Unlock the molecular secrets of cancer. Discover the 10 Hallmarks, cell cycle checkpoints, oncogenes (RAS, MYC, BCR-ABL), and pathways crucial for cancer develo
MBPA 3412 — ONCOPATHOLOGY HALLMARKS OF CANCER Comprehensive Revision Notes Dr. A. Irungu --- THE HALLMARKS OF CANCER 1. Self-sufficiency in growth signals 2. Insensitivity to growth inhibitory signals 3. Evasion of cell death 4. Limitless replicative potential 5. Development of sustained angiogenesis 6. Ability to invade and metastasize 7. Reprogramming of energy metabolism 8. Evasion of the immune system 9. Genomic instability (enabler) 10. Tumour-promoting inflammation (enabler) --- HALLMARKS OF CANCER — STORY MNEMONIC "Some Idiots Escape Life, Drinking Alcohol Recklessly, Even Getting Tipsy" Some — Self-sufficiency in growth signals Idiots — Insensitivity to growth inhibitory signals Escape — Evasion of cell death Life — Limitless replicative potential Drinking — Driving sustained angiogenesis (Development) Alcohol — Always invading (Ability to invade and metastasize) Recklessly — Reprogramming of energy metabolism Even — Evading the immune system Getting — Genomic instability (enabler) Tipsy — Tissue inflammation — Tumour-promoting inflammation (enabler) FOUNDATION: NORMAL CELL CYCLE Key players: Cyclins CDKs CDK Inhibitors (CKDIs) CDKs are constitutively inactive — activated only after binding their specific cyclin. Cyclins are synthesized at specific phases to activate CDKs. Over 15 cyclins identified. They appear sequentially: Cyclin D → E → A → B , each binding one or more CDKs. --- Cyclin D and RB Phosphorylation The most important cell cycle concept to know. - Cyclin D is the first cyclin to rise (mid-G1) - Cyclin D binds CDK4 → Cyclin D-CDK4 complex → phosphorylates RB protein - RB = the molecular on/off switch of the cell cycle Hypophosphorylated RB (active state): binds E2F transcription factor → blocks progression → cell STAYS in G1 Hyperphosphorylated RB (inactive state): releases E2F → E2F target genes transcribed → cell enters S phase --- Cell Cycle Progression G1/S Restriction Point - Cyclin E-CDK2 forms → E2F increases cyclin E transcription → DNA replication begins - S phase = point of no return G2/M Transition - E2F transcribes Cyclin A → Cyclin A-CDK2 (regulates mitotic prophase) - Cyclin B-CDK1 (activated by protein phosphatase) → breaks down nuclear membrane → mitosis begins --- Cell Cycle Checkpoints G1/S checkpoint — checks for DNA damage - DNA damaged → repair + cell cycle arrest - Irreparable damage → apoptosis G2/M checkpoint — confirms DNA replication is complete before mitosis - Critical after ionizing radiation exposure - Defects → chromosomal abnormalities --- CDK Inhibitors (CKDIs) — tumour suppressors Cip/Kip family: p21, p27, p57 - Bind and inactivate cyclin-CDK complexes - p21 transcription controlled by p53 (guardian of the genome) - p53 = surveillance protein; mutated in many cancers INK4/ARF family: p16INK4a and p14ARF - p16INK4a competes with Cyclin D for CDK4 binding → prevents RB phosphorylation → G1 arrest - Frequently mutated or inactivated by hypermethylation in cancers --- HALLMARK 1: SELF-SUFFICIENCY IN GROWTH SIGNALS Core concept: Cancer cells grow autonomously without external mitogenic signals via oncogenes. Definitions - Proto-oncogenes: Normal physiological regulators of cell proliferation and differentiation - Oncogenes: Mutated/activated proto-oncogenes that drive uncontrolled proliferation - Oncoproteins: Resemble normal proto-oncogene products but lack regulatory elements → constitutively active Mechanisms — 6 levels 1. Growth factors Cancer cells synthesize the same growth factors they have receptors for → autocrine self-stimulation 2. Growth factor receptors Mutant receptors constitutively dimerize and signal without ligand binding → continuous mitogenic signal 3. Signal-transducing proteins (RAS oncogene) Located under cell membrane, relay signals from receptors to nucleus. RAS oncogene — mutant RAS is permanently active (cannot hydrolyse GTP) 4. Non-receptor tyrosine kinases - c-ABL gene translocated t(9;22) in CML and some ALL - Creates BCR-ABL fusion gene → BCR-ABL protein loses inhibitory region → constitutive kinase activity - This translocation = Philadelphia chromosome 5. Transcription factors - MYC, MYB, JUN, FOS oncogene products found in nuclei of transformed cells - MYC = most commonly involved oncogene in human cancers; potent transcriptional activator 6. Cyclins and CDKs - Abnormal expression in: breast, oesophagus, head and neck, liver, mantle cell lymphoma - CDK4 gene amplification in sarcomas and glioblastoma --- HALLMARK 2: INSENSITIVITY TO GROWTH INHIBITORY SIGNALS Core concept: Tumour suppressor genes apply brakes to proliferation. Unlike oncogenes, both copies must be lost for tumour development (Knudson's two-hit hypothesis). --- RB Gene — "Governor of the Cell Cycle" - First tumour suppressor gene discovered Locus 13q14 - Knudson's Two-Hit Hypothesis — from studying retinoblastoma: - Familial: one germline mutation inherited + second somatic hit → tumour - Sporadic: both alleles lost by somatic mutation in a single retinoblast - Homozygous RB loss seen in many cancers - Heterozygosity at RB locus alone is NOT neoplastic Mechanism: RB (hypophosphorylated, active) binds E2F → blocks cyclin E transcription → no S phase entry In cancer: - Almost all cancers have a disabled G1 checkpoint via: RB mutation OR mutations in cyclin D, CDK4, or CDKIs - HPV and other oncogenic DNA viruses encode proteins that bind and inactivate RB --- TP53 Gene — "Guardian of the Genome" Activating stresses: DNA damage anoxia inappropriate oncogene signalling Activation mechanism: DNA damage → p53 phosphorylation → p53 activated Functions of activated p53: - Cell cycle arrest (G1/S block) - DNA repair - Cellular senescence - Apoptosis Mechanism: Activated p53 → transcribes CDKN1A → prevents RB phosphorylation → G1/S block → time for repair. If irreparable → senescence or apoptosis. In cancer: - 70% of tumours show biallelic TP53 loss - Li Fraumeni Syndrome: germline TP53 mutation (one allele) — second somatic hit later - HPV also inactivates p53 by protein binding --- TGF-β (Transforming Growth Factor-β) Pathway - Potent inhibitor of proliferation in normal epithelial, endothelial, and haematopoietic cells - TGF-β binds TGF-β receptor I + II → receptor dimerisation → cascade → activates CDKIs + represses MYC, CDK2, CDK4, cyclin A, cyclin E In cancer: - Mutated in 100% of pancreatic cancers and 83% of colon cancers - In late-stage tumours: TGF-β activates EMT (Epithelial-to-Mesenchymal Transition) → promotes invasion and metastasis (paradoxical pro-tumour effect) --- Contact Inhibition, NF2 and APC Contact inhibition — normal cells stop dividing on cell-to-cell contact; abolished in cancer cells - E-cadherin maintains contact inhibition → lost in malignant cells - NF2 gene → produces neurofibromin-2 (merlin) → facilitates E-cadherin-mediated contact inhibition APC gene → regulates destruction of cytoplasmic β-catenin - APC loss → β-catenin accumulates → translocates to nucleus → acts as growth-promoting transcription factor - Familial adenomatous polyposis (FAP): germline APC mutation → hundreds of colonic polyps → inevitable malignant transformation - Somatic loss of both APC alleles in ~70% of sporadic colon cancers --- HALLMARK 3: EVASION OF CELL DEATH Apoptosis Two pathways: - Extrinsic: death receptor-mediated (e.g., FAS ligand) - Intrinsic (mitochondrial): regulated by BCL2 family Both converge → caspase cascade → cell destruction BCL2 family — the critical balance: Pro-apoptotic Anti-apoptotic Regulators (BH3-only) --- --- --- BAX, BAK BCL2, BCL-XL BAD, BID, PUMA BH3-only proteins tilt balance toward pro-apoptotic molecules → apoptosis proceeds Cancer evasion mechanisms: - Overexpression of BCL2 (e.g., follicular lymphoma — t(14;18) ) - Downregulation of BAX, BAK - TP53 loss → reduced apoptosis signalling - Viral proteins that mimic BCL2 --- Autophagy - Stress-induced process: cells digest their own components for survival - Cancer cells either: - Accumulate mutations to avoid autophagy, O