HMM103: Cell Technology – Cancer
Cell Cycle Fundamentals
Human body contains ≈ 3\times10^{13} cells.
Lifetime divisions ≈ 10^{16} → 4\times10^{6} divisions s⁻¹.
Division rate tissue-dependent:
Bone marrow (RBC life ≈ 120 days) & gut epithelium (3‒4 days) = highly proliferative.
Post-natal brain & neurons = essentially non-dividing.
Interphase (≈ 90 % of cycle)
G1 (Gap 1): growth; organelle replication.
S (Synthesis): chromosomal DNA replication.
G2 (Gap 2): additional growth; preparation for mitosis.
Mitosis (M): prophase → metaphase → anaphase → telophase → cytokinesis.
Coordination & Homeostasis of Cell Number
Homeostatic equation: Rate division = Rate deaths
If \text{Division} > \text{Death} ⇒ uncontrolled expansion = cancer.
Checkpoints (Go / No-Go Gates)
G1 Growth Checkpoint (end G1):
Size, nutrient state, protein stock.
Failure → G0 resting state.
S (DNA Synthesis) Checkpoint:
Verifies faithful DNA replication before G2/M.
G2/M Checkpoint:
DNA damage, cell size before entering mitosis.
M (Spindle) Checkpoint: metaphase-to-anaphase transition; ensures all kinetochores attached.
Positive Regulators – Cyclins & CDKs (core drivers)
Cyclins: regulatory proteins with oscillatory expression.
CDKs: serine/threonine kinases; activated upon cyclin binding → phosphorylate substrates.
G1/S-cyclins (Cyclin E) + CDK2 → late G1 progression.
S-cyclins (Cyclin A) + CDK2 → DNA replication; remain high till mitosis.
G1 cyclins (Cyclin D1) + CDK4/6 → early G1 in response to growth signals (Ras).
M-cyclins (Cyclin B) + CDK1; activated by CDC25C; destroyed mid-mitosis.
PCNA (proliferating cell nuclear antigen): DNA polymerase processivity factor; marker of cycling cells.
Negative Regulators – “Brakes” of the Cycle
CDK Inhibitors (CKIs):
p15,\;p16,\;p18,\;p19 (INK4 family) – differentiation-induced.
p21^{Cip1},\;p27^{Kip1} – DNA damage & growth suppression.
Tumour Suppressor Proteins / Checkpoint Kinases:
p53 (guardian of genome): activates p21, apoptosis.
ATM/ATR → Chk1/Chk2 → cell-cycle arrest upon genotoxic stress.
Wee1 / MYT1: inhibit CDK1 if replication incomplete.
APC/C (anaphase-promoting complex): ensures spindle integrity.
Blockage persisting → apoptosis.
Mutations Disrupting the Cycle → Cancer
Gain of positive signals (oncogene activation).
Loss of negative signals (TSGs, CKIs).
Checkpoint bypass.
Apoptotic escape.
Cancer Terminology & Forms
Neoplasm / Tumour: abnormal mass; benign or malignant.
Benign: non-invasive, localized, rarely recur post-excision.
Pre-malignant: high probability of progression depending on additional hits.
Malignant: invasive, metastatic potential.
Classification by Tissue Origin
Carcinoma: epithelial origin (skin, breast, lung, colon, liver, stomach, prostate, pancreas).
Sarcoma: connective tissues (bone, cartilage, fat, nerve).
Leukaemia: haemopoietic progenitors → excessive abnormal blood cells in circulation.
Lymphoma / Myeloma: lymphoid lineage; nodes, stomach, brain, intestine.
Epidemiology Snap-Shot (Australia)
Most diagnosed (M vs F): prostate (16 665 M) / breast (17 586 F).
Deadliest: lung (5 179 M; 3 842 F), colorectal, prostate (M) or breast (F), pancreas, liver.
Cancer Risk Factors (Environmental & Genetic)
Lifestyle: smoking, alcohol, diet (processed meats, high fat), obesity, inactivity.
Occupational & environmental exposures: radiation, sunlight (UV), pollutants.
Chronic infections: oncogenic microbes (e.g., Helicobacter\;pylori\to gastric, Salmonella\;typhi → biliary).
Reproductive/hormonal, iatrogenic medical factors.
Family history: germline mutations increasing risk (breast, ovarian, colon, prostate, thyroid, bladder, leukaemia, etc.).
Hallmarks of Cancer (Hanahan & Weinberg – expanded)
Sustaining proliferative signalling.
Evading growth suppressors.
Resisting cell death.
Enabling replicative immortality.
Inducing or accessing vasculature (angiogenesis).
Activating invasion & metastasis.
Genome instability & mutation (enabler).
Avoiding immune destruction.
Deregulating cellular metabolism (Warburg effect).
Tumour-promoting inflammation.
Unlocking phenotypic plasticity.
Non-mutational epigenetic reprogramming.
Senescent cell influence.
Polymorphic microbiomes.
Treatment resistance appears as consequence of several hallmarks.
Step-Wise Development Model
DNA replication/repair defects (mutations accrue).
Hyper-proliferation.
Growth suppression evasion.
Apoptotic pathway disruption.
Senescence bypass.
Angiogenesis induction.
Immune evasion.
Metabolic rewiring.
Invasion/metastasis.
Therapy resistance.
Critical Gene Categories
Oncogenes (dominant gain-of-function; single allele suffices):
Growth ligands/receptors: EGFR, IL-6R.
Signalling kinases: RAS, RAF, PI3K.
Transcription factors: MYC.
Apoptosis blockers: Bcl-2.
Tumour Suppressor Genes (recessive loss-of-function; both alleles):
Signal moderators: SOCS proteins.
Tissue architecture: APC (colorectal).
Cell-cycle controllers: Rb.
Damage response: p53.
Genome Stability Genes (“caretakers”): maintain integrity; BRCA1/2, mismatch repair, checkpoint components.
Example: BRCA1 protein repairs double-strand breaks; mutation → defective repair → breast/ovarian cancer risk.
Diagnostics & Clinical Pathology
Laboratory assays:
Complete Blood Count (CBC); chemistry panels; urine cytology.
Tumour markers (e.g., PSA, CA-125) & cytogenetics.
Imaging:
CT, MRI for anatomical & functional information.
Biopsy:
Histopathology: architecture, dysplasia, in situ vs invasive, marker staining (IHC for Ki-67, HER2, etc.).
Morphological progressions (examples):
Colon: normal → hyperproliferative epithelium → adenoma → carcinoma.
Lung: normal → hyperplasia/metaplasia → dysplasia → carcinoma in situ → invasive squamous or adenocarcinoma.
Traditional Therapeutic Modalities
Surgery: physical excision; limitations—access, infection, residual cells.
Radiotherapy: DNA damage in dividing cells; collateral damage; contraindicated in infants.
Chemotherapy: systemic cytotoxics; non-specific, side-effects, resistance.
Multimodal regimens: combine above at lower doses; synergy yet resistance often emerges.
Targeted Agents Matching Hallmarks (Examples)
Sustained growth: EGFR inhibitors, CDK inhibitors.
Genome instability: PARP inhibitors.
Resisting death: BH3 mimetics (pro-apoptotic).
Angiogenesis: VEGF/VEGFR blockers.
Immune evasion: immune-activating anti-CTLA-4 mAbs.
Immortality: telomerase inhibitors.
Metastasis: HGF/c-Met inhibitors.
Metabolism: aerobic glycolysis (Warburg) inhibitors.
Anti-inflammatory drugs to curb tumour-promoting inflammation.
Emerging / Alternative Approaches
Radiomics & Pathomics: high-content imaging → feature extraction → patient stratification.
Thermal ablation & magnetic hyperthermia.
Nanomedicine: targeted drug delivery, enhanced permeability & retention.
Extracellular vesicles as drug carriers / biomarkers.
Gene therapy: replacement or editing of defective genes.
Natural antioxidants & dietary modulators as adjuncts.
Immunotherapy & precision targeted therapy.
Key Equations & Concepts Recap
Cell-cycle balance: \text{Net\,Growth} = (\text{Proliferation} – \text{Death}).
Mutation rate amplification when “caretaker” genes lost: \mu{\text{effective}} = \mu{0}\,\times\,\text{(destabilisation factor)}.
Dominant vs recessive genetic effects on cancer initiation: oncogene activation probability P{onco} \propto \mu per allele; TSG inactivation P{TSG} \propto \mu^{2} because both hits required.
Lecture Take-Home Messages
Cyclin–CDK complexes are pivotal; checkpoints ensure fidelity.
Oncogenes, TSGs, GSGs directly govern the cell cycle; their mutation initiates malignancy.
Cancers illuminated by hallmarks framework; understanding guides diagnostics & therapy.
Diagnosis triangulates lab tests, imaging, and histology.
Novel therapies target hallmark-specific processes, aiming for precision and reduced toxicity.