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High grade serous ovarian carcinoma (HGSOC) is the most lethal form of ovarian cancer and is the fifth leading cause of female death in the western world. Unlike many other cancers, few viable HGSOC screening methodologies exist. HGSOC is consequently diagnosed at an advanced stage with substantial extraovarian metastases in most cases. These late stage diagnoses have hindered discovery of screening methods due to infrequent analyses of precursor lesions and uncertainty regarding HGSOC initiation mechanisms. Both the HGSOC "cell of origin" and mutations necessary for HGSOC initiation are the subject of substantial debate. Several candidate origin tissues exist in the ovarian surface epithelium (OSE), distal fallopian tubal epithelium (TE) and stem cell subpopulation of either tissue. Mutations associated with advanced HGSOC tumors have also been identified by the Cancer Genome Atlas Research Network (TCGA). However, most HGSOC-associated mutations have not been assessed as putative cancer driver mutations or passenger mutations in several putative cells of origin. In this dissertation, I performed functional screening of random combinations of suspected HGSOC driver genes in different putative cells of origin using a lentiviral CRISPR/Cas9 library. Results support the ovarian surface epithelial stem cell (OSE-SC) theory of HGSOC initiation and suggest that most HGSOC-associated mutations are uninvolved in OSE-SC transformation. Random screening, along with in vitro and in vivo validation experiments, demonstrate that disruption of Trp53, Rb1 and/or Pten are minimal OSE-SC transformation requirements, and that a few other HGSOC-associated genes may enhance transformation via Trp53 and Rb1-related mechanisms. These results are the first published efforts to functionally test all putative drivers of HGSOC and have direct implications for production of HGSOC developmental models. Such models may be useful tools for ascertainment of novel HGSOC screening methodologies. Growth-inhibitory mutations uncovered via screening also have value as putative druggable targets. Finally, the screening methodology employed here represents a rapid means of differentiating driver and passenger mutations in any cell type for which in vitro culturing exists. It may therefore serve as an important tool for elucidation of driver mutations in other cancer types.
Epithelial ovarian cancer is the fifth-leading cause of cancer-related death for women in North America and is responsible for over 100 000 deaths/year worldwide (Ferlay et al., 2015). High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype and the vast majority of women are diagnosed with advanced stage disease (Bowtell, 2010). The current standard treatment is aggressive surgery combined with adjuvant and/or neo-adjuvant platinum/taxane-based chemotherapy. Despite initial efficacy of standard therapy, resistant cancer recurs and 70% of patients die within 5 years after initial diagnosis (Bast et al., 2009). Further understanding of the molecular and cellular features that promote HGSC progression may assist in identifying new opportunities for therapeutic intervention and ultimately improve the prognosis of women with HGSC. My research has generated an extensive functional and genomic characterization of serous ovarian cancer cell lines and provides a framework for identifying vulnerabilities associated with distinct molecular features. Using this dataset, I have focused on the identification of genes encoding for highly expressed cell surface molecules. I have identified a novel role of the tetraspanin CD151 in serous ovarian cancer. I have found that CD151 depletion impairs survival, proliferation and tumor growth in murine models of a subset of HGSC cell lines. In search of the mechanism underlying CD151-dependency, I have uncovered a novel association for CD151-dependency in cancer cells with mesenchymal features. In particular, high ZEB1 and ZEB2 expression is tightly coupled with CD151-dependency and thus, may be used as biomarkers for stratifying tumors requiring CD151 for growth. Moreover, CD151-binding antibodies block the migratory capacity of CD151-dependent cells, thereby implicating CD151 in metastasis and dissemination of HGSC tumors. These studies provide a resource of characterized HGSC cell lines and suggest that CD151 may be a biological target in HGSC tumors.
In an era of promising advances in cancer research, there are considerable and even alarming gaps in the fundamental knowledge and understanding of ovarian cancer. Researchers now know that ovarian cancer is not a single disease-several distinct subtypes exist with different origins, risk factors, genetic mutations, biological behaviors, and prognoses. However, persistent questions have impeded progress toward improving the prevention, early detection, treatment, and management of ovarian cancers. Failure to significantly improve morbidity and mortality during the past several decades is likely due to several factors, including the lack of research being performed by specific disease subtype, lack of definitive knowledge of the cell of origin and disease progression, and incomplete understanding of genetic and non-genetic risk factors. Ovarian Cancers examines the state of the science in ovarian cancer research, identifies key gaps in the evidence base and the challenges to addressing those gaps, considers opportunities for advancing ovarian cancer research, and examines avenues for translation and dissemination of new findings and communication of new information to patients and others. This study makes recommendations for public- and private-sector efforts that could facilitate progress in reducing the incidence of morbidity and mortality from ovarian cancers.
Patient Derived Tumor Xenograft Models: Promise, Potential and Practice offers guidance on how to conduct PDX modeling and trials, including how to know when these models are appropriate for use, and how the data should be interpreted through the selection of immunodeficient strains. In addition, proper methodologies suitable for growing different type of tumors, acquisition of pathology, genomic and other data about the tumor, potential pitfalls, and confounding background pathologies that occur in these models are also included, as is a discussion of the facilities and infrastructure required to operate a PDX laboratory. - Offers guidance on data interpretation and regulatory aspects - Provides useful techniques and strategies for working with PDX models - Includes practical tools and potential pitfalls for best practices - Compiles all knowledge of PDX models research in one resource - Presents the results of first ever global survey on standards of PDX development and usage in academia and industry
Ovarian cancer management is a rapidly changing field with new treatment agents available as a result of a greater understanding of the pathogenesis of this disease. In addition, both surgical and chemotherapeutic treatment strategies are evolving to maximise response in this disease. This book brings together leading specialists from around the world to discuss and outline a variety of new concepts in ovarian cancer, ranging from molecular biology and genetics through screening to both surgical and chemotherapeutic management.
WHO Classification of Tumours of Female Reproductive Organs is the sixth volume in the 4th Edition of the WHO series on histological and genetic typing of human tumours. This authoritative, concise reference book provides an international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design of studies monitoring response to therapy and clinical outcome. Diagnostic criteria, pathological features, and associated genetic alterations are described in a strictly disease-oriented manner. Sections on all recognized neoplasms and their variants include new ICD-O codes, epidemiology, clinical features, macroscopy, pathology, genetics, and prognosis and predictive factors. The book, prepared by 91 authors from 19 countries, contains more than 400 colour images and tables, and more than 2100 references
This book provides the readers with an up-to-date review of the design, structure and function of a representative selection of fibrous proteins in both health and disease. The importance of the α-helical coiled coil, a conformational motif based on the heptad repeat in the amino acid sequence of all α-fibrous proteins (and parts of some globular proteins) is underlined by three Chapters devoted to its design, structure, function and topology. Specific proteins covered in the text and which depend on the coiled coil for their structure and function, include the intermediate filament proteins, tropomyosin, myosin, paramyosin, fibrin and members of the spectrin superfamily. Also described are fibrous proteins based on the β-pleated sheet and collagen conformations. Recombinant structural proteins, especially of silk and collagen, are discussed in the context of developing new biomaterials with varied applications. Established researchers and postgraduate students in the fields of protein chemistry, biochemistry and structural biophysics will find Fibrous Proteins: Structures and Mechanisms to be an invaluable collection of topical reviews that describe the basic advances made in the field of fibrous proteins over the past decade. This book, written by recognized authorities in the field, provides a clear account of the current status of fibrous protein research and, in addition, establishes the basis for deciding the most appropriate directions for future activity, including the applications of protein engineering and the commercial exploitation of new biomaterials.
This updated second edition of Diagnosis and Management of Ovarian Disorders provides thorough, yet succinct insight into the ever-changing realm of ovarian disorders. It presents a novel multidisciplinary approach to the subject as described by clinicians, surgeons, pathologists, basic scientists and related medical researchers. Topics covered include reproductive technology, early diagnosis of ovarian cancer, and management of menopause among others. The breadth of information provided by this book will appeal to clinicians and researchers involved in the study and treatment of ovarian disorders.KEY FEATURES* Includes updated information on early diagnosis of ovarian cancer* Reviews new diagnostic techniques for ovarian disorders* Discusses latest information on reproductive technology* Presents translational treatment linking laboratory research with clinical medicine
New edition includes more than 350 new illustrations and 22 revised chapters Written by internationally recognized experts Each entry is structured the same way, from general to more specific information, which allows the reader to quickly access key information in every chapter Since the publication of the 1/e in 1977, Blaustein's Pathology of the Female Genital Tract has consolidated its position as the leading textbook of gynecological pathology. an essential reference for all pathologists and residents, this thoroughly updated Sixth Edition includes more than 1500 illustrations in color, i