Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical factors in Carcinogenesis 4. Viral oncogenesis 5. Genetic Predisposition
Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition
Introduction 肿瘤( tumor) 在致瘤因素作用下,细胞基因失去对细胞增殖、分化和死 亡的正常调控,导致组织细胞不断增生而形成的新生物。 良性肿瘤( benign tumor) 恶性肿瘤( malignant tumor) General Characteristics of Benign and Malignant Tumors Characteristic Benign Malignant Histology Typical of tissue of origin Anaplastic, with abnormal cell size and shape Few mitoses Many mitoses Growth rate Slow Rapid Localization/metastasis Strictly local, often encapsulated/no metastasis Infiltrative/frequent metastases Tumor necrosis Common Recurrence after treatment Common Prognosis Good Poor if untreated
2 肿瘤（tumor） 在致瘤因素作用下，细胞基因失去对细胞增殖、分化和死 亡的正常调控，导致组织细胞不断增生而形成的新生物。 良性肿瘤（benign tumor） 恶性肿瘤（malignant tumor） Introduction
肿瘤发病率和死亡率 口2010年国际抗癌联盟(UIcc): >2008年全世界1270万新增癌症患者,死亡人数760万。 口《2010中国卫生统计年鉴》 >2009年中国恶性肿瘤成为首位死因。 每年新发癌症病人约200万,死亡人数约150万。 ≯肺癌、肝癌、结直肠癌、乳腺癌、膀胱癌死亡率及其构成明显上升。 肺癌成为我国首位恶性肿瘤死亡原因
3 肿瘤发病率和死亡率 2010年国际抗癌联盟（UICC）： ➢2008年全世界1270万新增癌症患者，死亡人数760万。 《2010中国卫生统计年鉴》 ： ➢2009年中国恶性肿瘤成为首位死因。 ➢每年新发癌症病人约200万，死亡人数约150万。 ➢肺癌、肝癌、结直肠癌、乳腺癌、膀胱癌死亡率及其构成明显上升。 ➢肺癌成为我国首位恶性肿瘤死亡原因
INTRODUCTION Celebrating an Anniversary In this issue of Science, we commemorate the 40th anniversary of the U.S National Cancer Act, which provided a massive stimulus for cancer research At the start of this "Cancer Crusade, researchers were already tackling some tough gus ions as refected in papers published bey scie ie in 1 7 l mong Cancer Crusade H)2时at40 tumor cells as foreign invaders that must be eliminated from the body? Do viruses play a role in human cancer? Skeptics might argue that 40 years later, cancer researchers continue to grap- CONTENTS ple with the same questions. Perhaps theres some truth in this. But our hope is News that the selection of articles in this special section of Science will explain wby1540Cancer Research and the s90 Billion Metaphor contemporary cancer research is providing a clearer view of the biology that will U.S. Cancer Trends lead to answers. Stratton(p 1553)discusses international efforts to sequence Combining Targeted Drugs the complete genomes of a wide range of human tumor types and the impact that this sequence information is anticipated to have on our understanding of to Stop Resistant Tumors working model for cancer cell metastasis is presented by Chaffer and Weinberg 1548 A Push to Fight Cance (p. 1559), who highlight the important role of cancer stem cells and a develop. in the Developing World mental process called the epithelial-mesenchymal transition. Schreiber et al.(p. 1551 Brothers in Arms Against Cancer 1565)describe "cancer immunoediting, a conceptual framework that integrates the immune systems dual roles in inhibiting and promoting cancer growth Reviews News reports examine other significant challenges for the field: Jocelyn 1553 Exploring the Genomes of Kaiser (p 1542)describes how even the best new drugs eventually seem to fail Cancer Cells: Progress and Promise and how they might be made more effective, David Malakoff(p. 1545)outlines a M. R. Stratton key social issue: the fast-rising cost of care. Martin Enserink(p 1548)reports on 1559 A Perspective on Cancer efforts to close the huge disparity between cancer treatment in rich and develop- Cell Metastasi ing countries And Mitch Leslie (p. 155 1)describes how researchers are taking C L Chaffer and R A Weinberg a new look at the role of p53 and the related proteins p63 and p73 in tumors 1565 Cancer Immunoediting AvideoreportbyRobertFrederickappearsonlineatwww.sciencemag Integrating Immunity's Roles in org/special/cancer2011/, along with links to additional reading material Cancer Suppression and Promotion
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Hallmarks of cancer (Weinberg. Cell, 2000) Sustaining proliferative signaling Resisting Evading growth cell death suppressors Inducing Activating invasion angiogenesIs and metastasis Enabling replicative immortality Figure 1. The hallmarks of cancer this illustration encompasses the six hallmark capabilitie originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark.(Hanahan D, Weinberg 5 RA. Hallmarks of Cancer: The Next Generation Cell 2011, 144: 646)
5 Hallmarks of cancer (Weinberg, Cell, 2000) Figure 1. The Hallmarks of Cancer. This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
Hallmarks of cancer (Weinberg. cell, 2011) Sustaining Evading proliferative growth signaling suppressors Deregulating Avoiding cellular Immune energetics destruction Resistin Enable cell replicative death immortality G enome instability promoting mutation inflammation Inducing Activating angiogenesis invasion metastasis (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation Cell 2011, 144: 646)6
6 Hallmarks of cancer (Weinberg, Cell, 2011) . (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
The hallmarks of cancer Self-sufficiency in growth signals Cancer cells do not need stimulation from external signals ( in the form of growth factors) to multiply Insensitivity to anti-growth signals Cancer cells are generally resistant to growth-preventing signals from their neighbours Tissue invasion and metastasis Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread(metastasis)to distant body parts Limitless reproductive potential Non-cancer cells die after a certain number of divisions cancer cells escape this limit and are apparently capable of indefinite growth and division(immortality) Sustained angiogenesis Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients Evading apoptosis Apoptosis is a form of programmed cell death, the mechanism by which cells are programmed to die after a certain number of divisions or in the event they become damaged. Cancer cells characteristically are able to bypass this 7 mechanism
7 The Hallmarks of Cancer Self-sufficiency in growth signals Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply. Insensitivity to anti-growth signals Cancer cells are generally resistant to growth-preventing signals from their neighbours. Tissue invasion and metastasis Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasis) to distant body parts. Limitless reproductive potential Non-cancer cells die after a certain number of divisions. Cancer cells escape this limit and are apparently capable of indefinite growth and division (immortality). Sustained angiogenesis Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients. Evading apoptosis Apoptosis is a form of programmed cell death, the mechanism by which cells are programmed to die after a certain number of divisions or in the event they become damaged. Cancer cells characteristically are able to bypass this mechanism
Deregulated metabolism Most cancer cells use abnormal metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, but only now gaining renewed research interest Evading the immune system Cancer cells appear to be invisible to the body' s immune system Unstable dna Cancer cells generally have severe chromosomal abnormalities, which worsen as the disease progresses Inflammation Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer (Hanahan, D. Weinberg, R A(2011). Hallmarks of Cancer: The Next Generation". Cell 144(5):646-674.c0:10.1016cel201102.013)
8 Deregulated metabolism Most cancer cells use abnormal metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, but only now gaining renewed research interest. Evading the immune system Cancer cells appear to be invisible to the body’s immune system. Unstable DNA Cancer cells generally have severe chromosomal abnormalities, which worsen as the disease progresses. Inflammation Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer. (Hanahan, D.; Weinberg, R. A. (2011). "Hallmarks of Cancer: The Next Generation". Cell 144 (5): 646–674. doi:10.1016/j.cell.2011.02.013 )
Chemical Carcinogenesis Multi-stage Theory of Chemical Carcinogenesis Classification of chemical carcinogens Mechanisms of Chemical Carcinogenesis DNA Damage Induced by Ultimate Carcinogens ◆ DNA Repair
Chemical Carcinogenesis ◆ Multi-stage Theory of Chemical Carcinogenesis ◆ Classification of chemical carcinogens ◆ Mechanisms of Chemical Carcinogenesis ◆ DNA Damage Induced by Ultimate Carcinogens ◆ DNA Repair
Multi-stage Theory of Chemical Carcinogenesis Initiation --------Genetic events Chemical Carcinogens(Direct and Indirect Carcinogens) Promotion Epigenetic events Tumor promoters Murine skin carcinogenesis model A single dose of polycyclic aromatic hydrocarbon(PAH, Initiator) Repeated doses of croton oil(promoter) Malignant conversion Progression -----Genetic and epigenetic events
10 Multi-stage Theory of Chemical Carcinogenesis Initiation -----------Genetic events Chemical Carcinogens (Direct and Indirect Carcinogens) Promotion -------Epigenetic events Tumor promoters – Murine skin carcinogenesis model: • A single dose of polycyclic aromatic hydrocarbon (PAH, initiator) • Repeated doses of croton oil (promoter) Malignant conversion Progression ------Genetic and epigenetic events