Dr. Johnny Tang Department of Applied Biology & Chemical Technology, HKPU

1. Dr. Johnny Tang Department of Applied Biology & Chemical Technology, HKPU Department of Pathology, HKU Room Y 851 Office Tel: 3400 8727 E-mail: bccotang@polyu.edu.hk Johnny’s Teaching and Learning Homepage: http://myweb.polyu.edu.hk/~bccotang/index2.htm (or via Blackboard)

2. Introduction to General Pathology

3. Introduction to General Pathology: • Objectives: • To learn the function of adaptation as it relates to health and disease; • To understand the disease processes in terms of etiology, pathogenesis, morphology, clinical manifestations and prognosis; • To learn the reliability, validity, sensitivity, specificity, and predictive value as they relate to observations and tests used in the diagnosis of disease; • To study the etiology of cancers, their properties, molecular bases, host and environmental factors, and the related clinical manifestations

4. Introduction to General Pathology • Expected learning outcomes: • To explain the function of adaptation as it relates to health and disease; • To characterize the disease process in terms of etiology, pathogenesis, morphology, clinical manifestations and prognosis; • To explain the meanings of reliability, validity, sensitivity, specificity, and predictive value as they relate to observations and tests used in the diagnosis of disease; • To discuss the concepts associated with the etiology of cancer and the key features of clinical manifestations

5. Introduction to General Pathology • Recommended Textbook • Porth C. M. (2004 or newer). Pathophysiology. Concepts of Altered Health States. (5th or newer edition). Philadelphia: Lippincott • Other Textbooks • Nowak T.J. (2004 or newer). Pathophysiology: Concepts and applications for health care professionals (3rd or newer edition). McGraw Hill Higher Education • Carlson J. H. (1999 or newer). Pathophysiology (2nd or newer edition). Philadelphia: Lippincott • Mera S. L. (1997 or newer). Understanding disease: pathology and prevention. Cheltenham: Stanley Thomas Publishers Ltd. • McCance K. L. & Huether S. E. (2002 or newer). Pathophysiology: The biologic basis for disease in adults and children. (3rd or newer edition). St. Louis: Mosby

6. Health – WHO’s Definition • State of complete physical, mental, and social well-being and not merely the absence of disease and infirmity • US Department of Health and Human Services: interaction between an individual’s biology and behavior, physical and social environments, government policies and interventions, and access to quality health care

7. Health and Disease as States of Adaptation • Body’s physical and psychological adaptation to many stresses • Adaptation is affected by: • Availability of adaptive responses • Ability of body to select the most appropriate response • Decreased capacity of adaptation: • Immaturity of infant • Elderly

8. Disease and Pathophysiology – A Brief Review • Disease – any deviation from or interruption of the normal structure or function of a part, organ, or system of the body that is manifested by a characteristic set of symptoms or signs • Pathophysiology – cellular and organ changes that occur with disease; effects on total body function; mechanisms of disease • Aspects of disease processes – etiology, pathogenesis, morphological changes, clinical manifestations, diagnosis, and clinical course

9. Disease and Pathophysiology – A Brief Review(cont’d) • Etiology • Etiologic agents – biologic, physical forces, chemicals, nutritional excess or deficits • Defective molecules – gene defects (e.g. sickle cell anemia) • Multifactorial nature of diseases, e.g. cancer – predisposition of risk factors • Congenital conditions - defects present at birth; genetic and/or environmental factors • Acquired defects – acquired after birth; interaction with environment

10. Disease and Pathophysiology – A Brief Review(cont’d) • Pathogenesis • Sequence of cellular and tissue events that take place from the time of initial contact with an etiologic agent until the ultimate expression of a disease • Related to how disease process evolves, e.g. development of cancer after consuming food contaminated with carcinogens

11. Disease and Pathophysiology – A Brief Review(cont’d) • Morphology • Foundational structure or form of cells and tissues • Changes can involve both gross anatomic and microscopic features • Use of histological sections – histopathology • Detection of lesion – a pathologic or traumatic discontinuity of a body organ or tissue

12. Disease and Pathophysiology – A Brief Review(cont’d) • Clinical Manifestations • Signs – a manifestation that is noted by an observer, e.g. elevated temperature • Symptoms – a subjective complaint that is noted by the person with a disorder, e.g. pain and dizziness • Signs and symptoms can reflect primary disorders or compensatory changes (e.g. tachycardia that accompanies blood loss) • A single sign and symptom can imply different disease state, e.g. elevated temperature – infection, brain tumor, heat stroke, and many other disorders

13. Disease and Pathophysiology – A Brief Review(cont’d) • Diagnosis • Designation as to the nature or cause of a health problem • Careful history and physical examination • Weighing competing possibilities and selecting the most likely one – depending on age, sex, race, life-style, locality • Normality of diagnostic tests; statistics • Quality of data for diagnosis – reliability, validity, sensitivity, specificity and predictive value

14. Disease and Pathophysiology – A Brief Review(cont’d) • Diagnosis (cont’d) • Reliability – the accuracy for repeated observation • Validity – measuring what is intended to measure? • Sensitivity – how accurate is the true-positive result of a test or observation? • Specificity – how accurate is the true-negative result of a test or observation? • Predictive value – how good is a test or observation to predict the presence of a disease • +ve predictive value – proportion of true-positive observations in a population • -ve predictive value – proportion of true-negative observations in a population

15. Disease and Pathophysiology – A Brief Review(cont’d) • Clinical Course • Evolution of a disease • Acute (severe) , subacute and chronic (continuous; long term) course • Preclinical stage of disease – not clinically evident, but destined to progress to clinical disease, e.g. hepatitis B – virus can be transmitted at preclinical stage • Subclinical disease – not clinically apparent and not destined to become clinically apparent, e.g. some cases of tuberculosis; the presence is evidenced by skin test • Clinical disease – with signs and symptoms

16. Etiology of Cancer • Background of Cancer • Top leading cause of death, 2001-13 (Dep’t of Health, HKSAR Gov’t) • Affects all age groups • Disorder of altered cell differentiation and growth; lacks normal regulatory controls – proliferation, differentiation, apoptosis • Neoplasia – “new growth”; grows at the expense of the host • The behaviors of different tumor types depend on their parachymal (functional) origins

17. Etiology of Cancer Types of Neoplasms • Benign and Malignant Neoplasms • Benign tumor - well differentiated cells and clustered together in a single mass • not lethal unless its size and location affect other vital functions • Named with suffix –oma, e.g. adenoma, osteoma, papilloma * • Malignant tumor – less differentiated and show metastasis to other sites to form secondary malignant tumor • More lethal • e.g. carcinoma (epithelial origin; e.g. adenocarcinoma), sarcoma (mesenchymal origin; e.g. osteosarcoma) *

18. Examples of Benign and Malignant Tumors

19. Characteristics of Benign and Malignant Neoplasms

20. Etiology of Cancer Benign Neoplasms • Key features of benign neoplasms • Slower growth than malignant tumors • Inability to metastasize to distant sites • Well-differentiated cells • Enclosed in fibrous capsule – facilitates surgical removal, e.g. encapsulated fibroadenoma of the breast • Interference on other vital functions may cause death, e.g. compressing brain structures

21. Etiology of Cancer Malignant Neoplasms • Key features of malignant neoplasms • Grow more rapidly • Compress blood vessels and cause ischemia and tissue necrosis • Loss of contact inhibition • Metastasis • Solid and hematologic (non-solid) tumors • Malignancy is positively correlated to degree of anaplasia (lack of cell differentiation) *; histological assessment • Altered gene expression profile; tumor markers

22. Poorly and Well-differentiated Neoplasms

23. Etiology of Cancer Malignant Neoplasms • Invasion and Metastasis • Invasion - spreading of cancer cells • Seeding of cancer cells into body cavities, e.g. peritoneal, pleural, pericardial cavities • Metastasis – development of secondary tumor in a location distant from the primary tumor; via lymph channels (lymphatic spread) or blood vessels (hematogenic spread) • Metastatic sites can provide support to secondary tumor , e.g. transferrin (growth promoting) isolated from lung tissues • Clonality of multiple-site tumors – metastatic tumors share common properties (molecular or chromosomal) to the primary tumor; use of clonal markers

24. An Example of Detecting Chromosomal Abnormality in Cancer Cells (Full-article is HERE ; for reference only)

25. Abnormal Karyotype of Esophageal Cancer Cells (SLMT-1) as Clonal Markers† †Tang JCO, et al. Cancer Genetics and Cytogenetics, 124(1), 36-41 (2001)

26. An Example of Detecting Genetic Alterations in Esophageal Cancer (Full-article is HERE ; for reference only)

27. An Example of Altered Gene Expression in Esophageal Cancer (Full-article is HERE ; for reference only)

28. Another Example of Applying the Knowledge of Tumor Biology in Health-related Study

29. Another Example of Applying the Knowledge of Cell Biology in Health-related Study (cont’d)

30. Another Example of Applying the Knowledge of Cell Biology in Health-related Study (cont’d) (Full-article is HERE ; for reference only)

31. Other Suggested Journal Articles (Related to the Tumor Progression) • Novell PC. Mechanisms of Tumor Progression. Cancer Research 46:2203-2207 (1986) • Tang JCO, et al. Progression of spontaneous lymphomas in SJL mice: monitoring in vivo clonal evolution with molecular markers in sequential splenic samples. Laboratory Investigation 78:1459-1466 (1998)

32. Related findings (our previous and on-going work) Genomic Instability: Comparative DNA profiling (Tang et al.) and aCGH (Law et al.) analyses Molecular Targets: GAEC1 (Law et al.) & GAEC2 (chr 7q) JS-1 (Fatima et al.) & JK-1(Tang WK et al.) (chr 5p) Timm22, NM3585 & NP3694 (chr 17p) ESCC Cell Lines (HK): SLMT-1 (Tang et al.) , HKESC-1, HKESC-2, HKESC-3 (Hu et al.), HKESC-4 (Cheung et al.)

33. Etiology of Cancer Malignant Neoplasms • Invasion and Metastasis (cont’d) • Primary tumors secrete enzymes to break extracellular matrix and get access to blood vessels • Escape from the host immune response, e.g. forming tumor emboli with blood platelets * • Express cell surface attachment factors, e.g. laminin receptors, for anchoring to capillary basement membrane • Collagenase for degrading the basement membrane and migration to interstitial area to form secondary tumor • Metastatic tumors secrete angiogenic factors to enable growth of new vessels – angiogenesis

34. The Pathogenesis of Metastasis

35. Etiology of Cancer Malignant Neoplasms • Tumor Growth • More cells enter cell cycle than the normal counterparts; faster growth of cancerous tissues (greater value of growth fraction and shorter doubling time) • Undetectable until there are about 1 billion cells (~ 1cm in diameter) in a solid tumor *

36. Growth Curve of a Tumor

37. Etiology of Cancer Molecular Basis of Cancer • Molecular mechanisms of oncogenesis • Cause the transformation (changes) of normal cell physiology (functions) into cancer • Involve changes of genes which control cell growth and replication: proto-oncogenes, tumor suppressor genes, genes for controlling apoptosis and DNA repairing • Oncogenesis is a multi-factorial event at molecular level • Oncogenes – promote growth of cancer cells; derived from mutated proto-oncogenes (e.g. change in DNA sequence, amplification, overexpression) ; targets of therapeutic agents

38. Oncogenes in ESCC • Growth factors, e.g. EGF, TGF, hst-1/int-2 • Growth factor receptors, e.g. erbB-1 & -2, EGFR • Signal transducers, e.g. c-ras, frat1 • Nuclear factors, e.g. c-myc, cyclinD1, mdm-2 Epidermal growth factor receptor (EGFR) signal transduction pathways Clinical anti-epidermal growth factor receptor (EGFR) therapies Adopted from Claudia Mar´ıa Valverde C, et al. Critical Reviews in Oncology/Hematology 59, pp129, 2006

39. Etiology of Cancer Molecular Basis of Cancer • Molecular mechanisms of oncogenesis (cont’d) • Tumor suppressor genes – inhibit cell proliferation in normal cells; related to normal signaling pathways* • e.g. TP53 genes in chromosome 17p13 region encode p53 protein (a cell cycle regulator protein; regulator of apoptosis) • mutation correlates with development of many cancers and suggested as a prognostic marker for chemo- and radiotherapy • p53 also inhibits angiogenesis through induction of anti-angiogeneic factors, e.g. thrombospondin-1

40. Controls of Cell Growth and Replication

41. Etiology of Cancer Molecular Basis of Cancer • Molecular mechanisms of oncogenesis (cont’d) • Three stages of cell transformation leading to malignant tumors: initiation, promotion, progression • Initiation – exposure of cells to appropriate doses of carcinogenic agents; more susceptible to malignant transformation • Chemical, physical or biological factors; irreversible changes of genome of normal cells • Promotion – induction of accelerated growth in initiated cells • Chemicals or growth factors • Progression – tumor cells acquired malignant phenotypes are further promoted to increase invasiveness, metastatic competence, growth tendencies *

42. Clonal Evolution of Malignant Tumors

43. Etiology of Cancer Host and Environmental Factors for Carcinogenesis • Interactions among multiple risk factors to host’s cells • Risk factors: heredity, hormones, immunologic mechanisms, chemical carcinogens, radiation, oncogenic viruses • Heredity • Implicated in most cancer types; family history; carrier of gene mutations in cancer-related genes (oncogenes and tumor suppressor genes) • Hormones • Usually associated with tumors which are responsive to sex hormones, e.g. breast, ovarian, endometrial and prostate cancers • Implications on hormone supplements to the cancer risk

44. Etiology of Cancer Host and Environmental Factors for Carcinogenesis • Immunologic mechanisms • Cancer development is associated with impaired immune system • Increased cancer incidence found in: • Patients with immunodeficiency diseases; • Patients with organ transplants who received immunosuppressant drugs; • Elderly in whom the immune activities have declined; • B- and T-lymphocytes, antibodies, macrophages and NK cells are all involved in suppressing the growth of antigenic tumor cells

45. Etiology of Cancer Host and Environmental Factors for Carcinogenesis • Chemical Carcinogens • Dose and exposure-time dependent • Two groups: direct-reacting agents and indirect-reacting agents • Direct-reacting agents – no activation is required to become carcinogenic • Indirect-reacting agents – become carcinogenic after metabolic conversion, e.g. aflatoxins • Bind to DNA, RNA and proteins of cells to cause mutation and alterations of enzyme and structural proteins synthesis; altered cell replication and regulatory controls • Life style: smoking, dietary factors, alcohol consumption

46. Etiology of Cancer Host and Environmental Factors for Carcinogenesis • Radiation • Exposure to ionizing radiation has been well correlated to cancer risk in different professions • Time related - children exposed to ionizing radiation in utero increased the risk of early (2-3 yr-old) childhood leukemia; longer latency period (5 to 10 years) if exposed after birth. • Exposure of sunlight (ultraviolet radiation) to risk of skin cancer – intensity, body-site and melanin dependent

47. Etiology of Cancer Host and Environmental Factors for Carcinogenesis • Oncogenic viruses • Infection related to cancer development and etiology • Common examples: human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), human herpevirus-8 (HHV-8) • HPV -- squamous cell carcinoma of cervix • EBV -- lymphoma, nasopharyngeal carcinoma (NPC) • HBV -- hepatocellular carcinoma • HHV-8 – Kaposi’s sarcoma (malignancy of endothelial cells of small blood vessels)

48. Clinical Manifestations of Cancer • Initial manifestations can reflect the primary site of involvement, e.g. impaired pulmonary function for lung cancer patients • Other generalized manifestations are also found, e.g. fatigue, anorexia, weight loss, anemia • Tissue Integrity • Cancers disrupt tissue integrity, compress and erode blood vessels, leading ulceration, necrosis and possible hemorrhage • Tissues damaged by cancer growth do not heal normally • Obstruction of adjacent structures, e.g. abdominal cancers can cause bowel obstruction • Obstruct lymph node and penetrate serous cavities, e.g. pleural effusion, ascites

49. Clinical Manifestations of Cancer • Cancer Cachexia • Weight loss, wasting of body fat and proteins, weakness, anorexia and anaemia; decrease in survival time • Also called cancer anorexia-cachexia syndrome; severity increased with progression • Anorexigenic factors (from damaging cells, host cells and tumors) act on the satiety centers of hypothalamus • Cytokines (e.g. TNF- from macrophages) suppress the satiety centre, induce inflammatory responses, suppress bone marrow stem cell division • Hypermetabolic state – large amount lactate produced by tumors activates gluconeogenesis in liver to make more glucose to support tumor’s metabolic needs; over use of amino acids for gluconeogenesis leading to decreased muscle mass

50. Clinical Manifestations of Cancer • Paraneoplastic Syndromes • Manifestations in sites which are not directly affected by tumors • Endocrinologic, hematologic, neurologic and dermatologic nature* • Can be the early indications of cancer • Endocrinologic type - abnormal biochemical pathways of hormone synthesis in tumors • Abnormality due to changes in hormonal levels