Transplantation and Cancer Immunology

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Results Probl Cell Differ (42) P. Kaldis: Cell Cycle Regulation DOI 10.1007/b136682/Published online: 1 September 2005 © Springer-Verlag Berlin Heidelberg 2005 Modeling Cell Cycle Control and Cancer with pRB Tumor Suppressor Lili Yamasaki Department of Biological Sciences, Columbia University, New York, NY 10027, USA Abstract Cancer is a complex syndrome of diseases characterized by the increased abun- dance of cells that disrupts the normal tissue architecture within an organism. Defining one universal mechanism underlying cancer with the hope of designing a magic bullet against cancer is impossible, largely because there is so much variation between vari- ous types of cancer and different individuals. However, we have learned much in past decades about different journeys that a normal cell takes to become cancerous, and that the delicate balance between oncogenes and tumor suppressor is upset, favoring growth and survival of the tumor cell. One of the most important cellular barriers to cancer de- velopment is the retinoblastoma tumor suppressor (pRB) pathway, which is inactivated in a wide range of human tumors and controls cell cycle progression via repression of the E2F/DP transcription factor family. Much of the clarity with which we view tumor suppression via pRB is due to our belief in the universality of the cell cycle and our at- tempts to model tumor pathways in vivo, nowhere so evident as in the multitude of data emerging from mutant mouse models that have been engineered to understand how cell cycle regulators limit growth in vivo and how deregulation of these regulators facilitates cancer development. In spite of this clarity, we have witnessed with incredulity several stunning results in the last 2 years that have challenged the very foundations of the cell cycle paradigm and made us question seriously how important these cell cycle regulators actually are. 1 Introduction and Background 1.1 Epidemiology Cancer is the most frequent cause of death of individuals under 85 years of age in the United States, now even surpassing heart disease (American Can- cer Society, Cancer Facts and Figures 2005, http://www.cancer.org). Mutations in RB or in genes encoding upstream regulators of pRB (i.e. INK4A, CCND1, CDK4) are found frequently in a mutually exclusive pattern in almost all hu- man tumors (see Sect. 3 below and Palmero and Peters 1996,Sherr 1996). Two examples of human tumors that illustrate the impact of inactivating the pRB tumor suppressor pathway include lung cancer and cervical cancer, and are highlighted below. 228 L. Yamasaki The most frequent types of cancer diagnosed in the United States in de- creasing incidence are breast cancer, prostate cancer, lung cancer and colon cancer; yet lung cancer is the deadliest form of cancer in the United States (163 500 deaths annually and 172 500 new cases annually). Twenty percent of lung cancer is classified as SCLC (small-cell lung cancer; 32 700 deaths annually); the vast majority (∼ 90%) of cases carry mutations that directly inactivate the RB locus (encoding pRB)(Kaye 2002, Minna et al. 2004). It is in- deed sobering to consider the number of deaths due to lung cancer that are largely preventable with abstinence from or cessation of smoking, and the fact that while smoking is on the decline in the United States, smoking and its as- sociated lung cancer has been exported heavily to the developing world in the past 30 years. Moreover, the list of cancers for Transplantation and Cancer Immunology Transplantation and Cancer Immunology Bởi: OpenStaxCollege The immune responses to transplanted organs and to cancer cells are both important medical issues With the use of tissue typing and anti-rejection drugs, transplantation of organs and the control of the anti-transplant immune response have made huge strides in the past 50 years Today, these procedures are commonplace Tissue typing is the determination of MHC molecules in the tissue to be transplanted to better match the donor to the recipient The immune response to cancer, on the other hand, has been more difficult to understand and control Although it is clear that the immune system can recognize some cancers and control them, others seem to be resistant to immune mechanisms The Rh Factor Red blood cells can be typed based on their surface antigens ABO blood type, in which individuals are type A, B, AB, or O according to their genetics, is one example A separate antigen system seen on red blood cells is the Rh antigen When someone is “A positive” for example, the positive refers to the presence of the Rh antigen, whereas someone who is “A negative” would lack this molecule An interesting consequence of Rh factor expression is seen in erythroblastosis fetalis, a hemolytic disease of the newborn ([link]) This disease occurs when mothers negative for Rh antigen have multiple Rh-positive children During the birth of a first Rh-positive child, the mother makes a primary anti-Rh antibody response to the fetal blood cells that enter the maternal bloodstream If the mother has a second Rh-positive child, IgG antibodies against Rh-positive blood mounted during this secondary response cross the placenta and attack the fetal blood, causing anemia This is a consequence of the fact that the fetus is not genetically identical to the mother, and thus the mother is capable of mounting an immune response against it This disease is treated with antibodies specific for Rh factor These are given to the mother during the subsequent births, destroying any fetal blood that might enter her system and preventing the immune response 1/9 Transplantation and Cancer Immunology Erythroblastosis Fetalis Erythroblastosis fetalis (hemolytic disease of the newborn) is the result of an immune response in an Rh-negative mother who has multiple children with an Rh-positive father During the first birth, fetal blood enters the mother’s circulatory system, and anti-Rh antibodies are made During the gestation of the second child, these antibodies cross the placenta and attack the blood of the fetus The treatment for this disease is to give the mother anti-Rh antibodies (RhoGAM) during the first pregnancy to destroy Rh-positive fetal red blood cells from entering her system and causing the anti-Rh antibody response in the first place Tissue Transplantation Tissue transplantation is more complicated than blood transfusions because of two characteristics of MHC molecules These molecules are the major cause of transplant rejection (hence the name “histocompatibility”) MHC polygeny refers to the multiple MHC proteins on cells, and MHC polymorphism refers to the multiple alleles for each individual MHC locus Thus, there are many alleles in the human population that can be expressed ([link] and [link]) When a donor organ expresses MHC molecules that are different from the recipient, the latter will often mount a cytotoxic T cell response to the organ and reject it Histologically, if a biopsy of a transplanted organ exhibits massive infiltration of T lymphocytes within the first weeks after transplant, it is a sign that the transplant is likely to fail The response is a classical, and very specific, primary T cell 2/9 Transplantation and Cancer Immunology immune response As far as medicine is concerned, the immune response in this scenario does the patient no good at all and causes significant harm Partial Table of Alleles of the Human MHC (Class I) Gene # of alleles # of possible MHC I protein components A 2132 1527 B 2798 2110 C 1672 1200 E 11 F 22 G 50 16 Gene # of alleles # of possible MHC II protein components DRA DRB 1297 958 DQA1 49 31 DQB1 179 128 DPA1 36 18 DPB1 158 136 DMA DMB 13 DOA 12 DOB 13 Partial Table of Alleles of the Human MHC (Class II) Immunosuppressive drugs such as cyclosporine A have made transplants more successful, but matching the MHC molecules is still key In humans, there are six MHC molecules that show the most polymorphisms, three class I molecules (A, B, and C) and 3/9 Transplantation and Cancer Immunology three class II molecules called DP, DQ, and DR A successful transplant usually requires a match between at least 3–4 of these molecules, with more matches associated with greater success Family members, since they share a similar genetic background, are much more likely to share MHC molecules than unrelated individuals In fact, due to the extensive polymorphisms in these MHC molecules, unrelated donors are found only through a ...National Cancer InstituteNational Cancer Institute The Early Detection Research Network U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health JANUARY 2008 Division of Cancer Prevention Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk 2 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk Contents 5 Foreword 7 Introduction 8 Executive Summary Part I: Progress and Disease-Specific Developments 14 Chapter 1 Overview 26 Chapter 2 Breast and Gynecologic Cancers 34 Chapter 3 Colorectal and Other Gastrointestinal Cancers 47 Chapter 4 Lung and Upper Aerodigestive Cancers 56 Chapter 5 Prostate and Other Urologic Cancers Part II: Process and Collaboration 66 Chapter 6 Validation Stages and Processes 77 Chapter 7 Enabling Technologies Part III: Investing in Biomarker Research 91 Chapter 8 Business Model 99 Chapter 9 Evaluating Biomarker Progress in Translational Research 104 Chapter 10 Investing in Biomarker Research for Early Detection Appendix 115 I. Key Publications by Investigators 123 II. Publications Co-Authored by NCI Program Staff 124 Glossary 3 4 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk Foreword January 2008 In 2000, NCI’s Division of Cancer Prevention created an investigator- driven network designed to conduct translational research that identified markers both for the early detection of cancer and of cancer risk. That program, the Early Detection Research Network (EDRN), focuses on the goal of creating validated biomarkers ready for large-scale clinical test- ing and eventual application. Without a doubt, real progress has been made—and is being made—by this consortium of more than 300 inves- tigators and 40 private sector and academic institutions. These scientists represent divergent disciplines, including genomics, proteomics, metabo- lomics, bioinformatics and public health. EDRN is at the forefront of technology-driven research on the use of biomarkers for the early detection of cancer. By identifying and validat- ing biomarkers, such as novel proteins or changes in gene expression, it is possible to measure an individual’s disease risk, progression of disease, or response to therapy. Ultimately, EDRN research will aid in prevention and in early therapeutic intervention, based on early detection of disease. Researchers with EDRN have been instrumental in identifying and validating markers for many major cancers, such as prostate (protein profiling of BPH, HPIN and IGFb3/br), colon (K-ras mutations in stool and urine) and breast (alpha catenin genes). They have also joined forces with clinical trial communities to accelerate biomarker validation. To take just one example, EDRN investigators work with investigators in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and in the Specialized Programs of Research Excellence (SPORE) program, to test a panel of biomarkers for ovarian cancer in CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis Lois Swirsky Gold, Thomas H. Slone, Bruce N. Ames University of California, Berkeley Neela B. Manley Ernest Orlando Lawrence Berkeley National Laboratory 38.1 INTRODUCTION Possible cancer hazards from pesticide residues in food have been much discussed and hotly debated in the scientific lit- erature, the popular press, the political arena, and the courts. Consumer opinion surveys indicate that much of the U.S. pub- lic believes that pesticide residues in food are a serious cancer hazard (Opinion Research Corporation, 1990). In contrast, epi- demiologic studies indicate that the major preventable risk factors for cancer are smoking, dietary imbalances, endogenous hormones, and inflammation (e.g., from chronic infections). Other important factors include intense sun exposure, lack of physical activity, and excess alcohol consumption (Ames et al., 1995). The types of cancer deaths that have decreased since 1950 are primarily stomach, cervical, uterine, and colorectal. Overall cancer death rates in the United States (excluding lung cancer) have declined 19% since 1950 (Ries et al., 2000). The types that have increased are primarily lung cancer [87% is due to smoking, as are 31% of all cancer deaths in the United States (American Cancer Society, 2000)], melanoma (probably due to sunburns), and non-Hodgkin’s lymphoma. If lung cancer is in- cluded, mortality rates have increased over time, but recently have declined (Ries et al., 2000). Thus, epidemiological studies do not support the idea that synthetic pesticide residues are important for human cancer. Al- though some epidemiologic studies find an association between cancer and low levels of some industrial pollutants, the stud- ies often have weak or inconsistent results, rely on ecological correlations or indirect exposure assessments, use small sam- ple sizes, and do not control for confounding factors such as composition of the diet, which is a potentially important con- founding factor. Outside the workplace, the levels of exposure to synthetic pollutants or pesticide residues are low and rarely seem toxicologically plausible as a causal factor when com- pared to the wide variety of naturally occurring chemicals to which all people are exposed (Ames et al., 1987, 1990a; Gold et al., 1992). Whereas public perceptions tend to identify chem- icals as being only synthetic and only synthetic chemicals as being toxic, every natural chemical is also toxic at some dose, and the vast proportion of chemicals to which humans are ex- posed are naturally occurring (see Section 38.2). There is, however, a paradox in the public concern about possible cancer hazards from pesticide residues in food and the lack of public understanding of the substantial evidence indi- cating that high consumption of the foods that contain pesticide residues—fruits and vegetables—has a protective effect against many types of cancer. A review of about 200 epidemiological studies reported a consistent association between low consump- tion of fruits and vegetables and cancer incidence at many target sites (Block et al., 1992; Hill et al., 1994; Steinmetz and Potter, 1991). The quarter of the population with the lowest dietary intake of fruits and vegetables has roughly twice the cancer rate for many types of cancer (lung, larynx, oral cavity, esopha- gus, stomach, colon and rectum, bladder, pancreas, cervix, and ovary) compared to the quarter with the highest consumption of those foods. The protective effect of consuming fruits www.ext.vt.edu Produced by Communications and Marketing, College of Agriculture and Life Sciences, Virginia Polytechnic Institute and State University, 2009 Virginia Cooperative Extension programs and employment are open to all, regardless of race, color, national origin, sex, religion, age, disability, political beliefs, sexual orientation, or marital or family status. An equal opportunity/affirmative action employer. Issued in furtherance of Cooperative Extension work, Virginia Polytechnic Institute and State University, Virginia State University, and the U.S. Department of Agriculture cooperating. RIck D. Rudd, Interim Director, Virginia Cooperative Extension, Virginia Tech, Blacksburg; Alma C. Hobbs, Administrator, 1890 Extension Program, Virginia State, Petersburg. PUBLICATION 348-141 The Diet and Cancer Connection Kathleen M. Stadler, Extension Specialist, Human Nutrition and Foods, Virginia Tech Introduction One out of every three Americans will be diagnosed with cancer at some time. Cancer affects three of every four families. Cancer is the second leading cause of death in the U.S. Each year, nearly 500,000 Americans die from cancer. While the rates for coronary heart attacks and uncontrolled high blood pressure are declining, certain cancer rates are increasing. Many people assume that getting cancer is a matter of bad luck and environmental hazards. But many cancer experts now believe that lifestyle factors-smoking, diet, stress, sun- bathing, etc are more important factors than thought pos- sible a few years ago. Lifestyle factors are involved in most cancers, with controllable factors estimated to be as high as 80 to 90 percent of all causes. Diet may account for some 35 percent, and smoking another 30 percent. A critical factor needing much more study is the inuence of heredity on cancer susceptibility. Some people never develop cancer despite years of exposure to tobacco, poor diet, alco- hol, sunlight, etc., while others, unexposed, will get it. Why? The answer must involve heredity. For some, the genes, with all their inherited deoxyribonucleic acid (DNA), resist per- manent damage (mutation) by cancer-causing agents, known as carcinogens. For unlucky others, a combination of modi- ed genes and a suitable internal environment results in the dreaded diagnosis. Maintaining good nutrition and avoiding tobacco, certain heavy metals, pesticides, excessive ultraviolet light and radiation provides a strong defense against many common cancers. Food with protective nutrients may add many dis- ease-free years as well as pleasure from good eating. Researchers believe that everyone harbors initiated cells that will not become cancerous if they are destroyed or kept in check by the immune system. In most cases, the body’s immune system recognizes and destroys these strange, initiated cells. However, in cancer, the immune system may become overwhelmed or lose its ability to recognize the foreign cells, allowing them to escape destruction and multiply. A number of agents are known to cause DNA mutations: ultraviolet light, radiation, certain chemicals such as those found in tobacco, smog and pesticides, a few viruses and cer- tain diet-related agents. Known dietary agents include oxidized fats, nitrates and nitrites, and chemicals produced during charcoaling, smok- ing or grilling meat. Contrary to popular opinion, food additives have few, if any, cancer-causing properties. New food additives are care- fully researched before being allowed in food and are safer than many natural chemicals. Some experts believe there is much more risk from natural food substances than from food additives. In animal studies, two commonly INFLAMMATION, CHRONIC DISEASES AND CANCER – CELL AND MOLECULAR BIOLOGY, IMMUNOLOGY AND CLINICAL BASES Edited by Mahin Khatami Inflammation, Chronic Diseases and Cancer – Cell and Molecular Biology, Immunology and Clinical Bases Edited by Mahin Khatami Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. 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ISBN 978-953-51-0102-4 Contents Preface IX Part 1 Dynamics of Immune System and Inflammatory Diseases 1 Chapter 1 Inflammation, Aging and Cancer: Friend or Foe? 3 Mahin Khatami Chapter 2 The Impact of Macrophage Membrane Lipid Composition on Innate Immune Response Mechanisms 31 Julia Schumann Chapter 3 The Innate Immune Response Mediated by TLRs in Atherosclerosis 53 Luis Chávez-Sánchez, Karina Chávez-Rueda, María Victoria Legorreta-Haquet, Eduardo Montoya-Díaz and Francisco Blanco-Favela Chapter 4 Autoimmunity, Atherosclerosis and Apoptotic Cell Clearance 75 Tamar Aprahamian Chapter 5 The Platelet as an Immunomodulator: The Old Thespian with New Roles in Atherosclerosis, Sepsis and Autoimmune Disease 97 Omar L. Esponda, Yaliz Loperena, Gladiany Ramos and A. Valance Washington Chapter 6 Regulatory T Cells and Viral Disease 121 Tanya LeRoith and S. Ansar Ahmed Chapter 7 Inflammation, Immunity and Redox Signaling 145 Joshua Jabaut and Karina Ckless Chapter 8 Complement Receptors in Inflammation 161 Priyanka Pundir and Marianna Kulka VI Contents Chapter 9 Parasitic Infections and Inflammatory Diseases 205 Joziana M.P. Barçante, Thales A. Barçante, Ana Paula Peconick, Luciano J. Pereira and Walter S. Lima Chapter 10 The Role of Chemokines and Cytokines in the Pathogenesis of Periodontal ... two types of cancer by stimulating the immune response Karposi’s Sarcoma Lesions (credit: National Cancer Institute) 4/9 Transplantation and Cancer Immunology On the other hand, as cancer cells... most polymorphisms, three class I molecules (A, B, and C) and 3/9 Transplantation and Cancer Immunology three class II molecules called DP, DQ, and DR A successful transplant usually requires a... Treated cancer cells are injected into cancer patients to enhance their anti -cancer immune response and thereby prolong survival The immune system has the capability to detect these cancer cells and