Cancer Biology

Cancer is a disease of uncontrolled cell proliferation resulting from the accumulation of genetic and epigenetic alterations that subvert normal regulatory mechanisms. It is not a single disease but a heterogeneous collection of disorders sharing common biological principles — the hallmarks of cancer.

The Hallmarks of Cancer

Hanahan and Weinberg (2000, updated 2011 and 2022) described the defining functional capabilities that normal cells acquire during tumour development:

1. Sustaining proliferative signalling: Cancer cells generate their own mitogenic signals or upregulate growth factor receptors. RAS mutations lock RAS in the active GTP-bound state, constitutively activating downstream proliferation pathways (MAPK, PI3K/Akt). EGFR overexpression or mutation (L858R, exon 19 del in NSCLC) drives constitutive signalling.

1. Evading growth suppressors: Inactivation of tumour suppressor genes. RB loss (retinoblastoma): constitutive E2F activity → unrestrained S-phase entry. p16^INK4a/CDKN2A deletion: fails to inhibit CDK4/6 → Rb remains unphosphorylated... except Rb itself is often lost. These are the most commonly mutated tumour suppressors.

1. Resisting cell death: Upregulation of anti-apoptotic proteins (BCL-2 in follicular lymphoma — t(14;18) BCL2/IgH translocation; BCL-XL, MCL-1) or downregulation of pro-apoptotic proteins (BAX, BIM). Loss of p53 (>50% of cancers) eliminates the apoptotic response to DNA damage. BH3-mimetics (venetoclax targets BCL-2) restore apoptotic sensitivity.

1. Enabling replicative immortality: Normal somatic cells have a finite replicative lifespan due to telomere shortening (Hayflick limit, ~50 divisions). Cancer cells reactivate telomerase (hTERT catalytic subunit + hTERC RNA) to maintain telomere length. ~90% of cancers express telomerase; the rest use ALT (alternative lengthening of telomeres) via homologous recombination.

1. Inducing angiogenesis: Tumours require a blood supply beyond ~1–2 mm diameter (diffusion limit for O₂/nutrients). Cancer cells upregulate pro-angiogenic factors, particularly VEGF (vascular endothelial growth factor), in response to hypoxia (HIF-1α transcriptionally activates VEGF) and oncogenic signalling. New vessels are structurally and functionally abnormal. Anti-angiogenic therapy: bevacizumab (anti-VEGF antibody), sunitinib, sorafenib (multi-kinase inhibitors including VEGFR).

1. Activating invasion and metastasis: The hallmark most responsible for cancer mortality. The epithelial-mesenchymal transition (EMT) is a key molecular programme: cancer cells downregulate E-cadherin (encoded by CDH1; loss of cell-cell adhesion), upregulate N-cadherin, vimentin, and fibronectin, and gain mesenchymal properties including motility and invasiveness. Transcription factors driving EMT: TWIST, SNAIL, ZEB1/2. Matrix metalloproteinases (MMPs) degrade the basement membrane and ECM. The metastatic cascade: invasion → intravasation → survival in circulation → extravasation → colonisation of distant organs (organ tropism — breast → bone, lung, liver, brain; prostate → bone; colon → liver, lung).

1. Reprogramming energy metabolism (Warburg effect): Preferential aerobic glycolysis even in the presence of O₂ (described earlier). Fuels biosynthesis; exploited by FDG-PET.

1. Evading immune destruction: Tumours evolve multiple immune evasion strategies: downregulation of MHC class I (reduces CD8⁺ T cell recognition); expression of PD-L1 (exhausts T cells); secretion of immunosuppressive cytokines (TGF-β, IL-10); recruitment of regulatory T cells and tumour-associated macrophages (M2 polarisation). Immune checkpoint inhibitors restore T cell activity.

Additional emerging hallmarks: genomic instability and mutation, tumour-promoting inflammation, unlocking phenotypic plasticity, epigenetic reprogramming.

Oncogenes

Proto-oncogenes encode proteins that positively regulate cell growth and survival. They become oncogenes through gain-of-function mutations: point mutations (RAS G12V — constitutive activation), amplification (MYC, HER2/ERBB2, EGFR — increased protein levels), chromosomal translocation (BCR-ABL in CML; MYC/IgH in Burkitt lymphoma; EML4-ALK in NSCLC — creates a constitutively active fusion kinase targeted by crizotinib/alectinib), and insertional mutagenesis (retroviral integration near a proto-oncogene).

MYC (c-Myc) is a transcription factor (HLH-LZ family) that heterodimerises with MAX and activates transcription of >15% of all genes, including those for ribosome biogenesis, protein synthesis, cell cycle progression (CDK4, cyclin D2, cyclin E), and metabolic reprogramming. Myc is overexpressed or amplified in ~50% of cancers. NMYC amplification (MYCN on chromosome 2) in neuroblastoma is a major adverse prognostic factor.

Tumour Suppressor Genes

Tumour suppressors negatively regulate cell proliferation or promote apoptosis/DNA repair. They typically follow Knudson's two-hit hypothesis: both alleles must be inactivated for loss of function. First hit: somatic or germline mutation; second hit: loss of heterozygosity (LOH), deletion, promoter methylation, or second mutation.

TP53 (chromosome 17p13): The "guardian of the genome." p53 is a tetrameric transcription factor stabilised by DNA damage (blocked MDM2-mediated ubiquitination via ATM/CHK2 phosphorylation of p53). p53 transcriptionally activates: p21^CIP1 (CDK inhibitor → G1 arrest); GADD45 (DNA repair); BAX (pro-apoptotic); PUMA, NOXA (BH3-only proteins activating intrinsic apoptosis). The decision between arrest and apoptosis depends on damage severity, cell type, and cofactors. p53 is mutated in >50% of all cancers; Li-Fraumeni syndrome (germline TP53 mutation) confers high risk of multiple cancer types (sarcomas, breast cancer, brain tumours, leukaemias).

RB1: Encodes pRb, which restrains E2F transcription factors in G0 and early G1. Germline RB1 mutation → hereditary retinoblastoma (Knudson's two-hit model, 1971). Rb inactivation by viral oncoproteins: HPV E7 (in cervical cancer) binds and inactivates Rb; Adenovirus E1A; SV40 Large T antigen.

APC (chromosome 5q): Adenomatous polyposis coli; part of the β-catenin destruction complex (with Axin, GSK3β, CK1 → phosphorylates β-catenin → ubiquitination → proteasomal degradation). APC loss → β-catenin accumulates in nucleus → TCF/LEF transcription factor activation → Wnt target gene expression (MYC, cyclin D1) → colorectal cancer. Germline APC mutation → familial adenomatous polyposis (FAP) — hundreds to thousands of colonic polyps, near-certain colorectal cancer by age 40.

BRCA1 and BRCA2: Involved in HR repair. Loss → genomic instability, accumulation of DSBs → cancer. Synthetic lethality with PARP inhibition.

Apoptosis Pathways

Apoptosis is programmed cell death characterised by cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies phagocytosed by macrophages (no inflammation — vs necrosis). Two pathways: Intrinsic (mitochondrial): initiated by intracellular signals (DNA damage, oxidative stress, ER stress). Pro-apoptotic BCL-2 family members (BAX, BAK, BID, BIM) are activated; anti-apoptotic members (BCL-2, BCL-XL, MCL-1) are suppressed. BAX/BAK form pores in the outer mitochondrial membrane → cytochrome c release → apoptosome (APAF-1 + caspase-9 + cytochrome c) → caspase-9 → caspase-3 (executioner) → proteolysis of hundreds of cellular proteins → apoptosis. Extrinsic: initiated by death ligands (FasL, TRAIL, TNF) binding death receptors (Fas/CD95, TRAIL-R1/R2, TNF-R1) → DISC (death-inducing signalling complex) → caspase-8 → caspase-3.

Cell Cycle Checkpoints and Cancer

Nearly all cancers show dysregulation of the G1/S checkpoint. p16/CDKN2A (inhibits CDK4/6 → Rb remains active → E2F inactive → no S phase entry) is deleted, mutated, or silenced by methylation in ~50% of cancers. The spindle assembly checkpoint (SAC) failure → chromosome missegregation → aneuploidy → cancer driver chromosomal imbalances.

Targeted Therapy Principles

The therapeutic ratio of targeted therapy relies on oncogene addiction: cancer cells become dependent on the activity of a single activated oncogene for survival, and inhibiting that oncogene causes disproportionate cell death compared to normal cells. Examples: imatinib (BCR-ABL, CML), erlotinib/gefitinib (EGFR L858R/exon 19 del, NSCLC), vemurafenib/dabrafenib (BRAF V600E, melanoma), crizotinib (ALK, ROS1 fusions, NSCLC), venetoclax (BCL-2, CLL/AML), olaparib (BRCA1/2 synthetic lethality), CDK4/6 inhibitors (HR+ breast cancer).