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Author: Arun Amar
Publisher:
ISBN:
Category : Brain
Languages : en
Pages : 84
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Book Description
Author: Arun Amar
Publisher:
ISBN:
Category : Brain
Languages : en
Pages : 84
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Book Description
Author: Tom Mikkelsen
Publisher: Wiley-Liss
ISBN:
Category : Medical
Languages : en
Pages : 494
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Book Description
Brain Tumor Invasion Biological, Clinical, and Therapeutic Considerations Edited by Tom Mikkelsen Rolf Bjerkvig Ole Didrik Laerum Mark L. Rosenblum Recent advances in molecular biology have given us profound new insights into the behavior of primary brain tumors. Not only are such tumors more diffuse in their infiltration of brain tissue and therefore less amenable to surgery than brain tumors originating elsewhere in the body—it now appears that the central nervous system and the normal brain itself constitute a biological environment conducive to the uncontrolled spread of primary tumors. Brain Tumor Invasion is the first comprehensive reference devoted to the invasive behavior of primary brain tumors. It examines the biological mechanisms responsible for the increased ability of gliomas to metastasize in the central nervous system, and discusses the role of chemical carcinogens, growth factors, oncogenes, and tumor suppressors in the progression of such metastases. This book surveys the latest research in the field, reviews present and future prospects of anti-invasive brain tumor therapy, and even translates preclinical trials and other research results into potential new therapies. The material is divided into five main categories: Developmental biology and molecular neuro-oncology Pathological and clinical features of malignant brain tumors Models for the study of brain tumor invasion in vivo and in vitro Mechanisms of invasion New therapeutic strategies Brain Tumor Invasion offers dozens of maps and photographs that illustrate topics under discussion. This in-depth introduction to one of the most difficult problems in the management of brain tumors is indispensable to neuro-oncologists involved in brain tumor research and therapy. It is also useful to researchers in cancer biology, neuroscience, cell biology, and molecular genetics.
Author: Shay Soker
Publisher: Humana Press
ISBN: 3319605119
Category : Medical
Languages : en
Pages : 225
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Book Description
Cancer cell biology research in general, and anti-cancer drug development specifically, still relies on standard cell culture techniques that place the cells in an unnatural environment. As a consequence, growing tumor cells in plastic dishes places a selective pressure that substantially alters their original molecular and phenotypic properties.The emerging field of regenerative medicine has developed bioengineered tissue platforms that can better mimic the structure and cellular heterogeneity of in vivo tissue, and are suitable for tumor bioengineering research. Microengineering technologies have resulted in advanced methods for creating and culturing 3-D human tissue. By encapsulating the respective cell type or combining several cell types to form tissues, these model organs can be viable for longer periods of time and are cultured to develop functional properties similar to native tissues. This approach recapitulates the dynamic role of cell–cell, cell–ECM, and mechanical interactions inside the tumor. Further incorporation of cells representative of the tumor stroma, such as endothelial cells (EC) and tumor fibroblasts, can mimic the in vivo tumor microenvironment. Collectively, bioengineered tumors create an important resource for the in vitro study of tumor growth in 3D including tumor biomechanics and the effects of anti-cancer drugs on 3D tumor tissue. These technologies have the potential to overcome current limitations to genetic and histological tumor classification and development of personalized therapies.
Author: Gregory Joseph Baker
Publisher:
ISBN:
Category :
Languages : en
Pages : 265
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As glioma cells infiltrate the brain they associate with various microanatomic structures such as blood vessels and myelinated white matter tracts. How distinct invasion patterns coordinate tumor growth and influence clinical outcomes remains poorly understood. We have investigated how perivascular invasion affects glioma growth patterning and response to anti-angiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion also characterizes de-novo endogenous mouse brain tumors, biopsies of primary human glioblastoma and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors are vascularized by preexisting normal brain microvessels as individual gliomas cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma empirically by treating animals with the angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel-normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. The results of these studies provide compelling experimental evidence in support of the recently described failure of clinically used anti-angiogenics to extend the overall survival of human patients with newly diagnosed glioblastoma. To identify molecular factors driving perivascular invasion, we examined genome-wide microarray data from mouse GL26 gliomas harvested from the brains of syngeneic C57BL/6 mice. This analysis revealed that galectin-1 (mLgals1) was the most abundantly expressed mRNA transcript in mouse GL26 glioma. We tested the role of this gene in perivascular invasion based on its known role in mediating cell-extracellular matrix interactions and its correlation with increasing malignancy and poor patient prognosis in clinical glioma. Unexpectedly, shRNA-mediated galectin-1 knockdown did not inhibit perivascular glioma invasion, but led to the complete eradication of intracranial tumor implants in RAG1-/- mice, which grew normally in more severely immunocompromised NOD-scid IL2Rgnull mice. Natural killer cell depletion in both RAG1-/- and C57BL/6J mice permitted the growth of galectin-1-deficient glioma. Orthotopic galectin-1-deficient glioma implants in RAG1-/- mice contained more granzyme B+ cells. Interferon gamma ELISpot assays were used to assess the level of tumor-specific adaptive immunity raised against galectin-1-deficient glioma. These experiments showed that galectin-1-deficient glioma was eradicated prior to, and independent of, adaptive anti-tumor immunity. Further in vitro experiments demonstrated that galectin-1-deficient GL26-Cit glioma cells were approximately 3-fold more sensitive to natural killer cell-mediated tumor lysis compared to their galectin-1 expressing counterparts. These findings suggest that galectin-1 suppression in human glioma cells could improve patient survival by restoring natural killer cell immune surveillance, which we have demonstrated to be capable of eradicating these tumors. Further experiments were performed to elucidate the mechanism by which galectin-1-deficient glioma is rejected by natural killer cells at the cellular level. Our results indicate that a population of Gr-1+/CD11b+ myeloid cells from blood are crucial for stimulating natural killer cell-mediated eradication of galectin-1-deficient glioma. We show that immunodepletion of Gr-1+ cells in RAG1-/- mice permits galectin-1-deficient glioma growth and significantly reduces the amount of tumor-infiltrating granzyme B+ cells. In vitro experiments demonstrate that monocytic Gr-1+/CD11b+ myeloid cells isolated from peripheral blood upregulate NK1.1 and granyzme B expression in response to the presence of galectin-1-deficient glioma cells, and that these cells enhance natural killer cell-mediated tumor lysis. Since we demonstrate that monocytic Gr-1+/CD11b+ myeloid cells lack tumor lytic potential themselves, we postulate that these cells act by stimulating anti-tumor cytotoxic potential in natural killer cells. In vivo experiments reveal that 7-fold more Gr-1+/CD11b+ myeloid cells infiltrate galectin-1-deficient gliomas 48 hrs post-tumor implantation compared to gliomas expressing normal levels of galectin-1. On the contrary, the number of tumor-infiltrating natural killer cells is found to be the same between the two tumor types, suggesting that galectin-1 specifically inhibits the entry of Gr-1+/CD11b+ myeloid cells. Our most recent experiments indicate that glioma-derived galectin-1 acts as a molecular switch for monocytic Gr-1+/CD11b+ myeloid cells to become anti-inflammatory. We demonstrate that the application of recombinant mouse galectin-1 protein onto monocytic Gr-1+/CD11b+ myeloid cells co-cultured with glioma cells and natural killer cells inhibits the enhanced tumor lysis attributed to the addition of the monocytic myeloid cells. This view of galectin-1 as a protein with anti-inflammatory effects on monocytic myeloid cells helps explain why the few Gr-1+/CD11b+ myeloid cells that do infiltrate galectin-1-replete gliomas fail to active natural killer cell-mediated anti-tumor cytotoxicity. Together, our data suggest that glioma-derived galectin-1 acts to inhibit anti-tumor natural killer cell immune surveillance through a tripartite mechanism: (1.) by blocking the infiltration of Gr-1+/CD11b+ myeloid cells into the tumor microenvironment which stimulate cytotoxic activity in natural killer cells, (2.) by provoking immunosuppressive function in those Gr-1+/CD11b+ myeloid cells that do infiltrate the gal-1-replete tumor microenvironment, thus inhibiting the stimulation of natural killer cells by Gr-1+/CD11b+ myeloid cells, and (3.) by imparting an intrinsic resistance to natural killer cell-mediated tumor cell lysis as demonstrated by us previously. We now plan to perform enzyme-linked immunosorbent assays, quantitative reverse transcription polymerase chain reaction, and genome-wide gene expression profiling on monocytic Gr-1+/CD11b+ myeloid cells to identify genes/proteins responsible for the enhancement of natural killer cell-mediated lysis of galectin-1-deficient glioma. Ultimately, through a deeper understanding of the mechanisms of natural killer cell-mediated anti-tumor immune surveillance, we hope to design novel innate immunotherapeutic strategies to be tested in patients suffering from glioblastoma.
Author: Marc Craig Brande
Publisher:
ISBN:
Category :
Languages : en
Pages : 168
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Author: Danny Jomaa
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Glioblastoma is the most common and most lethal primary brain tumor to affect adults. While current treatment options provide temporary recourse, the majority of patients experience tumor recurrence and few survive five years past their initial diagnosis. Recently, tumor microtubes (TMs) were identified in an in vivo model of glioblastoma. These membrane-bound structures formed physical connections between tumor cells, over short and long distances, and facilitated intratumoral communication, invasion, treatment resistance, and post-treatment tumor recovery. To date, this is the first instance of TMs being reported in glioblastoma. The lack of an in vitro model for these structures has delayed further characterization of how TMs form between cells, facilitate intercellular exchange, and how they can be therapeutically targeted to increase treatment susceptibility. The study presented here is the first instance of TMs characterized in an in vitro model of primary glioblastoma (PriGO) cells. These TMs recapitulated many of the structural and functional properties of those observed in vivo, making it a suitable model for further experimentation. Using this model, Rac1, a known orchestrator of cytoskeletal remodeling and motility, was shown to be integral to establishing a TM network between PriGO cells, as demonstrated by siRNA-mediated protein knockdowns. PREX1, a GEF necessary for Rac1 signaling activity, also played a role in PriGO TM formation as evidenced by CRISPR/Cas9-based knockouts. Re-introducing a PREX1 domain with Rac-GEF activity into cells lacking the protein led to a functional rescue of TM growth, thus confirming PREX1's involvement. Characterizing a cell culture model of glioblastoma TMs is a necessary first step in the study of these structures, ultimately paving the way for future development of therapies that disrupt this network.
Author: Marten H. Hofker
Publisher: Springer Science & Business Media
ISBN: 1592593402
Category : Science
Languages : en
Pages : 382
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Book Description
Marten Hofker and Jan van Deursen have assembled a multidisciplinary collection of readily reproducible methods for working with mice, and particularlyfor generating mouse models that will enable us to better understand gene function. Described in step-by-step detail by highly experienced investigators, these proven techniques include new methods for conditional, induced knockout, and transgenic mice, as well as for working with mice in such important research areas as immunology, cancer, and atherosclerosis. Such alternative strategies as random mutagenesis and viral gene transduction for studying gene function in the mouse are also presented.
Author: Rahul Jandial
Publisher: CRC Press
ISBN: 9781587066597
Category : Medical
Languages : en
Pages : 312
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Book Description
Most cancer deaths are a result of metastasis. The spread of a primary tumor to colonize neighboring and distant organs is the relentless endgame that defines the neoplastic process. Patients who have been diagnosed with cancer are treated to prevent both the recurrence of the tumor at the site of origin and metastasis that would re-stage them as advanced stage IV cancer. Historically and still with some types of cancer, stage IV is perceived by patients as “terminal.” Fortunately, recent molecular therapies have extended the lives of patients with advanced cancer and reassuringly people living with metastatic disease increasingly visit our clinics. What is the path forward? Given that the consilience of science and medicine is a dynamic art from which therapies arise, it would be misguided to consider any single work adequate at capturing the horizon for research. So with humility we constructed this text as primer for scientists. It begins with a broad introduction to the clinical management of common cancers. This is intended to serve as a foundation for investigators to consider when developing basic science hypotheses. Unquestionably, medical and surgical care of cancer patients reveals biology and dictates how novel therapeutics will ultimately be evaluated in clinical trials. The second section of this text offers provocative and evolving insights that underscore the breadth of science involved in the elucidation of cancer metastasis biology. The text concludes with information that integrates scientific and clinical foundations to highlight translational research. This book serves as a framework for scientists to conceptualize clinical and translational knowledge on the complexity of disease that is metastatic cancer.
Author: Erwin G. Van Meir
Publisher: Springer Science & Business Media
ISBN: 1603275533
Category : Medical
Languages : en
Pages : 1294
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Book Description
Cancers of the central nervous system are among the most lethal of human neoplasms. They are recalcitrant to even intensive multimodality therapies that include surgery, radiotherapy, and chemotherapy. Moreover, especially in children, the consequences of these therapies can itself be devastating and involve serious cognitive and developmental disorders. It is small wonder that such cancers have come under the intense scrutiny of each of the subspecialties of clinical care and investigation as well as attracting some of the best basic research scientists. Their joint efforts are gradually peeling away the mysteries surrounding the genesis and progression of these tumors and inroads are being steadily made into understanding why they resist therapies. This makes it an especially opportune time to assemble some of the best investigators in the field to review the ‘‘state of the art’’ in the various arenas that comprise the assault on CNS tumors. The breadth of this effort by the clinical and basic neuro-oncology community is quite simply amazing. To a large extent, it evolves from the knowledge of the human genome and its regulation that has been hard won over the past two decades.
Author: Jorgen Fogh
Publisher: Springer Science & Business Media
ISBN: 1475716478
Category : Medical
Languages : en
Pages : 568
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Book Description
The study of cultured human tumor cells is a most obvious approach in experimental human cancer research. For many techniques in virology, immunology, biochemistry, and biophysics, for example, large amounts of cells may be required and such quantities are usually provided only when the cultures develop into established cell lines; when this happens, thorough characterization also becomes possible. The development of cell lines, therefore, is of prime importance. Recent major advances in research with animal cell systems see m to be a prologue for present and future efforts directed toward work with human tumor cells in culture. Conceivably, the most significant results in cancer research may develop from work with such cells, and so the time seemed right to define the present state of our knowledge. This is the first book dedicated exclusively to the subject: human tumor cells in vitro. Although so me of the fundamental aspects in the cultivation of human tumor ceIls, and the extent to which they represent human cancer in vivo are still unclear, I asked a number of the leading investigators in this area of research to collect and evaluate previous and present contributions, and to offer their thoughts on the questions to which answers are not yet available. Many of the chapters are concerned with techniques of cultivation. Cultures from some types of tumors have grown weIl; in many cases they have given rise to established cell lines.
