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Cancer-Leading Proteases

Cancer-Leading Proteases
Structures, Functions, and Inhibition

by Satya Prakash Gupta

  • Publisher : Academic Press
  • Release : 2020-02-03
  • Pages : 526
  • ISBN : 0128181680
  • Language : En, Es, Fr & De
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Cancer-Leading Proteases: Structures, Functions, and Inhibition presents a detailed discussion on the role of proteases as drug targets and how they have been utilized to develop anticancer drugs. Proteases possess outstanding diversity in their functions. Because of their unique properties, proteases are a major focus of attention for the pharmaceutical industry as potential drug targets or as diagnostic and prognostic biomarkers. This book covers the structure and functions of proteases and the chemical and biological rationale of drug design relating to how these proteases can be exploited to find useful chemotherapeutics to fight cancers. In addition, the book encompasses the experimental and theoretical aspects of anticancer drug design based on proteases. It is a useful resource for pharmaceutical scientists, medicinal chemists, biochemists, microbiologists, and cancer researchers working on proteases. Explains the role of proteases in the biology of cancer Discusses how proteases can be used as potential drug targets or as diagnostic and prognostic biomarkers Covers a wide range of cancers and provides detailed discussions on protease examples

Proteases and Their Inhibitors in Cancer Metastasis

Proteases and Their Inhibitors in Cancer Metastasis
A Book

by J-M. Foidart,R.J. Muschel

  • Publisher : Springer Science & Business Media
  • Release : 2002
  • Pages : 256
  • ISBN : 9781402009235
  • Language : En, Es, Fr & De
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In recent years, serine proteases and matrix metalloproteinases (MMPs) have gained considerable attention in tumor biology. For most of these proteases, their expression is a reliable indication of ongoing tissue remodeling. This book provides a comprehensive evaluation of the mechanisms of action of proteases and their inhibitors in tumor biology. The first part provides the reader with a selective overview of the molecular biology of serine proteases, MMPs and their physiological inhibitors. The most important proteases and their physiological as well as synthetic inhibitors are evaluated in the most relevant models of experimental and human cancer. The clinical aspects are also taken into account. This volume offers an update on this challenging aspect of cancer treatment, its interest bias, and possible clinical implication.

The Role of Force Generation in Metastatic Cancer Progression

The Role of Force Generation in Metastatic Cancer Progression
A Book

by Casey Marie Kraning-Rush

  • Publisher : Unknown Publisher
  • Release : 2013
  • Pages : 205
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Metastasis, or the process by which cancer cells escape a primary tumor and travel through the body to form secondary tumors, is believed to be responsible for over 90% of the 7.9 million annual cancer-related fatalities reported worldwide. To migrate from the original tumor, cancer cells must navigate an extremely dense and heterogeneous stromal environment to arrive at a blood or lymph vessel, which they can then penetrate to enter the circulatory or lymphatic system. Each of these steps requires cells to pull on its matrix using contractile, or traction, forces. However, the precise relationship of force generation to metastatic cell structure and function remains largely unknown. Herein, I demonstrate that metastatic cells exert increased contractile forces which facilitate the invasion of the extracellular microenvironment (ECM). Using traction force microscopy, I show that human metastatic breast, prostate, and lung cancer cell lines exhibit increased traction stresses compared to non-metastatic counterparts on physiologically-relevant substrates. Additionally, I find that the increased collagen density and matrix stiffness previously shown to be a hallmark of the tumor microenvironment promote increased traction forces through cell spread area-dependent and independent mechanisms. Finally, I develop a novel 3D model for one mode of metastatic migration in which secondary cancer cells follow microtracks that are formed by leading tumor cells secreting proteases and cleaving ECM fibers. iii By using physiologically relevant 3D collagen channels to study cancer cell migration, I specifically assessed the role of force in protease-independent migration, and, surprisingly, found that contractile force was dispensable for this form of protease independent migration. Instead, my results point to focal adhesion, actin filaments, and microtubules being key mediators of protease-independent migration within patterned collagen microtracks. Ultimately, these studies help to define the role that cellular force generation plays in metastatic invasion, and also yield insight into the biophysical mechanisms that tumor cells use to migrate. These insights could potentially lead to a targeted therapeutic approach to combating those mechanisms to delay or prevent metastasis and its subsequent fatal damage. iv.

Matrix Proteases in Health and Disease

Matrix Proteases in Health and Disease
A Book

by Niels Behrendt

  • Publisher : John Wiley & Sons
  • Release : 2012-07-10
  • Pages : 416
  • ISBN : 3527329919
  • Language : En, Es, Fr & De
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Presenting a comprehensive overview of the multifaceted field of proteases in the extracellular matrix environment, this reference focuses on the recently elucidated functions of complex proteolytic systems in physiological and pathological tissue remodeling. The proteases treated include both serine proteases such as plasminogen activators and TTSPs, metalloproteases such as MMPs and ADAMS and cysteine protease cathepsins. The text specifically addresses the role of extracellular proteases in cancer cell invasion, stroke and infectious diseases, describing the basic biochemistry behind these disease states, as well as therapeutic strategies based on protease inhibition. With its trans-disciplinary scope, this reference bridges the gap between fundamental research and biomedical and pharmaceutical application, making this required reading for basic and applied scientists in the molecular life sciences.

Autophagy

Autophagy
Chapter 18. Blockage of Lysosomal Degradation is Detrimental to Cancer Cell Survival: Role of Autophagy Activation

by Jessica L. Schwartz-Roberts,Robert Clarke

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-09-03
  • Pages : 440
  • ISBN : 0128069449
  • Language : En, Es, Fr & De
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Autophagy is a major catabolic process used by cells to remove superfluous or damaged proteins and organelles. In the final stages of autophagy, acidic organelles (lysosomes) act to degrade autophagic cargo and to facilitate their recycling. Little is known about how cancer cells undergoing autophagy, often as a consequence of stress, respond when lysosomal function is blocked. To elucidate this mechanism, several recent studies report that lysosomes and their hydrolytic proteases (cathepsins) play a critical role in autophagy and subsequent cancer progression. Our studies in breast cancer suggest that inhibition of cathepsins D and L using the BH3-mimetic, obatoclax, is effective in reducing the cell density of anti-estrogen sensitive and resistant breast cancer cells. Furthermore, blockage of cathepsin protein expression with obatoclax leads to the accumulation of autophagic vacuoles and impairs the ability of cells to use degraded material to restore homeostasis. While cancer cells are dependent on effective lysosomal function, neoplastic transformation induces changes in lysosomal volume, number, and protease activity. Recent reports suggest that pro-oncogenic changes render cancer cells more susceptible to lysosomal-associated death pathways. A number of distinct stimuli have been shown to permeabilize the lysosomal membrane, leading to the release of hydrolases into the cytosol and, ultimately, cell death. Thus, changes in cathepsin and lysosomal membrane permeabilization (LMP) regulation during cancer cell progression suggest that strategies targeting this cellular compartment may be exploited to improve outcomes for cancer patients.

Liquid Biopsies of Solid Tumors

Liquid Biopsies of Solid Tumors
Non-small-cell Lung and Pancreatic Cancer

by Madumali Kalubowilage

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Cancer is a group of diseases that are characterized by uncontrolled growth and spread of cells. In order to treat cancer successfully, it is important to diagnose cancers in their early stages, because survival often depends on the stage of cancer detection. For that purpose, highly sensitive and selective methods must be developed, taking advantage of suitable biomarkers. The expression levels of proteases differ from one cancer type to the other, because different cancers arise from different cell types. According to the literature, there are significant differences between the protease expression levels of cancer patients and healthy people, because solid tumors rely on proteases for survival, angiogenesis and metastasis. Development of fluorescence-based nanobiosensors for the early detection of pancreatic cancer and non-small-cell lung cancer is discussed in this thesis. The nanobiosensors are capable of detecting protease/arginase activities in serum samples over a broad range. The functionality of the nanobiosensor is based on Förster resonance energy transfer and surface energy transfer mechanisms. The nanobiosensors for protease detection feature dopamine-coated Fe/Fe3O4 nanoparticles, consensus (cleavage) peptide sequences, meso-tetra(4-carboxyphenyl)porphine (TCPP), and cyanine 5.5. The consensus peptide sequences were synthesized by solid-supported peptide synthesis. In this thesis, improved consensus sequences were used, which permit faster synthesis and higher signal intensities. TCPP, which is the fluorophore of the nanoplatform, was connected to the N-terminal end of the oligopeptides while it was still on the resin. After the addition of TCPP, the TCPP-oligopeptide was cleaved off the resin and linked to the primary amine groups of Fe/Fe3O4-bound via a stable amide bond. In the presence of a particular protease, the consensus sequences attached to the nanoparticle can be cleaved and release TCPP to the aqueous medium. Upon releasing the dye, the emission intensity increases significantly and can be detected by fluorescence spectroscopy or, similarly, by using a fluorescence plate reader. In sensing of arginase, posttranslational modification of the peptide sequence will occur, transforming arginine to ornithine. This changes the conformational dynamics of the oligopeptide tether, leading to the increase of the TCPP signal. This is a highly selective technology, which has a very low limit of detection (LOD) of 1 x 10−16 molL−1 for proteases and arginase. The potential of this nanobiosensor technology to detect early pancreatic and lung cancer was demonstrated by using serum samples, which were collected from patients who have been diagnosed with pancreatic cancer and non-small cell lung cancer at the South Eastern Nebraska Cancer Center (lung cancer) and the University of Kansas Cancer Center (pancreatic cancer). As controls, serum samples collected from healthy volunteers were analyzed. In pancreatic cancer detection, the protease/arginase signature for the detection of pancreatic adenocarcinomas in serum was identified. It comprises arginase, MMPs -1, - 3, and -9, cathepsins -B and -E, urokinase plasminogen activator, and neutrophil elastase. For lung cancer detection, the specificity and sensitivity of the nanobiosensors permit the accurate measurements of the activities of nine signature proteases in serum samples. Cathepsin -L and MMPs-1, -3, and -7 permit detecting non-small-cell lung-cancer at stage 1.

Development of Phosphoramidate Inhibitors for Cell Surface Proteases in Metastatic Cancers

Development of Phosphoramidate Inhibitors for Cell Surface Proteases in Metastatic Cancers
A Book

by Desiree Ellene Mendes

  • Publisher : Unknown Publisher
  • Release : 2016
  • Pages : 142
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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The development of highly tuned diagnostic agents are critical for the early detection of cancer and are commonly designed to bind cell surface receptors. A small library of first-generation phosphoramidate inhibitors leading to sub-micromolar potency as determined by a FRET-based spectrophotometric assay were generated as peptide mimics with a scaffold designed to interact with the S1, S1` register of the catalytic domain of the cell surface receptor matrix metalloproteinase (MMP-14). Candidate residues were selected for the scaffold using in silico modeling, and synthesized using organophosphate and peptide coupling methodologies. A phosphoramidate inhibitor and fluorescent conjugate were shown to specifically target prostate specific membrane antigen (PSMA) in human cancer cell lines was applied to a canine model of which the expression and enzymatic activity of PSMA were previously unknown. The expression of PSMA was determined by RT-PCR and western blot and found to be in lower abundance when compared to human prostate cancer PSMA expression. The kinetics of PSMA were established and inhibitory potency was determined by an end-point HPLC analysis, and was similar to that of human PSMA enzymatic activity. In addition, a fluorescent-conjugate was successfully used to label canine cancer cells in blood as detected using flow cytometry. Previous studies revealed that both PSMA and androgen receptor (AR) decreased following an extended period of androgen deprivation. When the biomarker expression of c-Met and calpain 2 are upregulated, it indicated a switch to a more aggressive prostate cancer phenotype. The expression of these biomarkers in prostate cancer cell lines subjected to prolonged androgen deprivation in an established in vitro model were investigated. After 10 passages of prolonged androgen deprivation, both c-Met and calpain 2 were found to be upregulated with the concomitant decrease in expression of PSMA and AR. In addition to switching signaling pathways, prostate cancer cells secrete exosomes as long-range cell-to-cell communication vehicles. The exosomes were found to be highly enriched with functionally active PSMA. Insights into inhibitor binding, signaling pathway alterations, and biomarker expression in extracellular vesicles could enable new trajectories for treatment and further the advancement toward powerful development of personalized cancer therapy.

Proteases in Human Diseases

Proteases in Human Diseases
A Book

by Sajal Chakraborti,Tapati Chakraborti,Naranjan S. Dhalla

  • Publisher : Springer
  • Release : 2017-07-13
  • Pages : 513
  • ISBN : 9811031622
  • Language : En, Es, Fr & De
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This book bridges the gap between fundamental research and biomedical and pharmacological applications on proteases. It represents a comprehensive overview of the multifaceted field of proteases in cellular environment and highlights the recently elucidated functions of complex proteolytic systems in different diseases. Several established investigators have elucidated the crucial role of proteases in biological processes, including how proteolytic function and regulation can be combined to develop new strategies of therapeutic interventions. Proteases form one of the largest and most diverse families of enzymes known. It is now clear that proteases are involved in every aspect of life functions of an organism. Under physiological conditions, proteases are regulated by their endogenous inhibitors; however, when the activity of proteases is not regulated appropriately, disease processes can result in. So, there is absolute need for a stringent control of proteolytic activities in cells and tissues. Dysregulation of proteases may cause derangement of cellular signalling network resulting in different pathophysiological conditions such as vascular remodelling, atherosclerotic plaque progression, ulcer and rheumatoid arthritis, Alzheimer disease, cancer metastasis, tumor progression and inflammation. Additionally, many infective microorganisms require proteases for replication or use proteases as virulence factors, which have facilitated the development of protease-targeted therapies for a variety of parasitic diseases.

National Railways of Mexico, the Most Important Railway System in Mexico, Extending from the United States to the Guatemalan Frontier

National Railways of Mexico, the Most Important Railway System in Mexico, Extending from the United States to the Guatemalan Frontier
Okt./Nov. 1931

by Anonim

  • Publisher : Unknown Publisher
  • Release : 1931
  • Pages : 8
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Heparanase

Heparanase
From Basic Research to Clinical Applications

by Israel Vlodavsky,Ralph D. Sanderson,Neta Ilan

  • Publisher : Springer Nature
  • Release : 2020-04-09
  • Pages : 885
  • ISBN : 3030345211
  • Language : En, Es, Fr & De
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Written by internationally recognized leaders in Heparanase biology, the book’s eight chapters offer an opportunity for scientists, clinicians and advanced students in cell biology, tumor biology and oncology to obtain a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications. Proteases and their involvement in cancer progression have been well addressed and documented; however, the emerging premise presented within this book is that Heparanase is a master regulator of aggressive cancer phenotypes and crosstalk with the tumor microenvironment. This endoglycosidase contributes to tumor-mediated remodeling of the extracellular matrix and cell surfaces, augmenting the bioavailability of pro-tumorigenic and pro-inflammatory growth factors and cytokines that are bound to Heparan sulfate. Compelling evidence ties Heparanase with all steps of tumor progression including tumor initiation, growth, angiogenesis, metastasis, and chemoresistance, supporting the notion that Heparanase is an important contributor to the poor outcome of cancer patients and a validated target for therapy. Unlike Heparanase, heparanase-2, a close homolog of Heparanase, lacks enzymatic activity, inhibits Heparanase, and regulates selected genes that promote normal differentiation and tumor suppression. Written by internationally recognized leaders in Heparanase biology, this volume presents a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications to scientists, clinicians and advanced students in cell biology, tumor biology and oncology.

STAT3- and STAT6-dependent Cytokine Interactions Educate Tumor-associated Macrophages Via Induction of Cathepsin Proteases

STAT3- and STAT6-dependent Cytokine Interactions Educate Tumor-associated Macrophages Via Induction of Cathepsin Proteases
A Book

by Hao-Wei Wang,Cornell University. Weill Cornell Graduate School of Medical Sciences

  • Publisher : Unknown Publisher
  • Release : 2013
  • Pages : 318
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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While macrophages are a fundamental element of the host innate immune system which constitutes the first line of defense against invading pathogens, tumor-associated macrophages (TAMs) have been shown to be co-opted by tumor cells and facilitate tumor initiation and progression. However, little is known about how TAMs acquire their tumor-promoting functions. One of the key pro-tumorigenic activities of TAMs is to provide proteases to the tumor microenvironment, including cysteine cathepsin proteases. We hypothesized that TAMs are educated by the cellular interactions within the tumor microenvironment, leading to the induction of their high cathepsin activity. The objective of my thesis research is to gain mechanistic insights into how complex cell-Cell interactions shape this phenotype of TAMs, and to investigate the significance of the intercellular communications in tumorigenesis. Consistent with our hypothesis, we found that interleukin-4 which is supplied by tumor cells and T cells, can induce cathepsin activity in TAMs. In addition, we also discovered the interaction between STAT3- and STAT6-dependent cytokine signaling pathways that leads to a synergistic induction of cathepsin secretion in macrophages. In order to elucidate the roles of these cellular interactions in tumorigenesis, we took a genetic approach to dissect the contributions of STAT3- and STAT6-mediated cytokine signaling pathways in different cell types to tumor development and progression in the RIP1 -Tag2 (RT2) model of pancreatic islet carcinogenesis. Our results revealed significant contributions to tumorigenesis from non-tumor cell-autonomous effects of both pathways. Together, our studies illustrate how the complex reciprocal intercellular interactions in the tumor microenvironment can significantly impact tumorigenesis, and also indicate the potential of these tumor-stromal cytokine signaling pathways as targets for cancer therapy.

The Role of Twist1-Mediated Induction of FAP-alpha in Invadopodia and Breast Cancer Metastasis

The Role of Twist1-Mediated Induction of FAP-alpha in Invadopodia and Breast Cancer Metastasis
A Book

by Navneeta Pathak

  • Publisher : Unknown Publisher
  • Release : 2014
  • Pages : 122
  • ISBN : 9781303990373
  • Language : En, Es, Fr & De
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Breast cancer metastasis, the dissemination of primary tumor cells to distant organs, is the leading cause of death among breast cancer patients. During metastasis, tumor cells must invade through the basement membrane and local tissues, intravasate into the circulatory system, travel to a distant organ, extravasate into the new tissue, and establish micrometastases, which eventually become secondary tumors. The basic helix-loop-helix transcription factor Twist1 is expressed in a variety of aggressive cancers, and is essential for metastasis to take place. Twist1 activates a developmental program known as the Epithelial-Mesenchymal Transition (EMT), during which tumor cells lose their cell-cell junctions and become more migratory and invasive. Twist1 endows tumor cells with an increased invasive capacity by inducing formation of subcellular structures known as invadopodia. Located on the ventral surface of invasive cells, invadopodia are actin-rich protrusions of the cell membrane that recruit proteases to points of cell-matrix contact, and thus degrade the surrounding extracellular matrix (ECM). It was found that Twist1-mediated formation of invadopodia is required for metastasis to take place, but the precise role that Twist1 plays in invadopodia assembly was not completely understood. This dissertation presents data demonstrating that Twist1 is involved in regulation of a serine protease known as Fibroblast Activation Protein alpha (FAP[alpha]). FAP[alpha] is located at invadopodia, and while not required for EMT or cellular migration, is essential for metastasis to take place. Further investigation found that FAP[alpha] expression is required for ECM degradation, but its protease activity is not. Although ECM degradation is impaired when FAP[alpha] expression is suppressed, early stages of invadopodia formation still take place, suggesting that FAP[alpha] may be involved in the later steps of invadopodia assembly, when proteases are recruited. Indeed, results show that the matrix metalloprotease MT1-MMP is mislocalized in the absence of FAP[alpha] expression, providing additional evidence that the role of FAP[alpha] at invadopodia is more structural than proteolytic. Further studies must be undertaken to examine how FAP[alpha] is trafficked to invadopodia, and which domain of the protein is important for its function.

Proteases in Health and Disease

Proteases in Health and Disease
A Book

by Enrico Di Cera

  • Publisher : Academic Press
  • Release : 2011-03-07
  • Pages : 328
  • ISBN : 0123855055
  • Language : En, Es, Fr & De
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Proteases occur naturally in all organisms. They are enzymes that are involved in many physiological reactions such as digestion of food and blood clotting. This volume reviews their role in health and disease and presents the latest research and developments. * Discusses new discoveries, approaches, and ideas * Contributions from leading scholars and industry experts * Reference guide for researchers involved in molecular biology and related fields

Bioengineered Technological Platforms for Quantitative Understanding of Cancer

Bioengineered Technological Platforms for Quantitative Understanding of Cancer
A Book

by Aereas Aung

  • Publisher : Unknown Publisher
  • Release : 2016
  • Pages : 200
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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In the United States, cancer is the second leading cause of death only to be surpassed by heart diseases (1). Within 2016, an estimated 1.6 million new cases of cancer will be diagnosed and approximately 0.6 million individuals will die from this disease (1). The survival rate of individuals afflicted with cancer have increased over the years due to early detection and increased fundamental understanding of this disease. However, the complex nature of cancer exceeds the current capacity to recapitulate its features in vitro. Additionally, the animal models that have been relied upon within the field of oncology may not be translatable to the human counterpart (2-5). In this dissertation, I have created novel in vitro technological platforms focusing on specific aspects of cancer progression to identify the underlying biological phenomena and recapitulate the physiological cancer microenvironment to provide better alternatives for cancer drug screening. Chapter 1 is a literature review focusing on cancer cell migration during metastasis and in vitro platforms used to model the cancer microenvironment. Specifically, I have focused on the role of the extracellular matrix (ECM) network on modulating the protease dependent or independent mode of migration during cancer metastasis. In vitro systems used to study cancer cell metastasis within 3D matrices are also briefly reviewed. Next, I have described the use of organ-on-a-chip technology as the next generation platforms towards creating low cost, efficient, and realistic tumor models for screening of oncologic drugs. Lastly, I have summarized the emergence of a potent cancer treatment, immunotherapy, and its mechanism through the immune cells within the tumor environment are activated to eliminate cancer. Furthermore, I have discussed the crucial role of cytotoxic T-cells in immunotherapies and the means by which they are recruited to the tumor stroma. Studies have implicated the physical cues of the cancer microenvironment in modulating the particular mode of migration. In Chapter 2, I have investigated how these various cues activate an intracellular "trigger" to dictate a cell's mode of invasion. I have developed a novel single cell invasion assay to quantitatively investigate the interplay between cell generated traction forces and protease activity during cancer cell invasion into basement membrane-like extracellular matrix (ECM) network. Within these studies, I observed the translocation of a crucial membrane bound protease, MT1-MMP, from the cytoplasm to the cell surface to degrade the surrounding ECM network. Chapter 3 further investigates the transport pathway through which this translocation occurs. The results from this study implicate a regulated secretory pathway known as CARTS that is necessary for MT1-MMP transport and the protease dependent invasion of cancer cells into an ECM network. In addition to understanding cancer cell metastasis, I next shifted my research focus towards recreating the cancer microenvironment to test the efficacy of cancer drugs. Chapter 4 describes the development a state-of-the-art 3D tumor-on-a-chip platform containing cancer and endothelial cells to assess the penetration and efficacy of cancer drugs. Here, I have used a morphogen gradient to induce the self-assembly of an endothelial and cancer cell mixture resulting in a tumor mass enveloped by a vascular barrier. The drug screening capacity of this system was assessed using doxorubicin as a model drug. Current immunotherapies rely on the presence of cytotoxic T-cells within the tumor microenvironment to eliminate cancer cells. In Chapter 5, I have adapted the tumor-on-a-chip device to incorporate immune cells to recapitulate cancer-immune interactions and investigate its effect of recruitment of T-cells into the engineered microenvironment. In the last chapter, I have discussed the future directions in which these platforms can be directed towards to better understand cancer-immune interactions and improve future immunotherapies.

The Role of Fibroblast Activation Protein in Invadopodia and Tumor Metastasis

The Role of Fibroblast Activation Protein in Invadopodia and Tumor Metastasis
A Book

by Dong Mei Li

  • Publisher : Unknown Publisher
  • Release : 2014
  • Pages : 59
  • ISBN : 9781321536560
  • Language : En, Es, Fr & De
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Tumor metastasis, the leading cause of death among cancer patients, is a complex multi-step process during which tumor cells disseminate from their primary site to distant organs. The transcription factor Twist1 is overexpressed in many aggressive human cancers and is a potent inducer of tumor metastasis. Mechanistically, Twist1 activates a developmental program known as the Epithelial-Mesenchymal Transition (EMT), during which carcinoma cells lose cell-cell junctions and become more migratory and invasive. Twist1 can also induce the formation of invadopodia, actin-rich membrane protrusions that recruit various proteases to degrade the extracellular matrix (ECM). Various studies show that invadopodia are crucial for tumor invasion during metastasis. We have identified the membrane-associated serine protease Fibroblast Activation Protein (FAP) to be a critical gene induced upon Twist1 activation to promote invadopodia function. However, the precise role of FAP at invadopodia and its function in tumor metastasis is not well understood. This study presents data demonstrating that FAP is essential for invadopodia-mediated ECM degradation and breast tumor metastasis in vivo. Mechanistically, I found that FAP is required for the proper localization of matrix metalloproteinase MT1-MMP to invadopodia in order to generate mature and functional invadopodia for EMT degradation. Together, these results indicate that FAP is a critical regulator of invadopodia function and tumor metastasis. Given the unique expression of FAP in human cancers, FAP could be a promising target for anti-metastasis therapeutics.

The Role of Proprotein Convertases in Cancer

The Role of Proprotein Convertases in Cancer
A Book

by Xiaowei Sun

  • Publisher : Unknown Publisher
  • Release : 2013
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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"Cancer is a leading cause of death worldwide and accounts for about one fifth of all death in the Western world. In 2008, nearly 12.7 million new cancer cases and 7.6 million cancer deaths occurred worldwide. The development of cancer is a multistage process, during which cells acquire a series of mutations that eventually lead to unrestrained cell growth, evasion of cell death, angiogenesis, invasion of the surrounding tissue and finally spreading to other parts of the body. The mammalian proprotein convertases (PCs) constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. They have been associated with cancer since the early 1990s. By processing cancer-associated factors, PCs are believed to play key roles in almost every step of cancer development. Seven of these PCs (PC1, PC2, furin, PC4, PC5/6, PACE4 and PC7) activate, or less frequently inactivate, a wide variety of substrates, including hormones, growth factors, receptors, adhesion molecules, angiogenic factors, metalloproteases. Among these substrates, some of them are key factors controlling cancer progression and metastasis. The last member of this family proprotein convertase subtilisin kexin 9 (PCSK9) only cleaves itself and participates in maintaining the levels of cholesterol, which was shown to have impacts on cancer incidence.In this thesis, I focused on the role of two PCs, PC5/6 and PCSK9, in cancer development. I first showed that PC5/6 is systematically down-regulated in human and mice intestinal tumors. In ApcMin/+ mice which are a colonic cancer model and develop numerous adenocarcinomas along the intestinal tract, the specific knockout of PC5/6 in the intestine and colon leads to higher number of tumors, particularly in duodenum. This suggests that PC5/6 plays a protective role against tumorigenesis in the intestine. Although PC5/6 is protective in intestinal cancer, it has been shown to promote tumor progression in other cancer types e.g., brain and skin. Interestingly, PC5/6 is inhibited by some natural inhibitors, the latent TGFbeta binding proteins 2 and 3 (LTBP-2, -3). These two proteins reduce the enzymatic activity of PC5/6A and reduce the bio-availability of PC5/6A by sequestering the zymogen proPC5/6 in the extracellular matrix. Finally, I demonstrated that the lack of PCSK9 leads to a significantly lower level of liver metastasis of melanoma cells. This cancer protective effect is due to low plasma cholesterol levels as well as high apoptosis in liver stroma and metastasized tumors that are associated with PCSK9 deficiency.In summary, the present cumulative data define some of the in vivo roles of PC5/6 and PCSK9 in cancer and should enhance our appreciation of the physiological impact of PC inhibition." --

The Role of Resveratrol and Its Analogs in Inflammation, Preadipocyte Differentiation & Neuroblastoma Differentiation

The Role of Resveratrol and Its Analogs in Inflammation, Preadipocyte Differentiation & Neuroblastoma Differentiation
A Book

by Priti S. Tiwari

  • Publisher : Unknown Publisher
  • Release : 2014
  • Pages : 149
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Development of Novel Strategies for Detection and Treatment of Cancer

Development of Novel Strategies for Detection and Treatment of Cancer
A Book

by Thilani Nishanthika Samarakoon

  • Publisher : Unknown Publisher
  • Release : 2010
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Cancer is one of the leading causes of death in the world. Billions of dollars are spent to treat cancer every year. This clearly shows the need for developing improved treatment techniques that are affordable to every person. Early diagnosis and imaging of tumors is equally important for the battle against this disease. This dissertation will discuss new approaches for discovering and developing novel detection and treatment techniques for cancer using organic ligands, and Fe/Fe3O4 core/shell magnetic nanoparticles. A series of o-phenylenediamine derivatives with nitro-, methyl- and chloro- substituents were synthesized and studied their ability to act as anticancer agents by using steady-state, UV/Vis-, and fluorescence spectroscopy. In the absence of zinc(II), intercalation with DNA is the most probable mode of interaction. Upon addition of zinc(II), DNA-surface binding of the supramolecular aggregates was observed. The interaction of the supramolecular ( -ligand-Zn2- )n aggregates with MDA 231 breast cancer cells led to significant cell death in the presence of UVA at [lambda]=313 nm displaying their potential as anticancer agents. Bimagnetic Fe/Fe3O4 core/shell nanoparticles (MNPs) were designed for cancer targeting after intratumoral or intravenous administration. Their inorganic center was protected by dopamine-oligoethylene glycol ligands. TCPP (4-tetracarboxyphenyl porphyrin), a fluorescent dye, was attached to the dopamine-oligoethylene glycol ligands. These modified nanoparticles have the ability to selectively accumulate within the cancerous cells. They are suitable candidates for local hyperthermia treatment. We have observed a temperature increase of 11°C in live mice when subcutaneously injecting the MNPs at the cancer site and applying an alternating magnetic field The system is also suitable for Magnetic Resonance Imaging (MRI), which is a diagnostic tool to obtain images of the tumors. Our superparamagnetic iron oxide nanoparticles have the ability to function as T1 weighted imaging agents or positive contrasting agents. We were able to image tumors in mice using MRI. Various proteases are over-expressed by numerous cancer cell lines and, therefore, of diagnostic value. Our diagnostic nanoplatforms, designed for the measurement of protease activities in various body fluids (blood, saliva, and urine), comprise Fe/Fe3O4 core/shell nanoparticles featuring consensus sequences, which are specific for the target protease. Linked to the consensus sequence is a fluorescent organic dye (e.g. TCPP). Cleavage of the sequence by the target protease can be detected as a significant increase in fluorescence occurring from TCPP. We were able to correlate our diagnostic results with cancer prognosis.

Proteases as Targets for Therapy

Proteases as Targets for Therapy
A Book

by M. Abdel-Meguid,Klaus von der Helm,Bruce D. Korant,John Chris Dion Cheronis

  • Publisher : Springer Science & Business Media
  • Release : 2000
  • Pages : 410
  • ISBN : 9783540661184
  • Language : En, Es, Fr & De
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This volume is the first to combine latest information on viral, microbial and cellular proteolytic enzymes as potential targets for human therapeutics. Proteases control a large array of physiological reactions, and are involved in a variety of pathological processes for which effective medications are currently needed and/or being sought after. Although protease inhibitors have been investigated for many years, few have been employed therapeutically. Recent break- through by HIV protease inhibitors as therapeutic drugs has re-encouraged the search for inhibitors of other proteolytic enzymes. Klaus von der Helm, who described the first viral protease has brought leading experts together to discuss not only the success and problems of clinical use and continuing prospects, but to review further potential drug targets. This volume provides detailed information and evaluations of key viral, bacterial, fungal, and cellular proteases as potential future drug candidates.

Signaling by ErbB Receptors in Breast Cancer: Regulation by Compartmentization of Heterodimeric Receptor Complexes

Signaling by ErbB Receptors in Breast Cancer: Regulation by Compartmentization of Heterodimeric Receptor Complexes
A Book

by Anonim

  • Publisher : Unknown Publisher
  • Release : 2000
  • Pages : 17
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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MEK kinase 1 (MEKKl) is a serine threonine kinase that induces apoptosis. Activation of specific apoptotic pathways leads to cleavage of MEKKl by caspase 3-like proteases into a 9lkDa fragment containing the kinase domain. Upon cleavage, MEKKl activates the caspase 3-like proteases in a feedback loop leading to apoptosis. MEKKl is also cleaved into the 9lkDa kinase domain in response to genotoxic agents such as etoposide or ultraviolet irradiation (Uv). Thus, overexpression of kinase inactive MEKKl inhibits both etoposide and UV-induced apoptosis. Akt is an anti-apoptotic serine threonine kinase that inhibits both etoposide and Uv- induced apoptosis. We show that Akt blocks MEKKl-induced apoptosis in HEK 293 cells. MEKKl-induced caspase 3-like protease activation is inhibited with expression of Akt. This inhibition by Akt prevents cleavage of endogenous MEKKI following exposure to etoposide and uV. Also, in an early signaling event, we show that MEKKl leads to activation of death receptor 4 (DR4) and death receptor 5 (DR5). Expression of either the decoy receptor 1 (DcRl) or FADD dominant negative protein (FADD DN) inhibits MEKKl-induced apoptosis. Akt, however, failed to block etoposide induced upregulation of DR4 and DRS expression and activation of caspase 8. In addition, Akt does not block MEKKl-induced JNK activation. Thus, we delineate that Akt inhibits MEKKl-induced apoptosis specifically through blocking caspase 3-like protease activation and amplification, resulting in inhibition of cleavage of MEKKl to its 91 kDa fragment.