Carcinogenesis - World Toxicologic Pathology Congress

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Index of Slides

1. Carcinogenesis World Toxicologic Pathology Congress April 21st to 26th 2018 São Paulo, SP, Brazil https://focusontoxpath.com
2. Carcinogenesis The process by which normal cells are transformed into cancer cells
3. CARCINOGENESIS OUTLINE • Introductory Comments • Overview of carcinogenesis • Lexicon of pathology • Basics of carcinogenesis
4. Overview of Carcinogenesis • Complex disease with multiple causes • Influenced by multiple intrinsic and extrinsic factors • Multistep progressive process at the genetic and phenotypic level • Two main components • Hereditary (genetics) • Non-heredity
5. Heredity & Non-Heredity • Heredity (Genetics & Epigenetics) • BRCA1 & 2 susceptibility genes – breast & ovarian cancer • Familial adenomatous polyposis – colon cancer • Xeroderma pigmentosa & squamous cell carcinoma • Non-Heredity • 5% Viral/infectious (Epstein-Barr virus & lymphoma; Helicobacter pylori & gastric carcinoma) • 5% Radiation (ultraviolet – BCC & SCC; radon – lung CA) • 90% Chemically related • Environmental (pollutants), occupational, dietary (fried food, red meats), medicinal, life-style (smoking; stress)
6. Overview of Cancer • Complex disease with multiple causes • Influenced by multiple intrinsic and extrinsic factors • Multistep progressive process at the genetic and phenotypic level • Two main components • Hereditary (genetics) • Non-heredity • Uncontrolled increase in cell proliferation
7. A Short Reminder Before Considering Some Definitions Used by Pathologists • Cell proliferation cycle • Programmed cell death cycle
8. From Robbins and Cotran Pathologic Basis Of Disease, 7th Edition, 2004.
9. CARCINOGENESIS OUTLINE • Introductory Comments • Overview of carcinogenesis • Lexicon of pathology • Basics of carcinogenesis
10. Lexicon of Carcinogenesis • Neoplasia (tumor, neoplasm, cancer) • Hyperplasia • Physiological • Pathological • Hypertrophy • Metaplasia • Dysplasia • Anaplasia
11. Tumor Tumor = swelling of a part of the body Soccer goalie after being kicked by the member of the other team
12. Defining “Tumor” in the Context of Carcinogenesis • Tumor – a swelling of a part of the body, generally without inflammation, caused by an abnormal growth of tissue, whether benign or malignant
13. These Terms Used Interchangeably • Tumor – a swelling of a part of the body, generally without inflammation, caused by an abnormal growth of tissue, whether benign or malignant • Cancer – a malignant growth or tumor resulting from uncontrolled proliferation of abnormal cells • Neoplasm – a new and abnormal growth of tissue in some part of the body, especially as a characteristic of cancer
14. Definitions are Context Driven • Depending upon the context in which these terms are used: • Tumor = Cancer = Neoplasm • Carcinogenesis = Tumorigenesis = Neoplasia • Researchers, clinicians & the general public tend to use tumor, cancer, and neoplasm as if they are synonymous • In general use, the term tumor is usually qualified as benign or malignant while the term cancer is more typically considered malignant
15. Is It a Tumor? A Cancer? A Neoplasm? Normal Mouse Liver Mouse Liver with a Lesion
16. Neoplasia “….abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change” Willis 1952.
17. • Neoplasia (neoplasm, tumor, cancer) • Hyperplasia • Physiological • Pathological • Hypertrophy (and atrophy) • Metaplasia • Dysplasia • Anaplasia Lexicon Related to Carcinogenesis
18. Hyperplasia = increase in the number of cells in an organ or tissue • Typically adaptive and physiological changes • Increased volume of the organ or tissue Hypertrophy = increase in the size of cells in an organ or tissue Hypertrophy and Hypertrophy
19. Hyperplasia and Hypertrophy
20. Muscle Hypertrophy
21. • Physiological hyperplasia • Hormonal – mammary gland proliferation at puberty • Compensatory – myth of Prometheus • Pathological hyperplasia • Excessive (potentially reversible) hormonal stimulation • Excessive (but controlled) growth factor stimulation Two Categories of Hyperplasia
22. Physiological hyperplasia Hormonal – mammary gland proliferation at puberty Compensatory – myth of Prometheus
23. Physiological hyperplasia Hormonal – mammary gland proliferation at puberty Compensatory – myth of Prometheus Prometheus stole fire from Zeus and gave it to mortals. Zeus punished him by chaining him to a rock while a great eagle ate his liver every day only to have it grow back and get eaten again every day.
24. Mechanisms of physiological hyperplasia Increased local growth factors and/or receptors Activation of intracellular signaling pathways Transcription factors turn on specific genes Cell cycle genes ~70 other genes
25. Proliferation of existing cells and also stem cells Hepatectomy – paracrine stimulation from cytokines & polypeptide growth factors
26. Pathological hyperplasia Excessive (potentially reversible) hormonal stimulation Excessive (but controlled) growth factor stimulation May be associated with concurrent toxicity Normal uterus Physiological hyperplasia of uterus Pathological hyperplasia of uterus
27. Mechanisms of pathological hyperplasia Exaggerated response to growth factors and/or hormonal stimulation Hormone imbalance – excessive androgens & benign prostatic hyperplasia Wound healing – a specific form of hyperplasia where parenchymal cells are replaced by scar tissue Viral infections – papilloma virus-induced growth factors leading to skin warts and mucosal epithelial hyperplasias Chronic hepatitis – oval cells and hepatocytes proliferate Oval cell proliferation in liver Cirrhosis
28. • Physiological hyperplasia • Hormonal – mammary gland proliferation at puberty • Compensatory – myth of Prometheus • Pathological hyperplasia • Excessive (potentially reversible) hormonal stimulation • Excessive (but controlled) growth factor stimulation Two Categories of Hyperplasia
29. Lexicon Related to Carcinogenesis • Hyperplasia • Physiological • Pathological • Hypertrophy • Metaplasia • Dysplasia – bad formation • Anaplasia – backward formation (undifferentiated)
30. Metaplasia – one mature adult cell type replaced by another mature adult cell type Adaptive process – more sensitive cells replaced by cells less sensitive cells to an adverse environment Frequently – columnar epithelium to squamous epithelium Cigarette smoke Vitamin A deficiency Mesenchymal metaplasia – connective tissue  osseous tissue If stimulus persists – malignant transformation of the metaplastic cells can occur
31. Mechanisms of metaplasia •Differentiation of stem cells along a new pathway •Cytokines, growth factors, and extracellular matrix components induce transcription factors that trigger phenotypic-specific genes •Vitamin A affects differentiation pathways of stem cells •Some cytostatic drugs disrupt DNA methylation with potential to lead to metaplasia 6-Mercaptopurine Methotrexate Dacarbazine Procarbazine Carboplatin
32. Lexicon Related to Carcinogenesis • Hyperplasia • Physiological • Pathological • Hypertrophy (& atrophy) • Metaplasia • Dysplasia – bad formation • Anaplasia – backward formation (undifferentiated)
33. Dysplasia is not Exclusively Related to Carcinogenesis Canine Hip Dysplasia
34. Dysplasia is not Exclusively Related to Carcinogenesis Normal Fibro-osseous Dysplasia
35. Morphological Aspects of Dysplasia • Pleomorphism = variation in size and shape • Abnormal nuclear morphology • Hyperchromatism • Karyomegaly • Large nucleoli • Mitoses tend to be increased • Giant cells & multinucleated cells
36. Morphological aspects of dysplasia •Pleomorphism = variation in size and shape •Abnormal nuclear morphology •Hyperchromatism •Karyomegaly •Large nucleoli •Mitoses tend to be increased •Giant cells and multinucleated cells
37. Another example of multinucleated giant hepatocytes. Chronic exposure to chlordane in a mouse.
38. Dysplasia = disordered growth Primarily an epithelial change Constellation of changes Loss of polarity Loss of uniformity Pleomorphism Nuclear abnormalities Normal forestomach Forestomach dysplasia If marked and involves the entire thickness of the epithelium but is confined there = carcinoma in situ
39. Lexicon Related to Carcinogenesis • Hyperplasia • Physiological • Pathological • Hypertrophy (& atrophy) • Metaplasia • Dysplasia – bad formation • Anaplasia – backward formation (undifferentiated) The terms dysplasia and anaplasia have varied definitions depending on the author and are often used interchangeably or together.
40. Differentiation and Anaplasia •Differentiation in neoplasia refers to morphological and functional similarity to normal •Anaplasia is lack of differentiation •Benign tumors are typically well-differentiated •Malignant tumors range from some degree of differentiation to loss of differentiation •Anaplasia = “to form backward” •The terms anaplasia & dysplasia often used together
41. Normal Mouse Trachea
42. Normal mouse trachea
43. 90-Day Formaldehyde Inhalation Study in Mice
44. 90-Day Formaldehyde Inhalation Study in Mice
45. Squamous metaplasia Normal columnar epithelium
46. 90-Day Formaldehyde Inhalation Study in Mice Squamous metaplasiaDysplasia
47. • -plasia = formation • Neoplasia – new formation • Hyperplasia – enhanced formation • Metaplasia – changed formation • Dysplasia – abnormal formation SUMMARY Lexicon Of Carcinogenesis
48. CARCINOGENESIS OUTLINE • Introductory Comments • Overview of carcinogenesis • Lexicon of pathology • Basics of carcinogenesis
49. Molecular/Genetic Factors Involved in Carcinogenesis • Non-lethal genetic damage • Alteration of normal regulatory genes • Growth promoting proto-oncogenes • Growth inhibiting cancer suppressor genes • Genes that regulate programmed cell death (apoptosis) • Alteration of genes that regulate DNA repair • Epigenetic changes (methylation, imprinting) • Multistep cascade of events
50. Basics of Carcinogenesis • Genetic (molecular) factors • Morphologic factors • Modulators and modifiers
51. GENETIC DAMAGE BIOLOGICAL STATES FIGURE 1. Process of carcinogenesis depicted schematically showing the postulated pathway in which accumulation of genetic damage leads to malignant neoplasia. Normal somatic or germinal cell Predisposed somatic cell Homozygous clone Selective growth Persistent growth Malignant growth HISTOPATHOLOGIC FEATURES CLINICAL FEATURES OPERATIONAL PHASES MECHANISMS INITIATION PROMOTION PROGRESSION Persist as latent genetic change Redifferentiate (disappear) or persist Expansive growth (Conversion) PATHOLOGIC HYPERPLASIA and PRENEOPLASIA BENIGN NEOPLASM MALIGNANT NEOPLASM Invasion Metastasis Permanent genetic damage Differential growth stimulus Transformation & oncogene/suppressor gene involvement Chromosomal alterations & oncogene/suppressor gene involvement
52. GENETIC DAMAGE BIOLOGICAL STATES FIGURE 1. Process of carcinogenesis depicted schematically showing the postulated pathway in which accumulation of genetic damage leads to malignant neoplasia. Normal somatic or germinal cell Predisposed somatic cell Homozygous clone Selective growth Persistent growth Malignant growth HISTOPATHOLOGIC FEATURES CLINICAL FEATURES OPERATIONAL PHASES MECHANISMS INITIATION PROMOTION PROGRESSION Persist as latent genetic change Redifferentiate (disappear) or persist Expansive growth (Conversion) PATHOLOGIC HYPERPLASIA and PRENEOPLASIA BENIGN NEOPLASM MALIGNANT NEOPLASM Invasion Metastasis Permanent genetic damage Differential growth stimulus Transformation & oncogene/suppressor gene involvement Chromosomal alterations & oncogene/suppressor gene involvement DNA Repair
53. GENETIC DAMAGE BIOLOGICAL STATES FIGURE 1. Process of carcinogenesis depicted schematically showing the postulated pathway in which accumulation of genetic damage leads to malignant neoplasia. Normal somatic or germinal cell Predisposed somatic cell Homozygous clone Selective growth Persistent growth Malignant growth HISTOPATHOLOGIC FEATURES CLINICAL FEATURES OPERATIONAL PHASES MECHANISMS INITIATION PROMOTION PROGRESSION Persist as latent genetic change Redifferentiate (disappear) or persist Expansive growth (Conversion) PATHOLOGIC HYPERPLASIA and PRENEOPLASIA BENIGN NEOPLASM MALIGNANT NEOPLASM Invasion Metastasis Permanent genetic damage Differential growth stimulus Transformation & oncogene/suppressor gene involvement Chromosomal alterations & oncogene/suppressor gene involvement
54. GENETIC DAMAGE BIOLOGICAL STATES FIGURE 1. Process of carcinogenesis depicted schematically showing the postulated pathway in which accumulation of genetic damage leads to malignant neoplasia. Normal somatic or germinal cell Predisposed somatic cell Homozygous clone Selective growth Persistent growth Malignant growth HISTOPATHOLOGIC FEATURES CLINICAL FEATURES OPERATIONAL PHASES MECHANISMS INITIATION PROMOTION PROGRESSION Persist as latent genetic change Redifferentiate (disappear) or persist Expansive growth (Conversion) PATHOLOGIC HYPERPLASIA and PRENEOPLASIA BENIGN NEOPLASM MALIGNANT NEOPLASM Invasion Metastasis Permanent genetic damage Differential growth stimulus Transformation & oncogene/suppressor gene involvement Chromosomal alterations & oncogene/suppressor gene involvement
55. Growth Factors • Normal development • Embryogenesis • Normal cell function • Locomotion, contractility • Regeneration • E.g., hepatectomy • Repair • Wound healing • Scar tissue formation
56. Growth Factors • Normal development • Embryogenesis • Normal cell function • Locomotion, contractility • Regeneration • E.g., hepatectomy • Repair • Wound healing • Scar tissue formation From Robbins and Cotran Pathologic Basis Of Disease, 7th Edition, 2004.
57. From Robbins and Cotran Pathologic Basis Of Disease, 7th Edition, 2004.
58. Proto-oncogene Proto-oncogene: A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer. Proto-oncogenes may have many different functions in the cell. Some proto- oncogenes provide signals that lead to cell division. Other proto-oncogenes regulate programmed cell death (apoptosis).
59. Multiple Roles of Proto-oncogenes • Participate in functions related to cell growth and proliferation • Encode proteins that function as: • Growth factor ligands • Growth factor receptors • Signal transducers • Transcription factors • Cell cycle components
60. From Robbins and Cotran Pathologic Basis Of Disease, 7th Edition, 2004.
61. Proto-oncogene Activation Growth Factor (Proto-oncogene) [Mode of Action] PDGF-β (SIS) [overexpression] FGF (HST-1; INT-2) [overexpression; amplification] TGTFa (TGFα) [overexpression] HGF (HGF) [overexpression] Growth Factor Receptor (Proto-oncogene) [Mode of Action] EGF receptors (ERB-B1