Applied Pathophysiology Lecture Notes PDF

Lecture Material is adapted from © 2022 Wolters Kluwer Health, Lippincott Williams & Wilkins Applied Pathophysiology: A Conceptual Approach to the Mechanisms of Disease Chapter 7: Altered Cellular Proliferation and Differentiation Module 1: The Impact of Cancer on the Cell Dr. Romeo Batacan Jr. M...

Lecture Material is adapted from © 2022 Wolters Kluwer Health, Lippincott Williams & Wilkins Applied Pathophysiology: A Conceptual Approach to the Mechanisms of Disease Chapter 7: Altered Cellular Proliferation and Differentiation Module 1: The Impact of Cancer on the Cell Dr. Romeo Batacan Jr. MPAT12001 Medical Pathophysiology Lecture Series Copyright © 2017 Wolters Kluwer Health | Lippincott Williams &Wilkins Bullock S, Hales M. Principles of pathophysiology. 1st ed. Frenchs Forest, Pearson Australia; 2012. Bullock S, Hales M. Principles of pathophysiology. 1st ed. Frenchs Forest, Pearson Australia; 2012. Cancer Uncontrolled proliferation of cells Derived from Greek word for crab, carcinos and carcinoma Hippocrates (Greek physician) description: finger like projections Celsus (Roman physician) translation: cancer Malignant growths or tumours Also referred to as a neoplasm – "new growth" Can be a chronic disease characterized by remission and relapse Not all tumors or neoplasms are cancerous Cell proliferation Process of increasing cell numbers Generation of new daughter cells Normal tissue: regulated process Actively dividing equivalent to number of dying/shed Injury increase reproduction Humans have 2 major categories of cells: gametes + somatic cells Gametes: meiosis Somatic cells: mitosis 200 cell types in our body divided into 3 large groups: Undifferentiated stem cells that can be triggered to enter cell division when needed Progenitor or parent cells that continue to divide and reproduce (blood, skin) Well differentiated and rarely divide/reproduce cells (neurons, cardiac and skeletal muscle) Cell differentiation The process whereby proliferating cells become progressively more specialized cell types Results in fully differentiated adult cells: Specific structure Specific function Specific life expectancy ie. RBC is terminally differentiated: concave, oxygen carrier, 120 days All of our cells is from the fertilized ovum Specialization is exchanged for the loss of ability to develop into different cell types Stem cells Highly undifferentiated Reserve cells, potential to divide into progenitor cell Stem cell division: stem cell + progenitor Two properties: self‐renewal and potency Normal cell Grow, divide and differentiate Aware of their neighbours and curb their growth to accommodate them Monitor their own growth Respond to their environment Die when required Carcinogenesis Carcinogenesis: the origin and development of cancerous neoplasms Neoplasms: irreversible deviant cellular developments Cancer: highly invasive and destructive neoplasms Do not respond to cellular proliferation and differentiation Can develop from proliferating parenchymal (functional) tissue/organ proliferating stromal (supportive) cells Labile cells (ie. epithelial cells, blood cells) highly prone to neoplasm development Permanent (undividing) cells (neurons, mature cardiac cells) are not prone Genetics basis of cancer 1. Cancer arises through genetic mutations 2. Multiple mutations are required Genetic mutation may be Acquired (after conception): exposure, spontaneous Inherited or germline (before birth) Inherited predisposition: high risk of developing cancer Exposure to mutagens, spontaneous mutation If the mutation occurs in somatic cells, it is not passed to offspring If the mutation occurs in germline cells, it can be passed to future generations Genetics basis of cancer Body cells are not immortal and can only divide a limited number of times Telomeres are protective caps (repetitive sequences) on each chromosome Telomeres become smaller and smaller with each cell division Cancer cells become immortal by repairing telomeres Bullock S, Hales M. Principles of pathophysiology. 1st ed. Frenchs Forest, Pearson Australia; 2012. Role of genes 1. Mutator genes 2. Oncogenes 3. Tumor suppressor genes  Altered Genes Leading to Cancer: MutatorGenes DNA is constantly being damaged Mutator genes repair DNA and protect genome Mutations in mutator genes: DNA damage is not repaired Cells become unstable Large number of mutations in mutator genes required for cancerous neoplasm  Altered Genes Leading to Cancer:Oncogenes Oncogene: cancer gene Mutant genes that in their non‐mutant state (proto‐oncogenes) direct protein synthesis and cellular growth Mutant state: Promote unregulated cell growth and development Inhibit cell death Activation: proto‐oncogene (normal gene) becomes oncogene Rare activation (spontaneous mutation) in germ line: incompatible with life Spontaneous abortion or develop into inheritable neoplasms More common: activation (spontaneous mutation) in somatic cells  Altered Genes Leading to Cancer:Oncogenes Proto‐oncogenes are normal genes Have vital role in regulating cell function Precursor genes Activated through 1 of 3 ways: 1. Point mutations 2. Translocation 3. Gene amplification  Altered Genes Leading to Cancer:Oncogenes 3 basic actions of oncogenes: Encoding growth factors to stimulate cell overproliferation Disturbing cell surface receptors and restricting cell‐to‐cell communication Encoding proteins in the cell nucleus to alter cell cycle, restrict apoptosis, impact on differentiation  Altered Genes Leading to Cancer: Tumor suppressor genes Regulate the rate at which cells divide and die Cell becomes immortal Unrestricted proliferation and neoplastic transformation Can occur in germline or somatic cells Intact tumor suppressor genes: controlled growth, restricted Mutated tumor suppressor genes: uncontrolled growth, unrestricted 3 common when mutated neoplasms form p53 Retinoblastoma (Rb) BCL‐2 gene Altered Genes Leading to Cancer: Cancer Cancer promotion prevention Carcinogens Identification: Epidemiology studies Experimental research Cell and molecular pathology Carcinogen: Known cancer causing agent Interfere with molecular pathways Initiate tumors Promote tumors Direct: cause modification in cell’s DNA Indirect: induce immunosuppression, chronic inflammation, act with others Identification is difficult Prolonged latent period The Hateful 13 McCance KL, Huether S. Pathophysiology. 7th ed. N.S.W, Mosby; 2015  Carcinogens Bullock S, Hales M. Principles of pathophysiology. 1st ed. Frenchs Forest, Pearson Australia; 2012. Carcinogenesis Initiation‐Promotion‐Progression theory Initiating event must be combined with a promoting event 1. Initiating event (initiator): causes mutation in a cell 2. Promoting event (promoter): expansion of the mutated cell’s growth Continuing exposure to promoter required Common promoters: chronic inflammation Chronic gastritis >> gastric cancer Ulcerative colitis >> colorectal cancer hormones chemicals in environment Carcinogenesis Initiating event must be combined with a promoting event Carcinogenesis: 3. Progression: extension of promotion phase Cancerous growth NO longer depend on promoter Growth become autonomous Cancerous cell functioning without regulation Growth Division Death (Apoptosis) Multifactorial etiology Initiation-Promotion-Progression Summary Craft AJ, Gordon C, Tiziani A. Understanding pathophysiology. 1st ed. Chatswood, Mosby; 2011