Pathophysiology of Cancer - Lecture 5 - IBSI

PATHOPHYSIOLOGY CANCER Ass. Prof. Eman Ramadan & Yasmeen M Attia, PhD Lecture 5 Department of Pharmacology, BUE What best describes epigenetics? -Study of alterations in the DNA sequence. -Study of heritable phenotype changes not involving changes in the DNA sequence. -Study...

PATHOPHYSIOLOGY CANCER Ass. Prof. Eman Ramadan & Yasmeen M Attia, PhD Lecture 5 Department of Pharmacology, BUE What best describes epigenetics? -Study of alterations in the DNA sequence. -Study of heritable phenotype changes not involving changes in the DNA sequence. -Study of genotypes of complex organisms. -Study of gene activity What are histones? a) Lipids b) Carbohydrates c) Nucleotides d) Proteins Which of the following is not a non-coding RNA? a) mRNA b) tRNA c) rRNA d) miRNA Monozygotic (MZ) twins have identical genotypes and, at birth, epigenetic patterns are similar in MZ twins. What happens to these epigenetic patterns as the twins age? a) Become more different b) Remain similar A genomic DNA possesses functioning units, a group of genes under the influence of promoters known as (a) genes (b) operons (c) anticodon (d) codon Seemingly, the vertebrate cells contain a protein which binds to clusters of 5-methylcytosine ensuring that the bound gene stays in the “off” position. This regulation on the role of gene regulation is an outcome of (a) Methylation (b) Translation (c) Enhancer expression (d) operator suppression. A chromosome is the thickest during (a) anaphase (b) prophase (c) interphase (d) metaphase  ILOs Discuss the genetic basis of carcinogenesis. Describe the genes involved in tumourigenesis and mechanism of involvement in tumour development. Realise the multistep process of tumourigenesis Differentiate types of genetics alterations in cancer development Determine role of cancer genetics in diagnosis and treatment. Introduce concept of tumour biology and targeted therapy 9  Principles of cancer genetics Cancer is a genetic disease at the somatic cell level Mutation causing cancer could be induced by environmental agents (sporadic cancer) or may be inherited (inherited cancer) 10  Cancer Arises From Gene Mutations Germline mutations Somatic mutations Parent Child All cells Somatic Mutation mutation affected in in egg or offspring (eg, breast) sperm Present in egg or sperm Occur in nongermline Are heritable tissues Cause cancer family Are nonheritable syndromes 11 12  Genetic changes that is inherited and passed onto the off springs is called Germ line mutations 13 14 15  Tumors Are Clonal Expansions Normal Tumor 16  Cancer Growth Detach that from It is the of Abnormal tend to original cells site Spread Invade To distant & Neighboring body sites tissue 18 Cancer All cancer involve changes in genes….. During mitosis and DNA replication. Mutations are normally corrected by DNA repair mechanisms If repair mechanisms or cell cycle regulation is damaged Cell accumulates too many mutations….tumor develops 19 The principal targets of genetic Mutations  Four classes of normal regulatory genes: Growth-promoting ( proto-oncogenes ) Growth-inhibiting (tumor suppressor genes) Genes that regulate programmed cell death (apoptosis) Genes involved in DNA repair 20 21 22 23  Cancer It is a condition of: Uncontrolled Cellular Proliferation that Knows no limits & Serves no purpose for the host  Cancer The term refers to > 100 Forms of the disease Although Each Cancer has unique features, All Cancers develop by following a Few Shared Processes (differ substantially from those of normal cells) that depend upon Crucial Genetic Alterations  Cancer For a cell To Become Cancerous, these genetic alterations: Must Stimulate Cell Growth, Inactivate genes that normally slow growth, & immortalizing preventing apoptosis Genetic Alterations Must occur that allow Cancer Cells To: - recruit normal cells to support & nourish them & - prevent the immune system from destroying them Physiological Concepts 1- Cellular Reproduction 2- Cellular Differentiation 3- Cellular Recognition & Adhesion to Like Cells 4- The Cell Clock  1- Cellular Reproduction All Cells reproduce during embryogenesis But Certain Cells continue to do so after birth - such cells by going through Tightly Controlled Cell Cycle (variety of genes responding to cues on cell crowding, tissue injury, & growth needs), replicate their DNA exactly before splitting into two new daughter cells Cells go through cell cycle when stimulated by: Hormones & growth factors secreted by distant cells, & by Growth factors produced locally, & by Chemicals released from neighboring cells, including Cytokines produced by immune & inflammatory cells  1- Cellular Reproduction These cues: Bind to Specific Receptors on target cell Form a complex that Activates a Second Messenger System, which Delivers the Growth Signal to the Nucleus - Certain Genes are activated to produce Certain Proteins (Transcription Factors), Turn On or Off Specific Genes to produce Other Proteins that Control Cell Proliferation Activated Genes also produce Proteins that Feed Back On each step of signaling & messenger stimulation to amplify or minimize the effects of the initial stimulus  1- Cellular Reproduction In Fact, the Two Broad Categories of Genes whose end products ultimately control the cell cycle are: Tumor Proto- Suppressor Oncogenes Genes  Control of Cellular Reproduction 1- Hormones, Growth Factors, & Chemicals 2- Physical Cues 3- Cytoplasmic Second Messenger System 4- Tumor Suppressor Genes 5- Proto-Oncogenes  Control of Cellular Reproduction 1- Hormones, Growth Factors, & Chemicals May stimulate cells to increase or decrease their rate of reproduction. Some Growth Substances stimulate cell division & growth in target cells While inhibit them in other cells Certain Chemicals may be Released By injured or infected neighboring cells or By immune & inflammatory cells drawn to an area after tissue injury  Control of Cellular Reproduction 2- Physical Cues Neighboring cells communicate with each other about tissue crowding & tissue type by releasing locally active chemicals, & by passing ions & other small molecules through channels (Gap Junctions) Normal cells : this allows cellular growth & proliferation to be controlled based on tissue space requirements These communication methods allow cells to recognize other cells of the same type (e.g. kidney cells recognize other kidney cells)  Control of Cellular Reproduction 3- Cytoplasmic Second Messenger System The Cytoplasmic Signal Cascade begins after a protein hormone, growth factor, or other chemical binds to a cell membrane receptor & Turns on a Specific Second Messenger System Activated Cytoplasmic Second Messenger Proteins (e.g. ras Protein) relay the growth-controlling signal to the Nuclear Transcription Proteins The Normal ras Protein Transmits Stimulatory Signals from bound growth factor receptors on a cell’s membrane To Other Proteins down the line that ultimately Turn on Cell Cycling  Control of Cellular Reproduction 3- Cytoplasmic Second Messenger System Many Cancer Cells show a Mutation in the Gene that produces the ras Protein, such that it is always produced (Uncontrolled Cellular Proliferation even when growth factors are not present) This Gene Mutation was discovered as the First Human Oncogene in Bladder Cancer Cells - Hyperactive ras Proteins are found in about 1/4 of All Human Tumors  Control of Cellular Reproduction 4- Tumor Suppressor Genes Control Cell Cycle (Code for Proteins that Inhibit Cellular Growth & Reproduction) In All Normally Functioning Cells, they are vitally important Although Cancer Results From Accumulated Mutations, the Code for Proteins that Slow Down or Stop the second messenger, First Mutation that sets a cell on its way to becoming cancerous Often including proteins that Interfere with the Functioning of the occurs in one of the tumor suppressor genes - For Cancer To Occur, the Stimulatory ras Protein tumor suppressor gene Must Be Inactivated Although Cancer Results From Accumulated Mutations, the First Mutation that sets a cell on its way to becoming cancerous Often occurs in one of the tumor suppressor genes - For Cancer To Occur, the tumor suppressor gene Must Be Inactivated  Control of Cellular Reproduction 4- Tumor Suppressor Genes May Also Code for Proteins that make up surface receptors that bind growth-inhibiting hormones or factors Others, when activated, Stimulate a damaged cell to undergo Apoptosis Some including the Rb Gene Rb Gene & the p53 p53 & the GeneGene produceproduce Proteins Proteins that that Code Code for for Important Important Brakes Brakes that that act act directly directly on on cells cells about about to to commit commit to to going going through through the the cell cell cycle cycle  Examples for Tumor Suppressor Genes 1- The Rb Gene Codes for the Rb Protein, the Master Brake of the Cell Cycle - without this protein, the cell cycle is constantly in the: “on mode” & cellular reproduction can occur non-stop Its Mutations have been Identified in a Variety of Human Cancers including bone, bladder, pancreatic, small cell lung, & breast cancer, + the cancer after which the gene was named, retinoblastoma Mutations in the Rb Locus have been identified in up to 70% of individuals with osteosarcoma  Examples for Tumor Suppressor Genes 2- The p53 Gene 1- Codes for p53 protein 2- Protein acts as a powerful brake 3- Protein causes the cell either to pause or undergo apoptosis 4- Ensures that a genetic error is not passed on 5- Its mutations occur in 75% of colorectal p53 cancers gene 6- Most common genetic cause of human cancer (50% of all tumor types)  Examples for Tumor Suppressor Genes Others Although Rb & p53 Genes have been the most extensively studied, other gene (APC, WT-1, NF-1, VHL, FHIT, p15 & p16, DPC4, BRCA1 & BRCA2, PTEN) mutation pathologies have been also identified  Control of Cellular Reproduction 5- Proto-Oncogenes ✓ Are genes found in all cells that, when activated, stimulate a cell to go through the cell cycle, resulting in: Cellular Growth Proliferation ✓ May stimulate cell cycling at all levels, including 1- Producing proteins 2- Increasing production 3- Producing transcription that make up receptors of 2nd messenger proteins factors that turn on vital for growth-stimulating (ex. ras) that transfer genes to force cell growth hormones growth signals to nucleus forward (ex. myc genes)  Examples for Proto-Oncogenes The myc Genes Are a Family of Proto-Oncogenes that code for transcription factor proteins that drive cellular reproduction In Healthy Cells, they are activated ONLY in response to growth factors acting on the cell surface In Many Types of Cancer, they are turned on constantly, even in the absence of growth factors When Normal Proto-Oncogenes become Overactive & cause Uncontrolled Cell Division, they are called Oncogenes (Cancer- Causing Genes)  Examples for Proto-Oncogenes The myc Genes Typically, after early embryonic life Oncogenes are turned off or tightly controlled Exposure to a Carcinogen can damage the cell’s DNA & cause overstimulation of the oncogene resulting in development of Cancer Cells - Overstimulated Oncogenes produce Excess Cyclins that Interfere With Suppressor Genes & thus interrupt the balance between cell growth initiation & suppression App. 70 Oncogenes have been identified & it is noteworthy that these Are Not Abnormal Genes - they are part of a normal cell & Only Become Problematic When Exposed to a Carcinogen Physiological Concepts 1- Cellular Reproduction 2- Cellular Differentiation 3- Cellular Recognition & Adhesion to Like Cells 4- The Cell Clock  2- Cellular Differentiation Is the process of development in which cells acquire specialized characteristics including Structure & Function Normal Cells differentiate during development & aggregate with similar differentiated cells  2- Cellular Differentiation The More Highly Differentiated a cell, the less frequently it will go through the cell cycle to reproduce & divide Neurons are highly specialized cells & do not ????? retain the ability to reproduce after the nervous system is completely developed - Skin & Mucosal Cells continue to be proliferative Cells that seldom or never go through the cell cycle are unlikely to become cancerous, whereas cells that go through the cell cycle frequently are more likely to become cancerous  3- Cell Recognition & Adhesion to like cells Normal Cells adhere to others of the same type & group together The mechanisms by which cells recognize each other may involve chemical cues secreted only by certain cells & bound by receptors present only on similar cells Surface Proteins present on one cell type that match up with proteins on similar cells, also appear to assist in similar cell recognition - These Surface Proteins (Cell Adhesion Molecules)  3- Cell Recognition & Adhesion to like cells Cell-to-Cell Recognition is demonstrated by placing cells of many different types together in a Petri dish; after a certain period, the cells will have moved into clusters with only same type cells in each cluster Other Adhesion Molecules exist between cells & the underlying tissue matrix - these connections anchor cells to ONE location - when normal cells become detached from each other or experience a loosening of their attachment to underlying tissue, they respond by initiating Apoptosis, which prohibits cells from floating free of their tissue of origin  4- The Cell Clock Normal Cells reproduce a predictable number of times, after which they stop & become Senescent - this predictability Implies that cells possess some Counting System that tells them When to Stop dividing - this system is important because if cells divided indefinitely we would have many more cells than is compatible with life The Mechanism by which cells Tick Off their Own Divisions Involves a Telomere-Based Counting System Telomeres, are the end pieces of chromosomes that shorten with each division - when the Telomere length becomes sufficiently short (indicating that it has divided a certain number of times) the cell stops dividing  4- The Cell Clock Putting the brakes on cell division in response to Telomere Shortening requires that the cell has Functioning Rb & p53 Proteins ( stop dividing). Occasionally, a cell continues to divide after the Telomere reaches its threshold length; usually these cells soon self- destruct as their chromosomes begin to chaotically fuse & randomly break Cell Crowding also results in neighboring cells releasing signals that inhibit the further replication of cells - this is called Contact Inhibition Pathophysiological Concepts 1- Uncontrolled Cellular Reproduction and Autonomy 2- Anaplasia 3- Loss of the Cell Clock 4- Nuclear & Cytoplasmic derangement  1- Uncontrolled Cellular Reproduction and Autonomy Cancer Cell go through the cell cycle more often than normal, resulting in an of abnormal cells Cancer Cells Spend little time in the G Stages of Interphase & are frequently found in the S Stage of Interphase as well as M Stage - this Information is vital When Selecting Treatment for different types of cancer Uncontrolled Cellular Reproduction occurs when cells become independent of normal growth control signals - this Characteristic = Autonomy Autonomy Autonomy results: when cells do not respond to the cues controlling contact inhibition – for example, ▪ Growth Inhibitors released by neighboring cells ▪ or Inhibitory Growth Factors & Hormones traveling in the circulation ▪ Cancer Cells may disregard these signals By : o Not producing membrane receptors that bind the inhibitory growth signals o By Not activating appropriate second messengers that transmit inhibitory information to the nucleus o Others may overproduce membrane receptors that respond to growth stimulatory signals o Cancer Cells may produce their own growth factors that bind to cell membranes, thereby promoting self-proliferation & allowing independency of any outside control  1- Uncontrolled Cellular Reproduction and Autonomy When placed in an In Vitro experimental setting, Cancer Cells aggressively grow on top of each other & produce layers of disorderly cells, ignoring not only chemical signals but the tendency to respect neighboring borders Autonomy is demonstrated in the tendency of Cancer Cells to detach from neighboring cells & spread to distant body sites it has been suggested that the Adhesion Molecules No Longer Exist for Cancer Cells - Autonomy may Result From the Inactivation of Tumor Suppressor Genes or the Change from Proto-Oncogenes to Oncogenes  2- Anaplasia A change in the cell's structure with loss of differentiation Cancer Cells demonstrate various degrees of Anaplasia By undergoing Anaplasia Cancer Cells lose ability to perform previous functions & bear little resemblance to their tissue of origin Some Cancer Cells may become Ectopic Sites of hormone production - - e.g Lung Cancers frequently become ectopic sites of hormone production (ADH or parathormone) Highly Anaplastic Cells may appear embryonic & begin to express functions of a different cellular type - because the Immune System Poorly Responds To Embryonic Antigens, the presence of Such Cells usually indicates a particularly aggressive cancer  3- Loss of the Cell Clock Many Cancer Cells secrete an enzyme, Telomerase, that acts to replace the telomere ends of chromosomes that shorten with each cell division = a Destruction of the Cell Counting System & Immortality of the cell Telomere replacement allow Cancer Cells to continue to divide, increasing its number Also it gives time to accumulate more mutations, some of which may improve the cell’s ability to evade the immune system or produce newer, more potent growth-stimulatory factors Thank you