They are frequently dysregulated in cancers and, via their protein targets, act as oncogenes or tumor-suppressors. As such, their effects are pervasive—miRNAs have been implicated in various biological processes including apoptosis, epithelial-to-mesenchymal transition, and angiogenesis. In this context, miRNA involved in metastasis have been termed “metastamiRs”. This chapter focuses on the role of miRNAs in the metastatic processes of prostate cancer. Our primary aims are to detail specific biological processes and molecular targets through which miRNAs act and that may serve as therapeutic targets. Secondly, we discuss the potential of miRNAs to serve as biomarkers of tumor aggression and thus potentially guide personalized therapy.</span></p> Adam Wiggins, MD Jonathan Xu, MD Aaron Perecman, MD Thomas Kalantzakos, BA Sanjna Das, BS Travis Sullivan, MS Kimberly Rieger-Christ, PHD Copyright (c) 2022 Adam Wiggins, MD, Jonathan Xu, MD, Aaron Perecman, MD, Thomas Kalantzakos, BA, Sanjna Das, BS, Travis Sullivan, MS, Kimberly Rieger-Christ, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 91 107 10.36255/exon-publications.metastasis.metastamirs-prostate-cancer Hematological Toxicity Induced by Bone Metastasis Radiation Therapy https://exonpublications.com/index.php/exon/article/view/metastasis.hematological-toxicity <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Radiotherapy is frequently used in patients with bone metastasis. However, radiotherapy for bone metastasis may cause clinically significant hematological toxicity both by depleting the blood cells and by damaging the proliferating bone marrow. In general, lymphocytes (T cells, B cells and natural killer cells) are among the most radiosensitive cells, followed by monocytes and macrophages. As the most radiosensitive cells in the hematopoietic system, radiotherapy induced lymphopenia occurs immediately after irradiation and shows a nadir within 1–2 months after the initiation of radiotherapy. Radio-induced hematotoxicity is a significant clinical problem affecting treatment outcome and survival of cancer patients. This toxicity results from the direct effects of radiation on circulating lymphocytes and the indirect effects on stem cells in the bone marrow.</span></p> Léa Vazquez, DVM, MSC Antoine Arnaud, MD Copyright (c) 2022 Léa Vazquez, DVM, MSC, Antoine Arnaud, MD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 109 115 10.36255/exon-publications.metastasis.hematological-toxicity DNA Damage Response and Cancer Metastasis: Clinical Implications and Therapeutic Opportunities https://exonpublications.com/index.php/exon/article/view/metastasis.dna-damage-response <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">The DNA damage response (DDR) system is critical to maintain genomic integrity and guard against DNA damages. DDR alterations, resulting from DDR gene mutations or epigenetic modifications, have been involved in cancer initiation, progression, and treatment response. However, the role of DDR alterations in cancer metastasis has not been well characterized. Recently, there is increasing evidence of an important role of DDR in regulating multiple facets of cancer metastatic process. In this chapter, we summarize current knowledge of the interplay among DDR alterations, tumor genomic evolution, tumor microenvironment remodeling and emergence of treatment resistance, which ultimately leads to tumor progression and metastasis development. We discuss several pre-clinical models of DDR gene alterations and cancer metastatic predisposition, and clinical evidence of potential DDR involvement in metastasis. We further discuss its clinical relevance in metastatic cancer management, such as the utilization of DDR defects as a biomarker and therapeutic target.</span></p> Ming Yin, MD Feng Hong, MD, PHD Qi-En Wang, MD, PHD Copyright (c) 2022 Ming Yin, MD, Feng Hong, MD, PHD, Qi-En Wang, MD, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 117 136 10.36255/exon-publications.metastasis.dna-damage-response The Roles of Tumor Endothelial Cells in Cancer Metastasis https://exonpublications.com/index.php/exon/article/view/metastasis.endothelial-cells <p><strong>ABSTRACT</strong></p> <p>Tumor metastasis is the main cause of cancer-related deaths. Tumor metastasis is orchestrated by a complex network of biological events. One such event is the formation of new blood vessels, termed as tumor angiogenesis. Tumor angiogenesis is essential for tumor progression. Without tumor angiogenesis, most solid tumors remain dormant. Apart from supplying tumors with nutrients and oxygen, tumor blood vessels provide a route for metastasis. Endothelial cells are key players in the formation of neovessels. Tumor endothelial cells that line tumor blood vessels differ from normal endothelial cells in many aspects. Tumor endothelial cells are irregular monolayers, have a higher expression of proangiogenic factors, and impaired endothelial barrier function when compared with their normal counterparts. The basement membrane thickness of tumor blood vessels is uneven and the association between pericytes and tumor endothelial cells is weak, leading to vascular leakiness. In this chapter, we highlight the role of endothelial cells in the initial steps of tumor metastasis.</p> Kyoko Hida, DDSc, PhD Nako Maishi, DDSc, PhD Ryo Takeda, DDSc Yasuhiro Hida, MD, PHD Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 137 148 10.36255/exon-publications.metastasis.endothelial-cells Apoptosis-Induced Compensatory Proliferation in Cancer https://exonpublications.com/index.php/exon/article/view/metastasis.apoptosis-proliferation <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Apoptosis is a biological process that allows adequate cellular turnover and the elimination of damaged or infected cells. However, there are compensatory molecular mechanisms that promote cell proliferation after increased apoptotic events. These events are commonly mediated by mitogenic proteins, released by apoptotic cells, and received by neighboring cells, that trigger mechanisms similar to cell repair after an injury or traumatic event. This effect is known as “apoptosis-induced proliferation”. This chapter addresses the process of apoptosis-induced proliferation, the regulatory mechanisms, and its importance in cancer development, progression, and therapy development.</span></p> Ulisses Moreno Celis, PHD Teresa García-Gasca, PHD Carmen Mejía, PHD Copyright (c) 2022 Ulisses Moreno Celis, PHD, Teresa García-Gasca, PHD, Carmen Mejía, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 149 161 10.36255/exon-publications.metastasis.apoptosis-proliferation Targeting Apoptosis to Overcome Chemotherapy Resistance https://exonpublications.com/index.php/exon/article/view/metastasis.chemotherapy-resistance <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Chemotherapy resistance is a major limiting factor for the extensive use of chemotherapeutic drugs in cancer treatment. Despite the large number of newly discovered medications, treatment success rates are still unsatisfactory. Programmed cell death, called apoptosis, is one of the main tissue homeostasis mechanisms that balances cell survival and death. Apoptosis can be induced through extrinsic and intrinsic pathways or repressed by inhibitor proteins. During tumor progression, homeostasis between the anti-apoptotic and pro-apoptotic regulators is disturbed and shifted towards survival through various escape mechanisms. Dysregulation of apoptosis-regulatory mediators, particularly high levels of anti-apoptotic proteins, is one of the main mechanisms by which tumor cells acquire resistance to chemo- and radiotherapy. Therefore, it is important to restore apoptosis in the chemo- and radiotherapy resistant tumor cells. In this chapter, we summarize general chemotherapy resistance mechanisms, discuss the role of extrinsic and intrinsic pathways in chemoresistance, and review the current experimental strategies to overcome chemotherapy resistance targeting the apoptotic pathways.</span></p> Eda Dogan, MSC Hale Guler Kara, PHD Buket Kosova, PHD Vildan Bozok Cetintas, PHD Copyright (c) 2022 Eda Dogan, MSC, Hale Guler Kara, PHD, Buket Kosova, PHD, Vildan Bozok Cetintas, PHD https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 163 180 10.36255/exon-publications.metastasis.chemotherapy-resistance Features of Metastatic Ewing Sarcoma https://exonpublications.com/index.php/exon/article/view/metastasis.metastatic-ewing-sarcoma <p><strong><span style="font-family: 'Segoe UI',sans-serif; color: black;">ABSTRACT</span></strong></p> <p><span style="font-family: 'Segoe UI',sans-serif; color: black;">Since its first description in 1921, Ewing sarcoma has been the subject of several morphologic and genetic investigations. Currently, the overall survival for localized Ewing sarcoma is 65–70%. However, in patients presenting with metastatic disease, the overall survival is poor, being in the range of 20–30%. There are several unknown features of Ewing sarcoma, such as its cell of origin, genetic background, chemotherapy resistance, and abnormal presentation sites, among others. A better understanding of the molecular basis of the development of Ewing sarcoma is needed to help improve survival, especially in metastatic/resistance cases. In this chapter, we provide an overview of the features of metastatic Ewing sarcoma.</span></p> Nikolas C. Zetouni, MSC Consolato M. Sergi, MD, PhD, FRCPC, FCAP Copyright (c) 2022 Nikolas C. Zetouni, MSC; Consolato M. Sergi, MD, PhD, FRCPC, FCAP https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 181 193 10.36255/exon-publications.metastasis.metastatic-ewing-sarcoma Index https://exonpublications.com/index.php/exon/article/view/metastasis.index Index Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 195 198 10.36255/exon-publications-metastasis.index About the Editor https://exonpublications.com/index.php/exon/article/view/metastasis.editor <p><img src="https://exonpublications.com/public/site/images/bchapter/consolato-sergi-150.jpg" alt="Consolato M. Sergi" width="150" height="216"></p> <p>Consolato M. Sergi, MD, PhD, MPH, FRCPC, FCAP, is a full professor of Pathology and adjunct professor of Pediatrics at the University of Alberta, Edmonton, Canada. He is also a consultant for Standards and Guidelines in Carcinogenesis of Chemical Compounds published by the World Health Organization/International Agency on Research on Cancer (WHO/IARC monographs), Lyon, France. His research interests include hepatic tumors, metabolic diseases, cholangiopathies, organ transplantation, and gut/bile microbiome using cell lines, animal models, and clinical samples. He identified the role of apoptosis in ductal plate malformation of the liver, characterized sialidosis, and found two new genes, WDR62, which encodes a centrosome-associated protein (Nat Genet 2010) and OTX2, mutations of which can contribute to dysgnathia (J Med Genet 2012). Professor Sergi has published more than 300 research/review articles and several books and book chapters. He has supervised and mentored many PhD students and clinical fellows. He is also on the editorial boards of several scientific journals.</p> Consolato M. Sergi, MD, PhD, MPH, FRCPC, FCAP Copyright (c) 2022 Exon Publications https://creativecommons.org/licenses/by-nc/4.0 2022-05-03 2022-05-03 10.36255/exon-publications-metastasis.editor