Tumor Microenvironment Regulation of Tumor Expansion

Tumor Microenvironment Regulation of Tumor Expansion
Author: Domenico Ribatti
Publsiher: Academic Press
Total Pages: 172
Release: 2021-04-04
ISBN: 0128228040
Category: Science
Language: EN, FR, DE, ES & NL

Tumor Microenvironment Regulation of Tumor Expansion Book Excerpt:

Tumor Microenvironment Regulation of Tumor Expansion is a practical guide to understand and perform research on tumor microenvironments, and to support related clinical decisions. Tumor progression is linked to an imbalance between positive and negative regulators, and mainly depends on the release of specific growth factors by inflammatory or neoplastic cells. Inflammatory infiltrate contributes to tumor progression and the metastatic process, and there are many reports of associations between tumor inflammatory infiltrate, progression, and prognosis. Understanding different contexts of organs is a key factor in improving treatment outcome, especially in new therapeutic treatments targeting components of the tumor microenvironment. This book is a valuable resource for cancer researchers, clinicians, graduate students, and scientists in many biomedical fields who are interested in the complex relationship between the tumor microenvironment and its context in specific organs. Provides a holistic approach to understanding the crucial role of the tumor microenvironment in tumor progression Encompasses the basic knowledge necessary to understand and undertake further studies related to tumor microenvironments Discusses new therapeutic approaches developed to control tumor progression by targeting different components of the tumor microenvironment

Effect of Cyclosporin A on the Tumor Microenvironment

Effect of Cyclosporin A on the Tumor Microenvironment
Author: Yao Zhou
Publsiher: Unknown
Total Pages: 298
Release: 2014
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Effect of Cyclosporin A on the Tumor Microenvironment Book Excerpt:

Tumor angiogenesis is a hallmark of cancer, and plays a critical role in tumor growth, expansion, and metastasis. Both physiological and pathological angiogenesis is assumed to be regulated by the balance between pro and anti-angiogenic factors. One of the best characterized and most potent pro-angiogenic regulators is vascular endothelial growth factor, or VEGF. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by increased expression of its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis. However, a potent pharmacological calcineurin inhibitor, the commonly used immunosuppressant cyclosporin A (CsA), significantly increases the incidence of cancer in organ transplant recipients. The mechanism by which CsA promotes cancer in this patient population is not well understood and despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, we show that long-term CsA treatment promotes tumor growth and angiogenesis. Further our data indicate that treatment of endothelial cells in vitro with CsA increases proliferation and migration, in a calcineurin-independent manner. Our studies reveal that CsA-induced endothelial cell activation was due to the interaction of CsA with cyclophilin D located on the mitochondrial inner membrane. CsA treatment in endothelial cells increased mitochondrial membrane potential and mitochondrial reactive oxygen species production, and was associated with sustained mitogen-activated protein kinase (MAPK) activity. Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings show that CsA functions independent of calcineurin to potentiate tumor growth by promoting tumor angiogenesis via mitochondrial reactive oxygen species production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants may inhibit the tumor promoting effects of CsA.

Immune Suppression and Inflammation in the Progression of Breast Cancer

Immune Suppression and Inflammation in the Progression of Breast Cancer
Author: Anonim
Publsiher: Unknown
Total Pages: 130
Release: 2008
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Immune Suppression and Inflammation in the Progression of Breast Cancer Book Excerpt:

Epidemiological and experimental evidence supports the concept that chronic inflammation promotes and enhances cancerous growth through several key mechanisms, although these processes are not well understood. Several important mechanisms by which inflammation may initiate and support malignant progression have been previously described, such as the induction of DNA damage, the promotion of angiogenesis and new vasculature, and the production of growth and survival factors. The purpose of this study is to identify a novel mechanism by which chronic inflammation may support and advance tumor progression, through the induction and expansion of immune suppressive mechanisms. We demonstrate that chronic inflammation induces tumor-associated immune-suppression, by enhancing the accumulation of a population of immature myeloid-derived suppressor cells (MDSC), which down regulate and inhibit anti-tumor immunity, allowing for the proliferation and outgrowth of transformed cells. To study the association between inflammation and immune suppression in the context of tumor progression, the 4T1 mammary carcinoma cell line engineered to secrete the pro-inflammatory cytokine interleukin 1 beta (4T1/IL-1beta) was used to create an inflammatory tumor microenvironment. Additionally, IL-1 receptor (IL-1R)-deficient mice, which have a reduced potential for inflammation, and IL-1 receptor antagonist (IL-1Ralpha)-deficient mice, which have an increased potential for inflammation, were used to modulate the inflammatory milieu, and the effects of inflammation on primary and metastatic tumor progression and immune suppression were examined. The presence of IL-1beta in the tumor microenvironment promotes the induction and expansion of a more potent suppressive population of MDSC, thereby enhancing tumor growth and reducing survival.

Role of ZEB1 in Macrophages During Homeostasis Inflammation and Cancer

Role of ZEB1 in Macrophages During Homeostasis  Inflammation and Cancer
Author: Marlies Cortés Hinojosa
Publsiher: Unknown
Total Pages: 156
Release: 2018
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Role of ZEB1 in Macrophages During Homeostasis Inflammation and Cancer Book Excerpt:

ZEB1 is a transcription factor whose expression in cancer cells promotes tumor initiation and progression. In this study, we for the first time characterized Zeb1 and study its function in macrophages under either homeostasis or activation conditions as well as in a murine cancer model. We found that macrophages deficient for Zeb1 showed aberrant characteristics in phenotype and functions, under physiological and pathological conditions. Here we clarified a functional role of Zeb1 on macrophages playing a role in macrophage phagocytosis, migration and inflammation as well as in tumor progression in a non-cell-autonomous manner modulating the tumor microenviroment. In fact the evidence presented indicates that the downregulation of Zeb1 in macrophages is associated with the inhibition of TAM characteristics and inhibition of tumor progression. ZEB1 plays important roles during embryogenesis and deletion of both alleles of Zeb1 in mice results in embryonic lethality. ZEB1 represses key genes involved in the terminal differentiation of multiple tissues, including inter alia epithelial cells, pituitary gland, skeletal and smooth muscle, cartilage, and bone. Although ZEB1 is expressed in lymphoid cells where it represses pivotal hematopoietic transcription factors, there was no evidence for a role of ZEB1 in the regulation of lymphoid or myeloid differentiation. We showed here that downregulation of Zeb1 in bone marrow precursors promoted their differentiation towards macrophages. These data further support a model, best characterized in epithelial tissues and skeletal muscle, where ZEB1 expression needs to decline for early precursors to terminally differentiate. ZEB1 has been extensively characterized in cancer cells where it promotes their stemness, survival and invasiveness. However, its role in the tumor microenvironment remained to be elucidated. Among cancer cells, ZEB1 is not expressed across the entire tumor mass but is rather restricted to a subpopulation of stem-like malignant cells at the invasive front, actually, at the interface where cancer cells and TAMs interact. Although ZEB1 expression among stromal cells has been noted, the identity of the cell types expressing ZEB1 has not been established. This study showed that ZEB1 is also expressed in TAMs and that ZEB1 not only bilaterally regulates the crosstalk between cancer cells and TAMs but that this crosstalk regulates ZEB1 expression itself. Thus, Zeb1 was upregulated in macrophages that have interacted with cancer cells as well as in cancer cells that have interacted with wild-type TAMs. The tumor-promoting role of ZEB1 is therefore supported by a positive feedback of its expression between malignant cells and TAMs. We found that Zeb1 is restricted to the F4/80low macrophage/TAM subpopulation—previously known to display stronger pro-tumor and pro-angiogenic functions—whose share is expanded by ZEB1. Soluble factors produced by the tumor—e.g., CSF1 and CCL2—attract F4/80low CCR2+ monocytes into their microenvironment where they are activated into TAMs. Inhibition of the CCL2–CCR2 axis blocks monocyte recruitment into the tumor stroma and inhibits tumor growth. We found that Zeb1 promotes monocyte migration both in response to chemotactic stimuli (CSF1 and CCL2) and in the context of cancer. Zeb1-deficient TAMs expressed lower levels of Ccr2 and were unable to induce Ccl2 in ID8 cells. At the same time, the maximum effect of ZEB1 as a biomarker of poorer prognosis in ovarian cancer patients depended on high levels of CCL2. These data establish Zeb1 as an important inducer of the pro-tumor and pro-metastatic CCR2-07P9-CCL2 loop between tumor cells and TAMs. It is important to note that this CCR2-07P9-CCL2 loop was inhibited by just a partial downregulation of Zeb1 in TAMs. Data here showed that the pro-tumor role of ZEB1 in TAMs also depends on a similarly narrow threshold of expression. Zeb1 (+/-) macrophages still express about half of the Zeb1 mRNA levels of wild-type macrophages, but this downregulation was enough to render Zeb1 (+/-) TAMs unable to promote tumor growth when transplanted into tumor-bearing mice as wild-type macrophages did. As in the case of ZEB1 expression in cancer cells, to the best of our knowledge, this is the first example of a heterozygous gene deletion being sufficient to block the tumor-promoting role of TAMs. Expression of ZEB1 in cancer cells has been associated to increased chemotherapy resistance. In parallel, we found here that expression of ZEB1 in TAMs also increased the cancer cell resistance to chemotherapy. In that line, we showed that Zeb1 in TAMs increased the expression of Il10, Mmp9 and Il1b—that have a suppressor effect on chemotherapy—and of the drug efflux transporter Mdr1. The dual role of ZEB1 promoting tumor progression in cancer cells and in TAMs—albeit through different mechanisms—has translational implications. Targeting ZEB1 in cancer cells is being considered in ongoing clinical trials but data here suggest that improving chemotherapy response would also require the downregulation of ZEB1 in TAMs. The fact that a partial downregulation of Zeb1 in TAMs was sufficient to abolish TAMs' tumor-promoting function is highly relevant for therapy approaches aiming at blocking ZEB1 expression and/or function. These results establish a new role for ZEB1 promoting tumor progression through its expression in TAMs, thus setting ZEB1 expression as a relevant target in cancer therapy.

Tumor Microenvironment

Tumor Microenvironment
Author: Alexander Birbrair
Publsiher: Springer Nature
Total Pages: 146
Release: 2020-02-08
ISBN: 3030357236
Category: Science
Language: EN, FR, DE, ES & NL

Tumor Microenvironment Book Excerpt:

Revealing essential roles of the tumor microenvironment in cancer progression, this book focuses on the role of hematopoietic components of the tumor microenvironment. Further, it teaches readers about the roles of distinct constituents of the tumor microenvironment and how they affect cancer development. Topics include neutrophils, basophils, T helper cells, cytotoxic lymphocytes, fibrocytes, and myeloid-derived suppressor cells, and more. Taken alongside its companion volumes, these books update us on what we know about various aspects of the tumor microenvironment as well as future directions. Tumor Microenvironment: Hematopoietic Cells – Part A is essential reading for advanced cell biology and cancer biology students as well as researchers seeking an update on research in the tumor microenvironment.

Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer and Related Diseases

Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer  and Related Diseases
Author: Youcef M. Rustum
Publsiher: MDPI
Total Pages: 166
Release: 2019-03-26
ISBN: 303897692X
Category: Science
Language: EN, FR, DE, ES & NL

Pleiotropic Action of Selenium in the Prevention and Treatment of Cancer and Related Diseases Book Excerpt:

Gene cloning and sequence has provided the opportunity to identify and characterize the functional role of biomarkers expressed in and on tumor cells and the surrounding microenvironment. Molecular and immunologic heterogeneity of cells in the tumor microenvironment contributes to instability, enhanced angiogenesis, and drug resistance of the tumor cell. Since tumor cells are the ultimate therapeutic targets for drugs and therapy development, the tumor microenvironment that regulates the growth and the delivery of effective drug concentrations to tumor cells is the gatekeeper. Thus, to have a significant impact on the overall survival and cure of patients with advanced cancer, the stabilization of the tumor microenvironment should be the initial treatment, followed by treatment that targets and kills tumor cells. Antiangeogenic therapies hold considerable promise in the treatment of a subset of cancer patients and are reported to have a significant impact on the stabilization of the tumor microenvironment. More recently, selenium-containing molecules, such as se-metylselenocysteine, seleno-L-methionine, and selenized yeast, among others, have been shown to target and modulate biomarkers associated with tumor cells and the tumor microenvironment. The effects are selenium type-, dose-, and schedule-dependent. The pleiotropic actions of selenium are necessary for tumor cell sensitization, and synergy with mechanism-based combinations. This Special Issue is devoted to highlighting evidence for the potential role of specific types, doses, and schedules of selenium alone and in combination with mechanism-based biologic and cytotoxic therapies for the prevention and treatment of cancer and related diseases. The collection of contributions should provide a comprehensive overview of the pharmacology, metabolism, and delineation of the pleiotropic action of different types of selenium molecules, relevant to the use of selenium as a potential modulator of the therapeutic efficacy and toxicity of biologic and cytotoxic therapies for cancer and related diseases. The pleiotropic action of specific types of selenium, doses, and schedule, as a selective and efficacious modulator of genetic, immunologic, and epigenetic biomarkers, should stimulate expanded preclinical research that could ultimately impact the development of new and novel approaches for the treatment of cancer.

Targeting the Tumor Microenvironment for a More Effective and Efficient Cancer Immunotherapy

Targeting the Tumor Microenvironment for a More Effective and Efficient Cancer Immunotherapy
Author: Salem Chouaib,James Lorens
Publsiher: Frontiers Media SA
Total Pages: 135
Release: 2020-07-02
ISBN: 2889638170
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Targeting the Tumor Microenvironment for a More Effective and Efficient Cancer Immunotherapy Book Excerpt:

Expansion of Highly Cytotoxic Human Natural Killer Cells by Osteoclast for Cancer Immunotherapy

Expansion of Highly Cytotoxic Human Natural Killer Cells by Osteoclast for Cancer Immunotherapy
Author: So-Hyun Park
Publsiher: Unknown
Total Pages: 105
Release: 2015
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Expansion of Highly Cytotoxic Human Natural Killer Cells by Osteoclast for Cancer Immunotherapy Book Excerpt:

Natural Killer (NK) cells have a crucial role in immune surveillance against a variety of infectious microorganisms and tumors. NK cells are known to mediate direct cytotoxicity as well as antibody dependent cellular cytotoxicity (ADCC) against a variety of tumor cells. Also, they are known to regulate the functions of other cells by producing key cytokines and chemokines. In the tumor microenvironment, cytotoxic function of NK cells is suppressed by a number of distinct effectors and their secreted factors. It has been shown that many cancer patients have decreased peripheral blood NK cell function, so NK cell-based immunotherapy has been used as a treatment in order to enhance NK cell function. However, limited availability of NK cells and ability to expand has restricted development of NK cell immunotherapy. Overcoming NK cell tolerance against tumors by developing new ways of activating endogenous NK cells that increase the expression of ligands for activating NK cell receptors or that render them more sensitive to NK cell mediated killing is crucial. In this study, we found the novel way to expand NK cells and the functionality of NK cells generated under this condition demonstrated enhanced expression of activating NK receptors. Also, significant cytotoxic killing potential after culture was discovered as well as augmented cytokine secretion. Therefore, these expanded NK cells are highly functional in comparison to primary NK cells. Through the help of cytokines, sAJ2 bacteria and osteoclast, NK cells can be expanded and activated in vitro and furthermore, these expanded NK cells can be used to target tumors in vivo. Expanded NK cells can be used in combination with other treatment modalities, potentially leading to synergistic antitumor activities.

Tumor Microenvironment

Tumor Microenvironment
Author: Alexander Birbrair
Publsiher: Springer Nature
Total Pages: 170
Release: 2020-02-06
ISBN: 3030355829
Category: Science
Language: EN, FR, DE, ES & NL

Tumor Microenvironment Book Excerpt:

Revealing essential roles of the tumor microenvironment in cancer progression, this book provides a comprehensive overview of the latest research on how different signaling pathways are important in the tumor microenvironment. Multiple signaling pathways are covered, including S1P, neuregulin, Notch, erythropoietin, Rho-ROCK, mTOR, and more. Taken alongside its companion volumes, these books update us on what we know about various aspects of the tumor microenvironment as well as future directions. Tumor Microenvironment: Signaling Pathways – Part A is essential reading for advanced cell biology and cancer biology students as well as researchers seeking an update on research in the tumor microenvironment.

The Role of CXCR2 in Pancreatic Cancer Development and Progression

The Role of CXCR2 in Pancreatic Cancer Development and Progression
Author: Abhilasha Purohit
Publsiher: Unknown
Total Pages: 236
Release: 2015
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

The Role of CXCR2 in Pancreatic Cancer Development and Progression Book Excerpt:

This dissertation examines the role of CXCR2, a seven transmembrane G- protein coupled receptor, in mediating autocrine as well as paracrine mechanisms during pancreatic cancer progression. Data presented in the initial section demonstrates the aberrant expression of the CXCR2 biological axis in human pancreatic cancer tissue specimens. A study performed within the first section of this dissertation investigates the contribution of CXCR2 signaling in pancreatic cancer initiation. These studies have identified a novel role of CXCR2 in mediating KRAS(G12D) -induced autocrine growth transformation of pancreatic cancer cells. The upregulation of the CXCR2 biological axis was found to be directly regulated by the KRAS(G12D) mutation using in vitro and in vivo model systems. Furthermore, the inhibition of CXCR2 by genetic and pharmacological tools was able to downregulate the protein level of KRAS. The tumor microenvironment in pancreatic cancer is composed of heterogeneous populations of cells including endothelial, fibroblast and immune cells. CXCR2 is known to be expressed by a majority of these cell types. Besides, CXCR2 is also known to mediate immune responses in various diseases including cancer. The studies in the later section of this dissertation investigate the role of CXCR2 in altering local and systemic host-mediated responses in pancreatic cancer. Two experimental strategies were used: 1) Evaluating the impact of host CXCR2 depletion on tumor growth in subcutaneous versus orthotopic tumor cell implants. 2) Examining the effect of host CXCR2 deletion on the infiltration of immune cells in orthotopic pancreatic tumors. The first approach identified a pancreatic-parenchyma specific role of CXCR2 in inhibiting fibrosis in pancreatic cancer. The second strategy unraveled an important role of CXCR2 in causing local immunosuppression where CXCR2 mediates the infiltration of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer. However, CXCR2 was found to be important for inhibiting extramedullary hematopoiesis and expansion of MDSCs in the spleen. Overall, the results presented in this dissertation suggest that CXCR2 signaling functions as a double-edged sword in pancreatic cancer by mediating both tumor-promoting and -inhibitory effects.

Tumor Microenvironment and Myelomonocytic Cells

Tumor Microenvironment and Myelomonocytic Cells
Author: Subhra Biswas
Publsiher: BoD – Books on Demand
Total Pages: 312
Release: 2012-03-30
ISBN: 953510439X
Category: Medical
Language: EN, FR, DE, ES & NL

Tumor Microenvironment and Myelomonocytic Cells Book Excerpt:

Tumor microenvironment represents an extremely dynamic niche shaped by the interplay of different cell types (e.g. tumor cells, stromal cells), their soluble products (e.g.cytokines, chemokines and growth factors) and varied physico-chemical conditions (e.g low oxygen concentration or hypoxia). Recent studies have identified myelomonocytic cells as key players in regulating the tumor microenvironment and hence, tumor progression in a variety of cancers. In view of these findings, the present book attemps to provide a comprehensive account of the diversity of tumor microenvironment across different cancers and how myelomonocytic cells have taken the center-stage in regulating this niche to direct cancer progression. A better understanding of the myelomonocytic cells and the mechanisms by which they regulate cancer progression will open new vistas in cancer therapeutics.

Reuglation of T Helper 17 by Bacteria

Reuglation of T Helper 17 by Bacteria
Author: Ying-Ju Cecilia Sung,宋穎如
Publsiher: Open Dissertation Press
Total Pages: 135
Release: 2017-01-27
ISBN: 9781361369074
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Reuglation of T Helper 17 by Bacteria Book Excerpt:

This dissertation, "Reuglation of T Helper 17 by Bacteria: an Approach for the Treatment of Hepatocellular Carcinoma" by Ying-ju, Cecilia, Sung, 宋穎如, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths in the world. It is a disease with poor prognosis with unsatisfactory long-term survival of patients, and thus new strategies to control this disease are warranted. T helper (Th) 17 cells and IL-17 have recently been detected with increased frequency in a number of tumors including HCC. Its role in tumor remains controversial but its presence in HCC has been linked to disease progression, possibly involving angiogenesis. Th17 cells could be homed to inflammatory sites such as tumor microenvironment via CCR6/CCL20 axis and expand locally, and studies from other inflammatory diseases such as autoimmune disease has shown that the gut is the potential source of Th17, where its induction is affected by signals from gut microbiota. Yet this link is not yet shown in extra-intestinal tumors. Probiotics are living microorganisms, which when administered in adequate amounts confer a health benefit on the host. They have been reported to relieve chronic inflammatory diseases in animal and in human intervention studies. It is believed that probiotics regulate signals to gut antigen-presenting cells, which act as the pivot in modulating the systemic immune responses and inactivated bacteria also exhibited immunomodulatory effects in this regard. Accordingly, it was hypothesized that oral feeding of probiotics to HCCbearing animals may affect Th17 polarization and distribution and thereby modulate tumor microenvironment, which may have beneficial effect in tumor development, possibly via affecting angiogenesis. To address this hypothesis, wild-type C57BL/6 mice were fed with different heat-inactivated or viable probiotics- Lactobacillus rhamnosus GG (LGG), Escherichia coli Nissle 1917 (EcN), VSL#3 or mixture of probiotics - Prohep (heat-inactivated LGG, heatinactivated VSL#3 and viable EcN) either one week in advance or at the time of subcutaneous tumor inoculation. Probiotic feeding had improved survival in tumor-bearing mice, slowed down tumor growth and reduced tumor burden when monitored for 38 days. Probiotics showed better efficacy when feeding was given in advance. The anti-tumor effect was related to reduced angiogenesis and reduced IL-17 serum and gene expression within tumor. The mechanistic link between IL-17 modulation and tumor development was further studied in animals by IL-17 neutralization. The anti-tumor efficacy of probiotics, in relation to tumor growth and angiogenesis, was lost after IL-17 neutralization, which was linked to recruitment of myeloid suppressor cells. Since cells from both adaptive and innate immune systems could secrete IL-17, the source of IL-17 production was then identified, and found that Th17 was the major IL-17 secretor being modulated by probiotic feeding. Reduced homing of Th17 to tumor via circulation, with a tendency being recruited from gut was observed. Probiotics-mediated Th17 cell modulation in the gut by inducing the skewing of IL-10 secreting type1 regulatory T cells via dendritic cells may link to limited IL-17 mediated angiogenesis in the tumor microenvironment. With better understanding of the immunomodulation properties of probiotics, prophylactic or therapeutic efficacy in management of other inflammation-associated cancer can be availed. DOI: 10.5353/th_b5387

Regulatory Mechanism of Myeloid Derived Suppressor Cell Activity

Regulatory Mechanism of Myeloid Derived Suppressor Cell Activity
Author: Cesar Alexander Corzo
Publsiher: Unknown
Total Pages: 202
Release: 2010
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Regulatory Mechanism of Myeloid Derived Suppressor Cell Activity Book Excerpt:

ABSTRACT: Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network that develops during cancer. MDSC down-regulate immune surveillance and antitumor immunity and facilitate tumor growth. The ability of MDSC to suppress T cell responses has been documented; however the mechanisms regulating this suppression remain to be understood. This work proposes a biological dichotomy of MDSC regulated by the tumor microenvironment. In peripheral lymphoid organs MDSC cause T-cell non-responsiveness that is antigen-specific. These MDSC have increased expression of NOX2, enabling them to produce large amounts of reactive oxygen species. Since the transcription factor STAT3 is substantially activated in MDSC, its potential role in upregulation of NOX2 expression was investigated. Over-expression of a constitutively active form of STAT3 increases expression of NOX2 subunits, whereas attenuation of STAT3 activity leads to decreased expression of NOX2. The significance of NOX2 in ROS generation is demonstrated in mice devoid of NOX2 function; NOX2-deficient MDSC are unable to inhibit antigen-induced activation of T cells. In contrast, MDSC within the tumor microenvironment have a diminished potential to generate ROS but acquire expression of arginase and inducible nitric oxide synthase, enzymes implicated in T cell non-responsiveness. Upregulation of these enzymes results in MDSC ability to inhibit lymphocyte response in absence of antigen presentation. The tumor microenvironment also promotes the differentiation of MDSC to tumor associated macrophages. Hypoxia is an exclusive feature to the tumor microenvironment and we investigated its involvement in the properties of MDSC at the tumor site. Exposure of spleen MDSC to hypoxia converts MDSC to non-specific suppressors and induces a preferential differentiation to macrophages. Stabilization of HIF-1alpha, a transcription factor activated by hypoxia, induces similar changes in MDCS as hypoxic exposure. Finally, ablation of HIF-1alpha prevents MDSC from acquiring factors that enable the suppression of T cells in absence of antigen. These findings help to expand our understanding of the biology of MDSC and suggest a regulatory pathway of myeloid cell function exclusive to the tumor microenvironment. They may also open new opportunities for therapeutic regulation as we now should take into consideration how systemic location affects the function of MDSC.

NK Cell Based Cancer Immunotherapy

NK Cell Based Cancer Immunotherapy
Author: Francisco Borrego,Susana Larrucea,Rafael Solana,Raquel Tarazona
Publsiher: Frontiers Media SA
Total Pages: 135
Release: 2016-09-08
ISBN: 2889199347
Category: Electronic Book
Language: EN, FR, DE, ES & NL

NK Cell Based Cancer Immunotherapy Book Excerpt:

Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.

Development of a Lymphatic Organotypic Microfluidic Model to Study the Influence of the Tumor Microenvironment in Lymphatic Vessel Function

Development of a Lymphatic Organotypic Microfluidic Model to Study the Influence of the Tumor Microenvironment in Lymphatic Vessel Function
Author: Karina Marie Lugo-Cintron
Publsiher: Unknown
Total Pages: 194
Release: 2020
ISBN: 1928374650XXX
Category: Electronic Book
Language: EN, FR, DE, ES & NL

Development of a Lymphatic Organotypic Microfluidic Model to Study the Influence of the Tumor Microenvironment in Lymphatic Vessel Function Book Excerpt:

Metastasis is the leading cause of death in cancer patients and, once cancer cells spread from the primary tumor, treatment becomes challenging. A key step during cancer metastasis is cancer cell intravasation (i.e., entry of cancer cells into the blood or lymphatic vasculature) that results in tumor cell dissemination to distant organs. Certain cancers (e.g., breast and head and neck), preferentially spread out of the primary tumor using the lymphatic vasculature, a process that is regulated by the interactions between cancer cells, the lymphatic vasculature and the surrounding tumor microenvironment (TME). Despite the identification of mechanisms that cancer cells use to intravasate into lymphatic vessels, lymphatic metastasis remains a problem. In this regard, recent studies have highlighted the critical role the TME plays in lymphatic metastasis and, recently emerged as a potential new target to inhibit tumor growth and metastasis. Therefore, there is a need to better understand how components of the TME influence lymphatic vessels to identify new therapeutic targets that prevent metastasis. To study lymphatics, traditional cell culture approaches (e.g., petri dishes) have been used, however, these approaches lack the complexity of the biological structures. Hence, to understand the influence of different TME components in lymphatics, a microfluidic in vitro model that can recapitulate the physiological conditions found in vivo would be a beneficial tool to advance cancer research. Thereby, this Ph.D. thesis presents the development of an organotypic lymphatic vessel model to study the influence of different tumor microenvironment components in lymphatic vessel remodeling. Altogether, this dissertation highlights the first microfluidic organotypic lymphatic model that enabled the examination of TME-lymphatics interactions, demonstrating that changes in ECM density and fibroblast composition can induce lymphatic vessel remodeling. This work has also demonstrated the potential of the model to use patient-derived cells to identify the changes induced to the lymphatic vessels. Overall, this thesis established the foundations and demonstrated the applications of the lymphatic organotypic model. Future studies are needed to better determine the influence of other TME components that could facilitate metastasis and, the use of this model could be expanded to a diverse set of research areas.

Oncoimmunology

Oncoimmunology
Author: Laurence Zitvogel,Guido Kroemer
Publsiher: Springer
Total Pages: 724
Release: 2017-12-13
ISBN: 3319624318
Category: Medical
Language: EN, FR, DE, ES & NL

Oncoimmunology Book Excerpt:

In this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing in particular on drugs with FDA/EMA approvals and breakthrough status. The aim is to deliver a landmark educational tool that will serve as the definitive reference for MD and PhD students while also meeting the needs of established researchers and healthcare professionals. Immunotherapy-based approaches are now inducing long-lasting clinical responses across multiple histological types of neoplasia, in previously difficult-to-treat metastatic cancers. The future challenges for oncologists are to understand and exploit the cellular and molecular components of complex immune networks, to optimize combinatorial regimens, to avoid immune-related side effects, and to plan immunomonitoring studies for biomarker discovery. The editors hope that this book will guide future and established health professionals toward the effective application of cancer immunology and immunotherapy and contribute significantly to further progress in the field.

Novel Immunotherapeutic Approaches to the Treatment of Cancer

Novel Immunotherapeutic Approaches to the Treatment of Cancer
Author: Paul D. Rennert
Publsiher: Springer
Total Pages: 276
Release: 2016-05-30
ISBN: 3319298275
Category: Medical
Language: EN, FR, DE, ES & NL

Novel Immunotherapeutic Approaches to the Treatment of Cancer Book Excerpt:

Cancer care is undergoing a radical transformation as novel technologies are directed toward new treatments and personalized medicine. The most dramatic advances in the treatment of cancer have come from therapeutics that augment the immune response to tumors. The immune checkpoint inhibitors are the best-known and most highly advanced examples of Immune Therapeutics targeting tumor cells and include approved antibody drugs directed at the cell surface proteins CTLA4 and PD-1. These are now considered foundational treatments for several solid tumor indications, and that list of indications is growing quickly. More broadly, antibodies have become workhorse molecules across the entire immunotherapy landscape. Antibodies to novel targets modulate the activity of diverse immune cell regulatory proteins. Engineered antibodies can induce tumor cell death or expose tumor cells to poisonous toxins (ADCC and ADC, respectively). Bi-specific antibodies can engage multiple tumor targets simultaneously, or can redirect lymphocytes to attack tumor cells. The antigen-binding domains within antibodies can be spliced onto cell stimulatory domains and transduced into T cells or NK cells, creating remarkable tumor-specific cellular therapeutics (CAR-T, CAR-NK). Beyond antibody-based therapies there are highly diverse and differentiated technology tool kits being applied to immunotherapy. Small molecule drugs are being developed to attack the tumor microenvironment, novel tumor vaccine approaches are showing great promise, patient lymphocytes are being isolated, expanded and reintroduced to patients, gene-editing techniques are becoming widely deployed, and a vast number of new tumor targets, and mutated tumor proteins (neoantigens), are being discovered. The past decade has seen unprecedented success in the treatment of diverse cancers. The authors of this volume have been asked to not only review progress to date, but importantly, to look ahead, and anticipate the evolution of cancer treatment across diverse Immune Therapeutic approaches. Our hypothesis is that the advances we are seeing across the immunotherapy landscape will further evolve and synergize, leading us finally to outright cures for many cancers.

Manipulating the Immunological Tumor Microenvironment

Manipulating the Immunological Tumor Microenvironment
Author: Peng Qu,Huanfa Yi,Keqiang Chen
Publsiher: Frontiers Media SA
Total Pages: 135
Release: 2022-03-31
ISBN: 2889748405
Category: Medical
Language: EN, FR, DE, ES & NL

Manipulating the Immunological Tumor Microenvironment Book Excerpt:

The Tumor Microenvironment Recent Advances and Novel Therapeutic Approaches

The Tumor Microenvironment  Recent Advances and Novel Therapeutic Approaches
Author: Sandra Orsulic,Hasan Korkaya
Publsiher: Frontiers Media SA
Total Pages: 135
Release: 2021-12-03
ISBN: 288971781X
Category: Science
Language: EN, FR, DE, ES & NL

The Tumor Microenvironment Recent Advances and Novel Therapeutic Approaches Book Excerpt:

Cancer Associated Thrombosis

Cancer Associated Thrombosis
Author: Alok A. Khorana,Charles W. Francis
Publsiher: CRC Press
Total Pages: 296
Release: 2007-09-26
ISBN: 1420048007
Category: Medical
Language: EN, FR, DE, ES & NL

Cancer Associated Thrombosis Book Excerpt:

Showcasing the expertise of top-tier specialists who contributed to the newly released guidelines for the care of thrombosis in cancer patients, this exciting guide was written and edited by members of the American Society of Clinical Oncology panel, (ASCO), on the prevention and treatment of cancer-associated thrombosis, among others, and provides