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Progression in Neoplastic Development Folder Title: Progress(NoTP) Updated: March 08, 2017 See “Multi-step Tumorigenesis, Chapter 11, Biology of Cancer, 2nd Edition, pp 439 - 509 In the Second Third of Biology of Cancer: How Do Cancers Get that Way? What are cancer cells like? (Cell Properties; Immortalization) Chapter 2 (Parts); Chapter 10 , pp 391 - 437 How do cancer cells interact and diverge? (Heterogeneity) Chapter 13: Heterotypic Interactions. pp 577 – 640) How do cancer develop and change? (Progression) Chapter 11: Multi-step Tumorigenesis. pp 439 - 510 How do cancer cells and cancerous neoplasms grow? Chapter 5: Growth Factors and Receptors, pp 131 - 174 How do cancer cells become invasive and become able to spread? (Invasion and Metastasis) Chapter 14: Moving Out: Invasion and Metastasis, pp 641 - 722 What do we study in order to understand metastatic cancers? (Met Models) Chapter 14 Progressive Steps in Neoplastic Cell Development: Hyperplasia and Dysplasia Progressive Steps in Neoplastic Cell Development: Cancer In situ and Invasive Cancer Definitions and Concepts of Progression in Neoplasia Transitions in Cancer Development: • Hyperplasia • Dysplasia • Anaplasia • Pre-neoplastic nodules • Carcinoma (or other histogenetic type) in situ • Malignant neoplasia Gradual Acquisition of Fully Neoplastic Character "Acquisition of permanent, irreversible, qualitiative changes in one or more characteristics of a neoplasm“ = Progression Progression from Intestinal Adenoma to Invasive Malignant Carcinoma Figure 11.8a The Biology of Cancer (© Garland Science 2007) p. 407 Effect of Age on Appearance of Carcinomas (Figure 11.1, p. 400, First Edition) (See Figure 11.1, p. 440, 2nd Ed) Note decline in incidence rate in the “Super-Old” A series of successive steps must be achieved before a cancer can appear. Each of these steps may take 10 or 15 years to complete. The rate of completing these steps can be accelerated by: a. Genetics of the host b. Exposure to carcinogens c. Diet and Life-Style d. Hormonal status Effect of Age on Appearance of Carcinomas (Figure 11.1, p. 400, First Edition) Enlarged version of previous slide Duration of exposure to carcinogenic agent is driving force in generating mesothelioma from asbestos exposure (Left panel) or skin cancer from solar exposure (Right Panel). Age at first exposure is not relevant. Figure 11.4 The Biology of Cancer (© Garland Science 2007) Figure 11.5, p. 444, 2nd Edition Slope of 5 in Log Death Rate vs Linear Age in Years in Carcinomas: ~ Five steps needed to generate full-blown carcinoma Figure 11.3 The Biology of Cancer (© Garland Science 2007) Patterns of Progression in Neoplasia • Permanent, irreversible changes; independent of other tumor cells in the developing neoplasm • Different characteristics within the tumor progress separately and independently • Pathways and sequences of steps vary in unpredictable and divergent ways • Progression need not be associated with tumor growth • Progression converges toward similar end-product neoplastic cells, but by diverse routes. Implications and Consequences of Progression in Cancer • For the biology of carcinogenesis • As an underlying cause for long latent periods • For screening human populations for cancers • For defining the "Biology of a Cancer" • For cancer diagnosis • For cancer treatment Properties or Characteristics Affected by Progression in Cancer Karyotype • Chromosome Numbers • Chromosome Structures (Visible Microscopically, or Detectible by Molecular Biology) Growth Rate and Immortalization Transplantability into Experimental Animals Morphology, Histology, Cytology Regulation: • Hormone Dependence and Independence • Response to Growth Control Signals Differentiation and Degree of "Dedifferentiation" Invasion and Metastasis Drug Responsiveness Progressive Development of Aneuploidy in Mouse Sarcoma Representative Times to Full Neoplastic Progression for Cancers of Various Histogenetic Sites of Origin CIN = Cervical Intra-epithelial neoplasia. DCIS = Ductal carcinoma in situ Figure 11.7 The Biology of Cancer (© Garland Science 2007) p. 406 Basis or Source of Progression Patterns Acquired, Self-perpetuating genetic lability • Cytological anaplasia at the chromosome level • Genetic instability inherent in the original cell lineage that became transformed? • Genetic instability induced in the transformed cells Immortalization and gradual accrual of additional genetic anomalies Fusion of normal and transformed cells Failure to repair damaged DNA Selective Survival of Aberrant Cells • Evolution toward increased autonomy UV-Associated Activation of Telomerase in Progression to Skin Cancer. Ueda et al., Cancer Research,57:373(1997). Telomerase + p53 Mutation Clonal Expansion Loss of heterozygosity (LOH) (Loss of variations) in Chromosomes in Human Colon-rectal Cancer Why is loss of alleles extra-ordinarily common in chromosomes 5, 6, 8, 17 and 18? Why does losing something support the progression on cancer? Figure 7.14 The Biology of Cancer (© Garland Science 2007) Loss of Tumor Suppressor Genes (TSG) and Activation on Oncogenes in Progression in Colon Carcinoma What is being lost during progression in chromosomes 5, 17 and 18? Loss of “DCC” Gene. Function unknown Loss of APC Gene Loss of p53 gene “APC” = Adenomatous polyposis coli gene (Cancer suppressor gene) “K-ras” = Oncogene activated, transduced, or mutated, first identified in virallyinduced rat sarcoma. (On chromosome 1*) TSG = Tumor Suppressor Gene p53 = Major cancer suppressor gene LOH = Loss of Heterozygosity (Loss of alleles) p. 409 Figure 11.9 The Biology of Cancer (© Garland Science 2007) Phenotypic effects of activated or mutated RAS Oncogene: See Oncogenes Later and Also Legend to Figure 11.43, p. 459 Widely acting oncogene: Acts immediately below the cell membrane in transducing growth factor signaling from outside the cell and transmitting it to the nucleus. Effects of RAS: Susceptibility to apoptosis Escape from need for exogenous mitogens (cell division signaling) Aberrant intra-cellular signaling and aberrant cell cycle entry Angiogenesis Detachment and Invasiveness Phenotypic effects of Lost or Mutated p53 See Oncogenes and Suppressor Genes Later and Also Legend to Figure 11.43, p. 459 Major Tumor Suppressor Gene Effects of p53: Susceptibility to apoptosis Controls cell cycle entry and cell growth Immortalization Two Turning Point Questions Please clear desktops No Communicating Among Students Response Counter Response Counter Clonal Origins of Leukemia in Human From a single Original Cell: How can we tell? Appearance of identical leukemia clones in monozygotic twins: Initial transformed cell lineage generated in utero in one twin and transferred to the other via shared placenta before birth ALL = Acute Lymphocytic leukemia T-ALL = T-Cell Acute Lymphocytic Leukemia MLL = Mixed cell leukemia NHL = Non-Hodgkins Lymphoma AML = Acute Myelogenous leukemia TEL = Telomerase Figure 11.22b The Biology of Cancer (© Garland Science 2007) Colon Cancers Appear at Different Times in Different Persons Negotiating the same progressive steps. Why the difference? Host genetics (e.g. familial APC gene defect) Cooperation on Oncogenes: Myc and RAS Diet Life-style Exercise Weight Vitamin D Intake Introduction of myc or ras oncogenes into rat embryo fibroblasts in cell culture Insertion of Oncogenes into Cells in Culture Adenovirus early oncogene Able to grow in suspension culture. No foci of transformed cell colonies Forms tumor cell colonies in cell cultures. Gives tumors in syngeneic or immunosuppressed mice Figure 11.23 The Biology of Cancer (© Garland Science 2007) Able to grow in suspension culture. Some colonies is dilute agar. (Fig. 11.22; page 472, 2nd Edition) Insertion of Oncogenes into Embryonic Mice: Tumor Appearance in Vivo Oncogene Collaboration in Mice with inserted (“transgenic”) oncogenes T50 = Time in Days to get 50% of the mice to develop mammary carcinomas . Myc and ras oncogenes cooperate in generating mamarry cancer in vivo Figure 11.24b The Biology of Cancer (© Garland Science 2007) Cancer Cell Genotypes and Phenotypic Expression (For a “Generic” Cancer) Suppressor Genes Figure 11.43 The Biology of Cancer (© Garland Science 2007) hTert = Telomerase catalytic subunit p. 459 Sequence of steps in colon carcinoma Code for growth promoting cancerinducing oncogene products Adenomatous polyposis coli gene Figure 11.11a The Biology of Cancer (© Garland Science 2007) Codes growth inhibitory tumor suppressor product. (Also called SMAD4) Tumor Promoting Agents: Drivers of Cancer Progression Effects of Progression on Treatment Selection and progression to increased autonomy and "dedifferentiation" • Poorly differentiated cells may becme increasingly difficult to affect with treatment • Poorly differentiated cells may become increasingly aggressive Emergence of Drug-Resistance • Selection of pre-exisiting variants with ability to survive treatment • Generation of variants by treatment Emergence of immune unresponsiveness Three Turning Point Questions Please clear desktops No Communicating Among Students Tobacco Use and Cancer Progression On Commercial Interests, Public Health, and Long Lag Phases Surgeon General’s Report on Smoking and Cancer: 1964 ~25 50 Years Years! Global cigarette consumption caused by smoking (estimated) Avoidable Deaths: 1964 to 2014; ~50 to 75 Million! non-tobacco related (estimated) 45-year lag phase: Start of wide-spread cigarette use & explosion of lung cancer Recognition that smoking causes Lung cancer. Post WWII Jump in lung cancer in veterans receiving cigarette rations during the war Public Health Problems, Lag Phases, and Effective Responses Initiation of Dangerous Behavior Appearance of the Problem Recognition of the Problem and Its Causes Lung Cancer and Cigarettes 1900-1945 1945 - 1964 1964 Luther Terry, S.G. CO2 and Climate Change 1765 - 1830 1860 - 2013 1824 -1896 Fourier & Arrhenius Public Control of Control of Acceptance of the the that Causative Problem: Recognition Agent: No Leveling off and Program Further of the for Increase in Increase in Responding Damage Cause of the Problem 2012 1964 – 1996 1990 (For Males) C. Everett Koop, S.G. ? ? Uncertain of whether it can be controlled On the Influence of Carbonic Acid in the Air upon the Temperature of the Ground Svante Arrhenius Philosophical Magazine and Journal of Science Series 5, Volume 41, April 1896, pages 237-276. Arthur Godfrey Chesterfield’s Ad, April 1953 http://www.flickr.com/photos/ capricornonevintage/559012 2667/lightbox/ End of Cancer Progression Presentation What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Handout: Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Handout: Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer Distinct Clonal Populations within a single tumor respond to signals and to chemotherapy differently from one another leading to differential clonal evolution and clonal survival . These differences are not based solely on genetic heterogeneity. Epigenetic differences and tumor micro-environment affect clonal heterogeneity. Other unknown factors may support heterogeneity. See accompanying research article conclusions, pp 543 to 548. Normal Karyotype Fluorescent in situ hybridization (FISH) of normal metaphase human chromosomes using chromosome specific DNA probes with different fluorescent dyes Figure 1.11b The Biology of Cancer (© Garland Science 2007) Aneuploidy During Tumor Progression Aneuploid karyotype of human breast cancer cell. Note “scrambling” of colors demonstrating chromosomal reciprocal translocations Figure 1.11c The Biology of Cancer (© Garland Science 2007) Response Counter