Mid-Sem Test 2 CAM107 PDF

CAM107 Cellular Basis of Disease | Mid-Sem Test 2/2 (Week 8 to Week 11) Module 3: Cellular response to injury Weeks Topics Learning Objectives Description Week 8 DNA Damage Response Various types...

CAM107 Cellular Basis of Disease | Mid-Sem Test 2/2 (Week 8 to Week 11) Module 3: Cellular response to injury Weeks Topics Learning Objectives Description Week 8 DNA Damage Response Various types of DNA damage Types of DNA Damage and the source of this damage 1. Single-Strand Breaks (SSBs): Breaks in one strand of the DNA helix. 2. Double-Strand Breaks (DSBs): Breaks in both strands of the DNA helix, which are more severe. 3. Base Modifications: Chemical changes to DNA bases, such as oxidative damage or deamination. 4. Thymine Dimers: Covalent linkages between adjacent thymine bases caused by UV radiation. 5. Other Types: Includes crosslinks, adduct formation, and mismatches. Sources of DNA Damage Internal Sources: ○ Spontaneous Mutations: Occur naturally at a rate of about 1 in every 10 billion base pairs. ○ Reactive Oxygen Species (ROS): Byproducts of cellular metabolism that can cause oxidative damage. ○ Metabolic Byproducts: Such as acetaldehyde from alcohol metabolism, which forms DNA adducts. External Sources: ○ UV Radiation: Causes thymine dimers. ○ Ionizing Radiation: Leads to various types of DNA damage, including DSBs. ○ Chemical Agents: Found in tobacco smoke or industrial chemicals. Examples of DNA Damage from Chemical Agents Acetaldehyde: A toxic byproduct of alcohol metabolism that forms DNA adducts, increasing the risk of mutations and cancer, particularly in the liver and upper digestive tract. Methylation: Another form of DNA adduct that can lead to mutations if not repaired. Endogenous DNA Lesions Hydrolysis and Oxidation: Frequent sources  of DNA damage, such as depurination (loss of a purine base) and formation of 8-oxo-G (an oxidized guanine base). Repair Capacity: Mammalian cells repair thousands of lesions daily to maintain genomic stability The consequences of DNA Consequences of DNA Damage damage and the failure of 1. Mutations: Permanent changes in the DNA repair mechanisms on cellular sequence that can lead to diseases like cancer. health and disease 2. Genomic Instability: Increased mutation development rates, driving disease progression and cancer evolution. 3. Tumor Formation: Damage to tumor suppressor genes or activation of oncogenes, leading to uncontrolled cell division. 4. Cell Death or Senescence: Extensive damage can trigger apoptosis (programmed cell death) or senescence (cell aging), contributing to aging and tissue degeneration. Failure of Repair Mechanisms 1. Genomic Instability: Increases the risk of cancer and genetic disorders. 2. Hereditary Syndromes: Linked to defective DNA repair mechanisms (e.g., BRCA1, BRCA2). 3. Increased Cancer Risk: Results from accumulated mutations. Cell Death Describe, compare, and Necrosis differentiate the main forms of cell death: Understand and Mechanism: Uncontrolled cell death due to contrast necrosis, apoptosis, external factors like trauma, infection, or toxins, necroptosis, pyroptosis, and leading to cell membrane rupture and release of NETosis, focusing on their cellular contents. function and biological Biological Significance: Triggers significance. inflammation and further tissue damage; considered pathological. Apoptosis Mechanism: Programmed cell death involving cell shrinkage, chromatin condensation, DNA fragmentation, and formation of apoptotic bodies. Biological Significance: Maintains tissue homeostasis, development, and immune function; eliminates damaged cells without causing inflammation. Necroptosis  Mechanism: Programmed necrosis mediated by RIPK1 and RIPK3, resulting in cell membrane rupture and release of cellular contents. Biological Significance: Acts as a backup for apoptosis, especially during viral infections; involved in inflammatory diseases. Pyroptosis Mechanism: Programmed cell death associated with inflammation, triggered by infection and involving inflammasomes and gasdermin D. Biological Significance: Eliminates infected cells and releases pro-inflammatory cytokines to recruit immune cells. NETosis Mechanism: Unique to neutrophils, involving the release of DNA fibers (NETs) loaded with antimicrobial proteins. Biological Significance: Traps and kills pathogens; excessive NETosis can contribute to inflammatory and autoimmune diseases. Comparison and Differentiation Necrosis vs. Apoptosis: Necrosis is uncontrolled and inflammatory, while apoptosis is controlled and non-inflammatory. Necroptosis vs. Apoptosis: Both are programmed, but necroptosis causes cell rupture and inflammation, whereas apoptosis does not. Pyroptosis vs. Apoptosis: Pyroptosis is inflammatory and involves cell lysis, while apoptosis involves cell shrinkage and is non-inflammatory. NETosis vs. Other Forms: Specific to neutrophils, involving the release of DNA traps, unlike other forms which involve cell membrane rupture or shrinkage. Explain the causes of cell Necrosis death: Discuss the triggers of various types of cell death, Infection: Caused by pathogens like bacteria, including necrosis from viruses, and fungi, either through direct cell infection and physical injury, damage or excessive immune response. and apoptosis initiated Physical Injury: Trauma such as cuts, burns, through both intrinsic and or crushing injuries disrupts the cell membrane, extrinsic pathways. leading to uncontrolled cell death.  Toxins: Harmful chemicals or toxins damage cellular components, causing necrosis. Ischemia: Lack of blood supply (e.g., heart attacks, strokes) deprives cells of oxygen and nutrients, leading to necrosis. Apoptosis Intrinsic Pathway: Triggered by internal signals in response to cellular stress or damage. ○ DNA Damage: Severe damage activates p53, initiating apoptosis. ○ Oxidative Stress: Excessive ROS damages cellular components, triggering apoptosis. ○ Mitochondrial Dysfunction: Release of cytochrome c from mitochondria activates caspases, leading to apoptosis. Extrinsic Pathway: Initiated by external signals involving death receptors on the cell surface. ○ Fas Ligand (FasL): Binding to its receptor (Fas) activates the extrinsic apoptotic pathway. ○ Tumor Necrosis Factor (TNF): Binding to its receptor can also trigger apoptosis. Necroptosis Death Receptors: Triggered by death receptors like TNFR1 when apoptosis is inhibited. Viral Infections: Some viruses inhibit apoptosis to evade the immune response, triggering necroptosis as an alternative. Inflammatory Signals: Certain cytokines activate necroptosis through RIPK1 and RIPK3. Pyroptosis Pathogen Infection: Triggered by bacterial and viral infections; PAMPs are recognized by PRRs like NLRs. Inflammasome Activation: Activation of inflammasomes (e.g., NLRP3) leads to cleavage of gasdermin D, forming pores in the cell membrane and causing cell lysis and release of pro-inflammatory cytokines. NETosis Bacterial Infections: Neutrophils release DNA  to form NETs that capture and kill pathogens. Inflammatory Stimuli: Various signals, including cytokines and chemokines, can induce NETosis. Reactive Oxygen Species (ROS): ROS production within neutrophils can trigger the release of NETs. Summary - Necrosis: Triggered by infection, physical injury, toxins, and ischemia. It is an uncontrolled process leading to inflammation. - Apoptosis: Initiated through intrinsic (DNA damage, oxidative stress, mitochondrial dysfunction) and extrinsic (FasL, TNF) pathways. It is a controlled, non-inflammatory process. - Necroptosis: Triggered by death receptors, viral infections, and inflammatory signals. It is a programmed form of necrosis. - Pyroptosis: Triggered by pathogen infection and inflammasome activation. It is an inflammatory form of programmed cell death. - NETosis: Triggered by bacterial infections, inflammatory stimuli, and ROS. It involves the release of DNA traps by neutrophils. Explain the function of Development apoptosis in different contexts: Explore how Embryonic Development: Apoptosis shapes apoptosis regulates organs and tissues during embryogenesis, such development, tissue as removing webbing between fingers and toes. maintenance, and immune Neuronal Development: Eliminates excess function by eliminating neurons during brain development, ensuring damaged or unnecessary only properly connected neurons survive. cells. Morphogenesis: Helps sculpt complex body structures by removing cells in specific patterns. Tissue Maintenance Homeostasis: Balances cell proliferation and death to maintain tissue homeostasis, preventing uncontrolled growth and removing damaged or aged cells. Cell Turnover: In high-turnover tissues like the intestinal epithelium and skin, apoptosis removes old cells to allow for continuous renewal. Response to Damage: Removes cells with severe DNA damage to prevent the accumulation of potentially harmful cells that could lead to diseases like cancer. Immune Function Elimination of Infected Cells: Removes cells infected by viruses or pathogens, preventing the spread of infection and aiding in immune response resolution. Negative Selection in the Thymus: Eliminates T cells that recognize self-antigens during T cell development, preventing autoimmune diseases. Regulation of Immune Responses: Terminates immune responses by inducing apoptosis in immune cells like activated T cells, preventing excessive inflammation and tissue damage. Summary - Development: Shapes organs and tissues, removes excess neurons, and aids in morphogenesis. - Tissue Maintenance: Maintains homeostasis, facilitates cell turnover, and removes damaged cells. - Immune Function: Eliminates infected cells, prevents autoimmunity through negative selection,  and regulates immune responses. Explain how aberrant Insufficient Apoptosis apoptosis can lead to disease: Understand how dysregulated Cancer: Cells that evade apoptosis can grow apoptosis contributes to uncontrollably. Mutations in pathological conditions with apoptosis-regulating genes like p53 are specific examples. common in cancers, such as colorectal cancer, where p53 mutations prevent normal apoptotic responses to DNA damage. Autoimmune Diseases: Insufficient apoptosis of autoreactive immune cells can contribute to autoimmune diseases. For example, in systemic lupus erythematosus (SLE), defective apoptosis and clearance of apoptotic cells lead to the accumulation of cellular debris, triggering an autoimmune response. Excessive Apoptosis Neurodegenerative Diseases: Conditions like Alzheimer’s, Parkinson’s, and Huntington’s diseases are associated with excessive apoptosis of neurons. In Alzheimer’s disease, amyloid-beta plaques and tau tangles trigger apoptotic pathways, leading to neuronal death and cognitive decline. Ischemic Injury: In myocardial infarction (heart attack) and stroke, ischemia leads to cell death. While necrosis is primary in the core of the ischemic area, apoptosis occurs in the surrounding penumbra, exacerbating tissue damage and impairing recovery. Dysregulated Apoptosis in Other Conditions HIV/AIDS: HIV induces apoptosis in CD4+ T cells, leading to immune system depletion and increased susceptibility to opportunistic infections and cancers. Chronic Inflammatory Diseases: In conditions like chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis, dysregulated apoptosis of structural and immune cells contributes to chronic inflammation and tissue damage. For example, in COPD, excessive apoptosis of lung epithelial cells leads to the destruction of alveolar structures and impaired lung function. Week 9 Inflammatory Responses Explain Sensing Mechanisms: Sensing Pathogens and Damage Describe how the body senses pathogens and damage. 1. Pathogen-Associated Molecular Patterns (PAMPs) ○ Definition: PAMPs are molecular structures found on pathogens but not on host cells. ○ Examples: Gram-negative bacteria: Lipopolysaccharides (LPS) Yeast and fungi: Glucan coating Viruses: Unmethylated GC-rich DNA, GU-rich RNA ○ Detection: Recognized by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). For instance, TLR4 detects LPS. 2. Damage-Associated Molecular Patterns (DAMPs) ○ Definition: DAMPs are molecules released by stressed cells undergoing necrosis. ○ Examples: HMGB1: A nuclear protein released during cell damage. ATP: Released from damaged cells and detected by receptors like P2X7. ○ Detection: Also recognized by PRRs, leading to the activation of inflammatory pathways. Signaling Molecules Cytokines: Proteins that mediate and regulate immunity, inflammation, and hematopoiesis. They can be pro-inflammatory (e.g., IL-1, TNF) or anti-inflammatory (e.g., IL-10). Chemokines: A subset of cytokines that specifically induce chemotaxis in nearby responsive cells. Prostaglandins: Lipid compounds that have diverse hormone-like effects, including the promotion of inflammation. Inflammatory Response 1. Vasodilation and Increased Permeability ○ Histamine: Released from mast cells and basophils, causing vasodilation and increased vascular permeability. ○ Prostaglandins: Produced by the  COX-2 enzyme, contributing to prolonged inflammation. 2. Cell Recruitment ○ Neutrophils: First responders that migrate to the site of infection or damage. ○ Monocytes/Macrophages: Arrive later to phagocytose debris and pathogens, and to release cytokines that further modulate the immune response. Resolution and Repair Resolution: The process of dampening the inflammatory response once the threat is neutralized. This involves the clearance of immune cells and the release of anti-inflammatory cytokines. Repair: Involves tissue restoration and the replacement of damaged cells, often mediated by growth factors and stem cells. Describe Immune Signaling: Key Signaling Molecules Explain how the immune system uses signaling 1. Cytokines molecules to orchestrate the ○ Definition: Small proteins released response. by cells that have a specific effect on the interactions and communications between cells. ○ Types: Pro-inflammatory cytokines: Such as IL-1, TNF, and IL-6, which promote inflammation. Anti-inflammatory cytokines: Such as IL-10, which help to resolve inflammation. ○ Functions: They regulate the intensity and duration of the immune response by promoting or inhibiting the activation, proliferation, and differentiation of various immune cells. 2. Chemokines ○ Definition: A subset of cytokines that specifically induce chemotaxis in nearby responsive cells. ○ Function: They guide the migration of immune cells to the site of  infection or injury. 3. Prostaglandins ○ Definition: Lipid compounds that have diverse hormone-like effects. ○ Function: They are involved in the inflammatory response, causing vasodilation and increasing the permeability of blood vessels. 4. Histamine ○ Definition: A biogenic amine released by mast cells and basophils. ○ Function: It causes vasodilation and increased vascular permeability, leading to the classic signs of inflammation (redness, heat, swelling). Immune Signaling Pathways 1. Detection of Pathogens and Damage ○ PAMPs (Pathogen-Associated Molecular Patterns): Recognized by pattern recognition receptors (PRRs) like Toll-like receptors (TLRs). For example, TLR4 detects lipopolysaccharides (LPS) from Gram-negative bacteria. ○ DAMPs (Damage-Associated Molecular Patterns): Released by stressed or damaged cells and also recognized by PRRs. 2. Activation of Signaling Pathways ○ TLR Signaling: Activation of TLRs by PAMPs or DAMPs leads to the activation of transcription factors such as NF-κB, which then induce the expression of pro-inflammatory cytokines. ○ Inflammasome Activation: Multiprotein complexes that activate inflammatory responses, leading to the production of IL-1β and IL-18. 3. Amplification of the Immune Response ○ Cytokine Release: Pro-inflammatory cytokines like IL-1, TNF, and IL-6 are released, amplifying the immune response by recruiting more immune cells to the site of infection or injury. ○ Chemokine Release: Chemokines such as IL-8 attract neutrophils and  other immune cells to the site. 4. Resolution of Inflammation ○ Anti-inflammatory Cytokines: Cytokines like IL-10 and TGF-β are released to dampen the inflammatory response and promote tissue repair. ○ Clearance of Immune Cells: Apoptosis of immune cells and the phagocytosis of apoptotic cells by macrophages help to resolve inflammation. Understand Innate Immune Key Components of the Innate Immune System Response: Explain how the innate immune system fights 1. Physical and Chemical Barriers pathogens and clears ○ Skin: Acts as a physical barrier to damaged tissues. prevent pathogen entry. ○ Mucous Membranes: Trap pathogens in mucus and contain antimicrobial peptides. ○ Acidic Environments: Such as the stomach, which kills many ingested pathogens. 2. Cellular Defenses ○ Phagocytes: Cells that engulf and digest pathogens and debris. Neutrophils: Rapidly respond to infection, engulfing and destroying pathogens. Macrophages: Engulf pathogens and dead cells, and release cytokines to recruit other immune cells. ○ Natural Killer (NK) Cells: Destroy infected or cancerous cells by inducing apoptosis. 3. Pattern Recognition Receptors (PRRs) ○ Toll-like Receptors (TLRs): Detect PAMPs (Pathogen-Associated Molecular Patterns) and DAMPs (Damage-Associated Molecular Patterns). ○ NOD-like Receptors (NLRs): Detect intracellular pathogens and stress signals. Steps in the Innate Immune Response 1. Detection of Pathogens and Damage ○ PAMPs and DAMPs: Recognized by  PRRs on immune cells, triggering an immune response. ○ Examples: PAMPs: Lipopolysaccharides (LPS) from Gram-negative bacteria, viral RNA. DAMPs: HMGB1 protein, ATP released from damaged cells. 2. Activation of Immune Cells ○ Phagocytosis: Neutrophils and macrophages engulf and digest pathogens. ○ Degranulation: Mast cells and basophils release histamine and other chemicals to increase vascular permeability and recruit more immune cells. 3. Inflammatory Response ○ Vasodilation: Blood vessels widen to increase blood flow to the affected area. ○ Increased Permeability: Allows immune cells and proteins to enter the tissue. ○ Cytokine Release: Pro-inflammatory cytokines (e.g., IL-1, TNF) are released to amplify the response and recruit more immune cells. 4. Recruitment of Additional Immune Cells ○ Chemokines: Attract neutrophils, monocytes, and other immune cells to the site of infection or damage. ○ Adhesion Molecules: Help immune cells adhere to blood vessel walls and migrate into tissues. 5. Destruction of Pathogens ○ Reactive Oxygen Species (ROS): Produced by phagocytes to kill engulfed pathogens. ○ Antimicrobial Peptides: Destroy bacterial cell membranes. 6. Clearance of Damaged Cells and Pathogens ○ Phagocytosis: Macrophages clear dead cells and debris. ○ Neutrophil Extracellular Traps (NETs): Neutrophils release DNA and antimicrobial proteins to trap and kill pathogens.  7. Resolution of Inflammation ○ Anti-inflammatory Cytokines: Such as IL-10, are released to dampen the immune response. ○ Clearance of Immune Cells: Apoptosis of immune cells and their removal by macrophages. 8. Tissue Repair ○ Growth Factors: Promote tissue regeneration and repair. ○ Extracellular Matrix Remodeling: Helps restore tissue structure and function. Describe Inflammation Steps in Inflammation Resolution Resolution: Outline how inflammation is resolved and 1. Cessation of Pro-inflammatory Signals how tissue repairs itself. ○ Reduction of Pro-inflammatory Cytokines: Levels of cytokines like IL-1 and TNF decrease. ○ Clearance of Pathogens and Debris: Effective elimination of pathogens and dead cells reduces the need for an ongoing inflammatory response. 2. Switch to Anti-inflammatory Signals ○ Anti-inflammatory Cytokines: Cytokines such as IL-10 and TGF-β are released to suppress inflammation. ○ Lipid Mediators: Specialized pro-resolving mediators (SPMs) like resolvins, protectins, and maresins derived from omega-3 fatty acids help to resolve inflammation. 3. Apoptosis of Immune Cells ○ Neutrophil Apoptosis: Neutrophils undergo programmed cell death (apoptosis) and are cleared by macrophages. ○ Macrophage Efferocytosis: Macrophages engulf apoptotic cells, preventing the release of toxic substances. 4. Clearance of Inflammatory Cells ○ Phagocytosis: Macrophages continue to clear apoptotic cells and debris. ○ Lymphatic Drainage: Excess fluid and immune cells are drained away from the site of inflammation.  Tissue Repair and Regeneration 1. Removal of Edema ○ Fluid Reabsorption: Excess fluid is reabsorbed by the lymphatic system. ○ Reduction of Swelling: As fluid is cleared, swelling decreases. 2. Restoration of Tissue Integrity ○ Extracellular Matrix (ECM) Remodeling: The ECM is remodeled to provide a scaffold for new tissue growth. ○ Fibroblast Activation: Fibroblasts produce collagen and other ECM components to repair tissue. 3. Angiogenesis ○ New Blood Vessel Formation: Growth factors like VEGF promote the formation of new blood vessels to supply nutrients and oxygen to the healing tissue. 4. Stem Cell Activation ○ Stem Cell Migration and Differentiation: Stem cells migrate to the site of injury and differentiate into the necessary cell types to replace damaged cells. 5. Re-epithelialization ○ Epithelial Cell Proliferation: Epithelial cells proliferate and migrate to cover the wound, restoring the barrier function of the tissue. Discuss Disease Mechanisms: Autoimmunity Explain how failures in these processes can lead to 1. Mechanism: diseases such as ○ Failure in Negative Selection: autoimmunity, allergies, During immune cell development, T inflammatory tissue damage, and B cells that react against and fibrosis. self-antigens are usually eliminated. Failure in this process can lead to the survival of self-reactive cells. ○ Molecular Mimicry: Pathogens may have antigens similar to self-antigens, leading the immune system to attack both the pathogen and the body’s own tissues. 2. Examples: ○ Type 1 Diabetes: The immune system attacks insulin-producing  beta cells in the pancreas. ○ Rheumatoid Arthritis: Immune cells attack the synovium (lining of the joints). ○ Lupus: The immune system attacks multiple organs and tissues, including skin, joints, and kidneys. Allergies 1. Mechanism: ○ Hyperreactivity to Non-harmful Antigens: The immune system overreacts to harmless substances (allergens) such as pollen, dust mites, or certain foods. ○ IgE-Mediated Response: Allergens trigger the production of IgE antibodies, which bind to mast cells and basophils, causing them to release histamine and other inflammatory mediators. 2. Examples: ○ Asthma: Inflammation and narrowing of the airways in response to allergens. ○ Hay Fever: Inflammation of the nasal passages due to pollen. ○ Food Allergies: Immune response to certain foods, leading to symptoms ranging from mild (hives) to severe (anaphylaxis). Inflammatory Tissue Damage 1. Mechanism: ○ Chronic Inflammation: Persistent inflammation due to ongoing infection, autoimmune reactions, or exposure to irritants (e.g., smoking). ○ Excessive Neutrophil Activity: Neutrophils release reactive oxygen species (ROS) and enzymes that can damage surrounding tissues. 2. Examples: ○ Chronic Obstructive Pulmonary Disease (COPD): Chronic inflammation and damage to the lungs, often due to smoking. ○ Inflammatory Bowel Disease (IBD): Chronic inflammation of the gastrointestinal tract, including  Crohn’s disease and ulcerative colitis. Fibrosis 1. Mechanism: ○ Excessive ECM Deposition: Chronic inflammation leads to the overproduction of extracellular matrix (ECM) components, such as collagen, by fibroblasts. ○ Failure in Resolution: Inability to properly resolve inflammation results in continuous tissue remodeling and scarring. 2. Examples: ○ Liver Fibrosis: Excessive scar tissue formation in the liver, often due to chronic hepatitis or alcohol abuse. ○ Pulmonary Fibrosis: Thickening and scarring of lung tissue, leading to reduced lung function. ○ Cardiac Fibrosis: Scarring of heart tissue, which can impair heart function and lead to heart failure. Resolution of Inflammation & (wut the xxxx) (wut the xxxx) Repair Module 4: Neoplasia Weeks Topics Learning Objectives Description Week 10 Fundamental Concepts Define some common terms 1. Neoplasia: This refers to the uncontrolled and relevant to cancer, including abnormal growth of cells, forming a neoplasm benign and metastatic or tumour. neoplasms (tumours), 2. Benign Neoplasm (Tumour): A non-cancerous metaplasia and dysplasia. tumour that does not invade nearby tissues or metastasize (spread to other parts of the body). Benign tumours typically grow slowly and are often encapsulated. 3. Malignant Neoplasm (Tumour): A cancerous tumour capable of invading nearby tissues and spreading to other parts of the body (metastasis). Malignant tumours tend to grow rapidly and are not encapsulated. 4. Metaplasia: A reversible change where one type of cell transforms into another type, often as an adaptive response to chronic irritation or inflammation. For example, in Barrett’s esophagus, the normal squamous cells of the esophagus change to columnar cells due to  chronic acid reflux. 5. Dysplasia: Abnormal cell growth with disordered architecture, which can be a precursor to cancer. Dysplasia indicates that cells are not growing or maturing normally, and it can range from mild to severe, with severe dysplasia being closer to cancer. 6. Metastasis: The process by which cancer cells spread from the primary site (where they first formed) to other parts of the body, forming new (secondary) tumours. Explain the fundamental cell Morphological Distinctions morphological distinctions between normal cells and 1. Cell Size and Shape: tumour cells and the cellular ○ Normal Cells: Uniform in size and basis of neoplastic shape, maintaining a consistent transformation. structure. ○ Tumour Cells: Often vary greatly in size and shape (pleomorphism), leading to an irregular appearance. 2. Nuclear Size and Structure: ○ Normal Cells: Have a regular, small nucleus with a consistent nuclear-to-cytoplasmic ratio. ○ Tumour Cells: Exhibit enlarged nuclei with an increased nuclear-to-cytoplasmic ratio. The nuclei may also show irregular shapes and prominent nucleoli. 3. Mitotic Figures: ○ Normal Cells: Undergo controlled and regular cell division with normal mitotic figures. ○ Tumour Cells: Display abnormal mitotic figures, indicating uncontrolled cell division. These can include multipolar mitoses and other irregularities. 4. Mitochondria: ○ Normal Cells: Mitochondria have a typical structure and function, primarily using oxidative phosphorylation for energy production. ○ Tumour Cells: Often have altered mitochondria with increased numbers. They rely more on glycolysis for energy production, even in the presence of oxygen (Warburg effect). 5. Golgi Apparatus:  ○ Normal Cells: The Golgi apparatus functions normally in protein modification and secretion. ○ Tumour Cells: The Golgi apparatus is often fragmented and shows increased secretion of proteins that promote cell migration, invasion, and metastasis. Cellular Basis of Neoplastic Transformation 1. Genetic Mutations: ○ Oncogenes: Mutations in proto-oncogenes convert them into oncogenes, which promote excessive cell growth and proliferation. Examples include RAS and MYC. ○ Tumor Suppressor Genes: Mutations that inactivate these genes remove the inhibitory controls on cell growth. Examples include TP53 and RB1. ○ Apoptosis Genes: Mutations in genes regulating programmed cell death (e.g., BAX, BCL-2) can prevent apoptosis, leading to cellular immortality. 2. Initial Mutation: ○ A single mutation provides a cell with a survival and proliferative advantage, leading to clonal expansion. 3. Second Mutation: ○ Additional mutations enable the cell to invade surrounding tissues, marking the transition to malignancy. 4. Third Mutation: ○ Further mutations and selection pressures produce a fully malignant tumour capable of aggressive growth and invasion. 5. Genetic Instability: ○ Tumour cells often exhibit chromosomal abnormalities and genetic instability, contributing to their rapid evolution and adaptation. 6. Cell Division and Apoptosis: ○ Normal Homeostasis: Balanced cell division and apoptosis maintain tissue equilibrium. ○ Tumour Growth: Increased cell division and/or decreased apoptosis  lead to tumour development. Both pathways are common in cancer. Discuss the involvement of Mitochondria specific cell organelles, such as mitochondria and the Golgi 1. Altered Metabolism: apparatus, in the survival and ○ Warburg Effect: Cancer cells often growth of cancer cells. exhibit a metabolic shift known as the Warburg effect, where they prefer glycolysis over oxidative phosphorylation for energy production, even in the presence of sufficient oxygen. This allows for rapid energy production and provides the building blocks needed for biosynthesis. ○ Energy Production: By relying on aerobic glycolysis, cancer cells can produce ATP quickly, which supports their rapid proliferation. 2. Regulation of Apoptosis: ○ Apoptosis Control: Mitochondria play a key role in regulating apoptosis (programmed cell death). In cancer cells, mitochondrial dysfunction can prevent apoptosis, allowing these cells to evade death and continue growing. ○ Therapeutic Target: Because of their role in apoptosis, mitochondrial pathways are potential targets for cancer therapies aiming to restore normal cell death mechanisms. 3. Cell Survival: ○ Mitochondrial Biogenesis: Cancer cells often have an increased number of mitochondria, which supports their high metabolic demands and enhances their survival and growth. Golgi Apparatus 1. Protein Modification and Secretion: ○ Increased Secretion: The Golgi apparatus in cancer cells is often fragmented and shows increased secretion of proteins. These proteins can promote cell migration, invasion, and metastasis. ○ Matrix Degradation: The Golgi apparatus is involved in the secretion  of matrix metalloproteinases (MMPs) and other proteases, which degrade the extracellular matrix and facilitate cancer cell invasion. 2. Epithelial-Mesenchymal Transition (EMT): ○ Role in EMT: The Golgi apparatus is critical in the process of EMT, where cancer cells gain migratory and invasive properties. This transition is essential for metastasis. ○ Protein Secretion and Migration: Alterations in Golgi function lead to increased secretion of proteins that promote cell migration and invasion, aiding in the spread of cancer cells to other parts of the body. 3. Impact on Cell Proliferation: ○ Enhanced Growth: The Golgi apparatus supports the rapid proliferation of cancer cells by modifying and sorting proteins necessary for cell growth and division. Discuss certain examples of Metaplasia metaplasia and dysplasia. 1. Barrett’s Esophagus: ○ Description: This condition involves the transformation of the normal squamous epithelium lining the esophagus into columnar epithelium, which is more typical of the intestinal lining. ○ Cause: Chronic acid reflux (gastroesophageal reflux disease, GERD) is the primary cause. ○ Clinical Relevance: Barrett’s esophagus is a significant risk factor for developing esophageal adenocarcinoma, a type of cancer. 2. Smoking-Induced Metaplasia: ○ Description: In the respiratory tract, chronic exposure to cigarette smoke can cause the normal columnar epithelium of the bronchi to transform into squamous epithelium. ○ Cause: Chronic irritation and inflammation from smoking. ○ Clinical Relevance: This type of metaplasia can increase the risk of developing squamous cell carcinoma  of the lung. Dysplasia 1. Cervical Dysplasia: ○ Description: Abnormal growth and development of cells on the surface of the cervix, often detected through a Pap smear. ○ Cause: Human papillomavirus (HPV) infection is a common cause. ○ Clinical Relevance: Cervical dysplasia can range from mild to severe and is considered a precursor to cervical cancer. Early detection and treatment are crucial to prevent progression to invasive cancer. 2. Dysplasia in Colonic Polyps: ○ Description: Abnormal growths in the lining of the colon or rectum, which can be pre-cancerous. ○ Cause: Genetic mutations and chronic inflammation can contribute to the development of dysplastic polyps. ○ Clinical Relevance: Dysplastic polyps have the potential to develop into colorectal cancer if left untreated. Regular colonoscopy screenings are essential for early detection and removal. Risk Factors Identify and categorise risk Genetic Predispositions factors for neoplasia, including genetic 1. Inherited Cancer Syndromes: predispositions, ○ BRCA1/BRCA2 Mutations: These environmental exposures, and mutations significantly increase the lifestyle choices that risk of breast and ovarian cancers. contribute to cellular injury ○ Proto-oncogenes and Tumor and certain types of cancers. Suppressor Genes: Mutations in these genes can lead to uncontrolled cell growth. ○ Epigenetic Changes: Alterations in gene expression without changes in DNA sequence can contribute to cancer. 2. Genetic Instability: ○ Chromosomal Abnormalities: These can lead to genetic disorders and increased cancer risk. ○ Single Nucleotide Polymorphisms  (SNPs): Variations in a single DNA building block can influence cancer risk. ○ Hereditary Syndromes: Conditions like Lynch syndrome are linked to defective DNA repair mechanisms. Environmental Exposures 1. Chemical Carcinogens: ○ Tobacco Smoke: Contains numerous carcinogens that can cause lung, oral, and esophageal cancers. ○ Asbestos: Leads to lung inflammation and mesothelioma. ○ Benzene: Damages DNA and disrupts cell division, leading to leukemia. 2. Radiation Exposure: ○ UV Radiation: Causes DNA damage like thymine dimers, leading to skin cancer. ○ Ionizing Radiation: Includes X-rays and gamma rays, which can cause significant DNA damage and mutations. 3. Chronic Infections: ○ HPV (Human Papillomavirus): Linked to cervical and other cancers. ○ H. pylori: Associated with stomach cancer. Lifestyle Choices 1. Diet and Obesity: ○ Poor diet and obesity are linked to various cancers, including colorectal and breast cancer. 2. Alcohol and Tobacco Use: ○ Alcohol: Metabolized into acetaldehyde, a toxic byproduct that forms DNA adducts, increasing cancer risk. ○ Tobacco: Contains over 70 known carcinogens. 3. Sedentary Lifestyle: ○ Lack of physical activity is associated with an increased risk of several cancers. Molecular Mechanisms DNA Damage and Mutation Accumulation: Chronic exposure to carcinogens leads to DNA  damage and mutations. Chronic Inflammation: Persistent inflammation can promote cancer development. Evasion of Apoptosis: Cancer cells often evade programmed cell death, leading to uncontrolled growth. Preventive Measures Screening and Early Detection: Especially important for high-risk populations. Lifestyle Modifications: Quitting smoking, reducing alcohol consumption, and maintaining a healthy diet can reduce cancer risk. Public Health Policies and Education: Essential for raising awareness and promoting preventive measures. Examine how cells respond on Response to Chemical Carcinogens a molecular level to environmental stressors like 1. DNA Adduct Formation: chemical carcinogens and ○ Chemical Modifications: radiation, and how these Carcinogens like acetaldehyde (from responses can lead to cellular alcohol metabolism) form DNA changes that increase adducts, which are chemical neoplasia risk. modifications that interfere with normal DNA function and replication. ○ Mutagenic Effects: Unrepaired DNA adducts can lead to mutations, promoting carcinogenesis. 2. Detoxification Enzymes: ○ Genetic Variability: The effectiveness of detoxification enzymes varies among individuals due to genetic differences, influencing susceptibility to carcinogens. ○ Role in Carcinogenesis: These enzymes help detoxify harmful substances, but their variability can affect how well cells handle carcinogenic exposure. 3. Oxidative Stress: ○ Reactive Oxygen Species (ROS): Chemical carcinogens can increase ROS levels, leading to oxidative stress and damage to cellular components, including DNA. ○ Inflammation: Chronic oxidative stress can cause inflammation, which is a known promoter of cancer development. Response to Radiation 1. DNA Damage: ○ Double-Strand Breaks: Ionizing radiation (e.g., X-rays, gamma rays) can cause double-strand breaks in DNA, which are particularly harmful and challenging to repair. ○ Thymine Dimers: UV radiation can cause thymine dimers, where two adjacent thymine bases become covalently bonded, disrupting DNA replication and transcription. 2. DNA Repair Pathways: ○ Repair Mechanisms: Cells have repair mechanisms like homologous recombination and non-homologous end joining to fix double-strand breaks. However, errors in these processes can lead to mutations. ○ Genomic Instability: Inefficient or faulty repair can result in genomic instability, increasing the risk of cancer. 3. Radiation-Induced Genomic Instability: ○ Persistent Damage: Radiation can cause persistent DNA damage, leading to genomic instability over time. ○ Influence of Dose and Type: The risk of cancer increases with the dose and type of radiation exposure, with high-energy radiation being more damaging. Cellular Changes Leading to Neoplasia 1. Gene Mutations: ○ Tumor Suppressor Genes: Mutations in tumor suppressor genes (e.g., TP53) can prevent cells from undergoing apoptosis, allowing damaged cells to survive and proliferate. ○ Proto-oncogenes: Mutations in proto-oncogenes (e.g., KRAS) can lead to their activation, promoting uncontrolled cell growth. 2. Inhibition of DNA Repair: ○ Repair Inhibition: Carcinogens can inhibit DNA repair mechanisms,  leading to the accumulation of mutations. ○ Accumulated Mutations: Over time, the accumulation of mutations can drive the transformation of normal cells into cancerous cells. 3. Promotion of Uncontrolled Cell Growth: ○ Cell Cycle Deregulation: Carcinogens can disrupt cell cycle control, leading to uncontrolled cell proliferation. ○ Evasion of Apoptosis: Cancer cells often develop mechanisms to evade apoptosis, allowing them to survive despite significant DNA damage. Week 11 Underlying mechanisms Describe how disruption to 1. Cell Cycle Dysregulation certain key cellular processes, including the cell cycle and The cell cycle is a series of phases that cells go through signalling pathways such as to grow and divide. It includes the G1, S, G2, and M kinase dysregulation phases. In cancer, this cycle is often disrupted, leading to contribute to cancer uncontrolled cell proliferation. development. Checkpoints: The G1/S and G2/M checkpoints ensure that cells only divide when they are ready and that any DNA damage is repaired before division. In cancer, mutations in key regulatory genes like p53 and RB1 allow cells to bypass these checkpoints, leading to unregulated growth. Cyclins and CDKs: These proteins regulate the cell cycle. Mutations or overexpression of cyclins and cyclin-dependent kinases (CDKs) can drive the cell cycle forward even when it shouldn’t, contributing to cancer progression. 2. Apoptosis Evasion Apoptosis, or programmed cell death, is a mechanism that removes damaged or unnecessary cells. Cancer cells often evade apoptosis, allowing them to survive and proliferate despite having genetic damage. p53: This tumor suppressor gene plays a key role in inducing apoptosis in response to DNA damage. Mutations in p53 are common in many cancers, leading to the survival of cells that should undergo apoptosis. Anti-apoptotic Proteins: Overexpression of proteins like BCL-2 can prevent apoptosis, contributing to the survival and accumulation of cancer cells.  3. Kinase Signaling Pathways Kinases are enzymes that transfer phosphate groups to other proteins, often activating signaling pathways that control cell growth and survival. Dysregulation of these pathways is a hallmark of cancer. Receptor Tyrosine Kinases (RTKs): These proteins, such as EGFR and ALK, are often mutated or overexpressed in cancers, leading to constant activation of growth signals. RAS-RAF-MEK-ERK and PI3K-AKT Pathways: These pathways are downstream of RTKs and are frequently hyperactivated in cancer, promoting uncontrolled cell proliferation and survival. 4. Oncogene Activation Oncogenes are mutated forms of normal genes (proto-oncogenes) that drive cancer development. EGFR and ALK Mutations: Mutations in these genes lead to constant activation of signaling pathways that promote cell growth and survival, particularly in cancers like non-small cell lung cancer (NSCLC). 5. Tumor Microenvironment The environment surrounding a tumor, including other cells, blood vessels, and signaling molecules, can influence cancer progression. Hypoxia: Low oxygen levels in the tumor microenvironment can lead to the activation of pathways that promote survival and resistance to therapy. Immune Evasion: Cancer cells can evade the immune system by various mechanisms, including the expression of immune checkpoint proteins that inhibit immune cell activity. 6. Genomic Instability Cancer cells often have a high rate of mutations, leading to genomic instability. This can result in the activation of oncogenes, inactivation of tumor suppressor genes, and resistance to therapy. Describe examples of current Current and Emerging Targeted Treatment Approaches and emerging targeted 1. EGFR Inhibitors treatment approaches and ○ Example: Erlotinib how cancer cells evade these ○ Mechanism: These drugs target the targeted treatments on a Epidermal Growth Factor Receptor cellular level. (EGFR), which is often mutated in cancers like non-small cell lung cancer (NSCLC). By inhibiting EGFR, these treatments block the signaling pathways that drive cancer cell proliferation and survival. ○ Resistance Mechanisms: Cancer cells can develop resistance through secondary mutations in EGFR (e.g., T790M) or by activating alternative pathways such as MET or HER2. 2. ALK Inhibitors ○ Example: Crizotinib ○ Mechanism: These inhibitors target Anaplastic Lymphoma Kinase (ALK) fusion proteins, which are common in certain types of lung cancer. By blocking ALK, these drugs prevent the activation of downstream signaling pathways that promote cancer cell growth and survival. ○ Resistance Mechanisms: Resistance can occur through secondary mutations in ALK (e.g., G1202R) or through tumor heterogeneity and adaptation, such as epithelial-mesenchymal transition (EMT) and phenotypic switching. 3. Next-Generation Inhibitors ○ Examples: Next-generation ALK and EGFR inhibitors ○ Mechanism: These drugs are designed to overcome resistance to first-generation inhibitors. They target the same pathways but are effective against resistant mutations. ○ Resistance Mechanisms: Despite their advanced design, cancer cells can still develop resistance through further mutations or by activating bypass signaling pathways. 4. Combination Therapies ○ Examples: Combining tyrosine kinase inhibitors (TKIs) with immunotherapy or chemotherapy ○ Mechanism: These approaches aim to enhance treatment efficacy by targeting multiple pathways simultaneously. For instance, combining TKIs with immune  checkpoint inhibitors can help to overcome resistance and improve patient outcomes. ○ Resistance Mechanisms: Cancer cells can adapt to combination therapies through various mechanisms, including changes in the tumor microenvironment, such as hypoxia and immune evasion. 5. Personalized Medicine ○ Mechanism: This approach uses genomic profiling to tailor treatments to the specific genetic mutations present in a patient’s tumor. By targeting the unique molecular characteristics of each cancer, personalized medicine aims to improve treatment efficacy and reduce side effects. ○ Resistance Mechanisms: Cancer cells can still develop resistance through genetic instability, leading to new mutations that render targeted treatments less effective. How Cancer Cells Evade Targeted Treatments 1. Genetic Mutations ○ Cancer cells can acquire new mutations that alter the target of the therapy, rendering the drug ineffective. For example, the T790M mutation in EGFR can prevent EGFR inhibitors from binding effectively. 2. Activation of Bypass Pathways ○ Cancer cells can activate alternative signaling pathways to bypass the blocked pathway. For instance, if EGFR is inhibited, cancer cells might upregulate MET or HER2 to continue proliferating. 3. Tumor Microenvironment ○ Factors in the tumor microenvironment, such as hypoxia (low oxygen levels) and immune evasion, can promote drug resistance. Hypoxia can induce changes in cancer cell metabolism and signaling that reduce the effectiveness of targeted therapies. 4. Phenotypic Switching  ○ Cancer cells can undergo phenotypic changes, such as epithelial-mesenchymal transition (EMT), which can make them more resistant to therapies. EMT can lead to increased invasiveness and resistance to apoptosis. 5. Cancer Stem Cells ○ A subpopulation of cancer cells known as cancer stem cells can survive initial treatments and cause relapse. These cells are often more resistant to therapies and can regenerate the tumor after treatment. Pathophysiology Describe the cellular Cellular Mechanisms Facilitating Tumour Growth mechanisms facilitating tumour growth and 1. Dysregulated Cell Proliferation: angiogenesis. ○ Genetic Alterations: Mutations in genes that control cell division lead to uncontrolled cell prolifer