Course 1: Introduction to Oncology PDF

Course 1 : Introduc/on to oncology 1. What is the definition and the origins of cancer a. Cancer is the uncontrolled division of cells in a specific tissue or organ, forming a tumor (mass of altered cells) impeding the good functionningof the system and that can invade ne...

Course 1 : Introduc/on to oncology 1. What is the definition and the origins of cancer a. Cancer is the uncontrolled division of cells in a specific tissue or organ, forming a tumor (mass of altered cells) impeding the good functionningof the system and that can invade nearby tissues and be fatal. b. Earliest record from the Edwin Smith Papyrus (3000 BC); evidence of tumors dating back 1.7 million years. c. Some datas : o Increased incidence of cancer worlwide (in both males and females). o Higher incidence and mortality in northern and richer countries. o Median age cancer diganosis is 66 years. 2. Causes of Cancer a. Chemical & Physical Carcinogens: Includes tobacco, benzene, asbestos, ionizing rays, Uvs, Radons etc. b. Biological Carcinogens: Viruses (e.g., EBV) (Virus inducing oncogenic transformation), bacteria, and parasites. c. Lifestyle Factors: Western diet, alcohol, sedentarity and obesity. d. Internal Factors: Genetics, hormonal factors, immune dysfunction, aging, epigenetic changes, chrnic inflammation. 3. Cell Cycle and Cancer a. G1 Phase (Gap 1) o Primarily focused on cell growth. The cell synthesizes proteins and organelles, preparing for DNA replication. o Can be long (22-23 hours). o G1/S Checkpoint: § Ensures the cell is ready to replicate DNA. § Checks if the cell is large enough, has sufficient nutrients, and lacks DNA damage. § Check external signals like EGF, FGF, and Sonic Hedgehog stimulate growth through pathways (e.g., Notch, Hedgehog, PI3K/Akt/mTOR, MAPK). § Restriction checkpoint (G1 -> S) - Production of Cdk4-6/Cyclin D. - Phosphorylation of Rb (Retinoblastoma) protein (restriction point passed) - Releasing of E2F transcription factor, which activates genes necessary for the S phase, including S phase cyclin E and A (+ feedback loop) - Genes associated with DNA replication are produced (DNA polymerase, Helicase etc.) b. S Phase (Synthesis) o DNA replication each chromosome is duplicated to ensure two complete sets of DNA for daughter cells. o Initiation of Replication: § Cdk2-Cyclin A initiates DNA replication by recruiting helicase, which unwinds the DNA to create replication forks. o DNA Repair Mechanisms During S Phase: § Mismatch Repair (MMR): Corrects mismatches that occur during DNA replication by recognizing errors and excising a segment, followed by re-ligation. - Detection of mismatch - MutS MMR proteins recognise DNA errors - MutL+PMS2 binds and recruit DNA repair process - Resynthesis and ligation § Homologous Recombination (HR): An error-free method that repairs double-strand breaks using a complementary DNA strand as a template. Involves BRCA1/BRCA2. High-fidelity repair process. § Non-Homologous End Joining (NHEJ): Repairs double-strand breaks but is error-prone, as it does not restore the original genetic sequence = strong mutagenic potential - Double strand break - Extremities recognize by Ku proteins - Recruitment - DNA ligase IV ligates DNA ends o Other events § Centrosome duplication controlled by Cdk2/CyclinA c. G2 Phase (Gap 2) o Cell growth and preparation for mitosis, including synthesis of necessary proteins and checkpoint control for DNA integrity. o G2/M Checkpoint: § Verifies that all DNA has been correctly replicated without damage and prepares for mitosis. § ATM/ATR detect DNA damage, activating Chk proteins, which inhibit the Cdk1/Cyclin B complex if damage is present. § Cdk1/Cyclin B Activation: - "Mitosis Promoting Factor" (MPF). Upon activation (phophorylation by CAK and Wee1 + cdc25 removes the inhibitory phosphate) , initiates chromatin condensation by phosphorylation of condensins § Regulation: The Cdk1/Cyclin B complex is controlled by phosphorylation. Wee1 kinase adds an inhibitory phosphate, while Cdc25 phosphatase removes it, activating the complex for mitosis. d. M Phase (Mitosis) o The cell divides, creating two daughter cells with identical genetic material. o Stages of Mitosis: § Prophase: Chromatin condenses into visible chromosomes. § Metaphase: Chromosomes align at the cell’s equator. Metaphase to Anaphase Checkpoint: - APC/C (Anaphase-Promoting Complex): complex ensures all chromosomes are correctly attached to the spindle apparatus. APC/C triggers the degradation of securin, allowing separase to cleave cohesin, leading to chromatid separation. - Checkpoint Failure: If chromosomes aren’t properly aligned, Mad2 inhibits APC/C, halting cell division until all chromosomes are correctly attached. § Anaphase: Sister chromatids separate and move to opposite poles. § Telophase: Nuclear membranes reform around each set of chromosomes.  4. Tumor suppressor genes and proto-oncogenes a. Proto-oncogenes o all genes contributing to controlling/inhibiting the cell cycle, cell growth and differentiation. In cancer they are hypo- activated/not functional (mutation). b. Tumor suppressor genes o all genes contributing to activating/entering/moving forward in the cell cycle, cell growth and differentiation. In cancer they are hyperactivated (mutation). § E.g. BRAC1/2 mutation involved in hereditary breast cancer and ovarian cancer (autosomal dominant inheritance. - 1 mutated gene suffice to increase cancer risk Take home message : § Tumor cells do not possess the same mutations, tumors are a « mosaic » of cancer cells with different mutations allowing them to « evade » different checkpoints or to specialize in processes 5. Tumor Microenvironment o Composed of immune cells, fibroblasts, extracellular matrix (ECM), and blood vessels. o Cancer Characteristics: Self-sufficiency in growth, insensitivity to anti-growth signals, evading apoptosis, limitless replication, sustained angiogenesis, and tissue invasion. 6. Cancer Cell Traits and Survival Mechanisms a. Evading Apoptosis: Cancer cells mutate p53, overexpress anti-apoptotic proteins (e.g., Bcl-2). b. Angiogenesis: Cancer cells secrete VEGF to attract blood vessels, ensuring nutrient supply. c. Metastasis: Spread through blood (hematogenous) and lymphatic systems; guided by "seed and soil" hypothesis. 7. Metastatic Mechanisms a. Migration Modes: Mesenchymal (adhesion-based) and amoeboid (contractility-based). b. Routes: Hematogenous, lymphatic, and transcoelomic spread. c. Organotropism: Cancer cells metastasize to organs with compatible microenvironments.