Molecular Basis of Cancer: Cell Cycle, OmpathStudy

SECTION FOUR: MOLECULAR BASIS OF CANCER, CELL CYCLE, APOPTOSIS & TUMOUR GROWTH Covers — Cell cycle regulation, Apoptosis in cancer, Angiogenesis, Tumour microenvironment, Cancer stem cells, Epigenetics in cancer, Cancer genetics & hereditary cancer syndromes ▸ 4.1 CELL CYCLE & ITS REGULATION IN CANCER ⟡ Normal Cell Cycle Phases: G1 → cell growth; preparation for DNA synthesis S → DNA replication G2 → preparation for division M → mitosis (cell division) G0 → quiescent/resting state (most normal cells) ⟡ Cell Cycle Checkpoints: G1/S checkpoint → most critical; "restriction point" — checks DNA integrity before replication G2/M checkpoint → ensures DNA replication is complete before mitosis Spindle assembly checkpoint → ensures chromosomes properly attached to spindle before separation ⟡ Key Regulators: Cyclins → regulatory proteins; levels rise and fall during cycle CDKs (Cyclin-Dependent Kinases) → enzymes activated by cyclins; drive cell cycle progression CDK inhibitors (CKIs) → e.g. p16 (CDKN2A), p21, p27 → brake on cell cycle RB protein (Retinoblastoma protein) → master brake of G1/S checkpoint Hypophosphorylated RB → binds and inactivates E2F transcription factors → cell cycle BLOCKED Phosphorylated RB → releases E2F → cell cycle PROCEEDS In cancer: RB is lost/mutated → uncontrolled E2F activity → unrestrained proliferation ⟡ TP53 — Guardian of the Genome: Activated by DNA damage, hypoxia, oncogene activation Actions of TP53: ✦ Activates p21 → CDK inhibition → cell cycle arrest (allows DNA repair) ✦ Activates BAX → apoptosis if damage irreparable ✦ Activates GADD45 → DNA repair Mutated in 50% of all human cancers Li-Fraumeni syndrome → germline TP53 mutation → multiple early-onset cancers in family ▸ 4.2 APOPTOSIS & ITS EVASION IN CANCER Definition: Programmed cell death — orderly, energy-dependent elimination of damaged or unwanted cells without inflammation ⟡ Two Pathways of Apoptosis: Intrinsic (Mitochondrial) Pathway: Triggered by: DNA damage, hypoxia, oncogene activation, growth factor withdrawal Pro-apoptotic proteins (BAX, BAK) → mitochondrial outer membrane permeabilisation → cytochrome c release Cytochrome c → forms apoptosome with APAF-1 → activates caspase-9 → executioner caspases (3, 6, 7) Anti-apoptotic proteins (BCL-2, BCL-XL) → block cytochrome c release In cancer: BCL-2 overexpression (e.g. follicular lymphoma t(14;18)) → cells resist apoptosis Extrinsic (Death Receptor) Pathway: Triggered by: FasL binding Fas receptor; TNF binding TNFR Receptor activation → FADD adaptor → activates caspase-8 → executioner caspases Leads to same downstream caspase cascade ⟡ How Cancer Evades Apoptosis: ✦ BCL-2 overexpression ✦ Loss of TP53 → no apoptosis signal after DNA damage ✦ Upregulation of IAPs (Inhibitor of Apoptosis Proteins) ✦ Downregulation of Fas receptor → immune evasion ✦ Activation of PI3K/AKT pathway → pro-survival signalling ▸ 4.3 ANGIOGENESIS IN TUMOURS Why tumours need angiogenesis: Tumours 1–2 mm cannot survive on diffusion alone → need blood supply Without new vessels → tumour cells become hypoxic → central necrosis ⟡ Mechanism: Tumour hypoxia → stabilises HIF-1α (Hypoxia Inducible Factor) HIF-1α → upregulates VEGF (Vascular Endothelial Growth Factor) and other angiogenic factors VEGF → stimulates endothelial cell proliferation, migration → new vessel sprouting New vessels are leaky, disorganised, inefficient → paradoxically creates more hypoxia ⟡ Angiogenic vs Anti-angiogenic balance: Pro-angiogenic: VEGF, FGF, PDGF, angiopoietins Anti-angiogenic: thrombospondin-1, angiostatin, endostatin In cancer: balance tips toward pro-angiogenic → "angiogenic switch" ⟡ Clinical relevance: Bevacizumab (Avastin) → anti-VEGF monoclonal antibody → anti-cancer therapy Anti-angiogenic drugs used in colorectal, lung, renal cell carcinoma ▸ 4.4 TUMOUR MICROENVIRONMENT (TME)A tumour is not just cancer cells — it is an entire ecosystem: ⟡ Components of the TME: Cancer-Associated Fibroblasts (CAFs) → secrete growth factors, remodel ECM, promote invasion Tumour-Associated Macrophages (TAMs) → M2-polarised; promote tumour growth, suppress immunity, promote angiogenesis Regulatory T cells (Tregs) → suppress anti-tumour immune response Myeloid-Derived Suppressor Cells (MDSCs) → block cytotoxic T cell function Extracellular Matrix (ECM) → remodelled by MMPs to facilitate invasion Blood vessels → tumour-induced, disorganised, leaky ⟡ Significance: TME actively promotes tumour growth, immune evasion, metastasis Target of modern immunotherapy (e.g. PD-1/PD-L1 checkpoint inhibitors) ▸ 4.5 EPIGENETICS IN CANCER Definition: Heritable changes in gene expression without alteration of DNA sequence ⟡ Epigenetic mechanisms: DNA methylation → methylation of CpG islands in gene promoters → gene silencing In cancer: hypermethylation of tumour suppressor gene promoters → silencing without mutation (e.g. RB, CDKN2A, MLH1) Global hypomethylation → genomic instability → oncogene activation Histone modification → acetylation (activ