Cancer Biology and Hallmarks of Cancer
Cancer biology encompasses the molecular and cellular mechanisms underlying malignant transformation, characterised by the hallmarks of cancer as described by Hanahan and Weinberg.
Key Facts
Hanahan and Weinberg (2000, updated 2011) described the hallmarks of cancer: 10 biological capabilities acquired during tumour development Original 6 hallmarks: sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis Added in 2011: reprogramming energy metabolism and evading immune destruction Enabling characteristics: genome instability/mutation and tumour-promoting inflammation Oncogenes (gain of function): e.g. RAS (30% of cancers), HER2, MYC, BRAF Tumour suppressor genes (loss of function): e.g. TP53 (most commonly mutated gene in cancer), RB1, APC, BRCA1/2 Knudson's two-hit hypothesis: both alleles of a tumour suppressor must be inactivated for loss of function Warburg effect: cancer cells preferentially use glycolysis even in the presence of oxygen (aerobic glycolysis)
Overview
Key Facts
Cancer biology is the study of the molecular and cellular mechanisms that drive malignant transformation. Understanding these mechanisms is fundamental to developing targeted therapies and personalised oncology.
Epidemiology
- Cancer affects approximately 1 in 2 people in the UK during their lifetime
- Approximately 375,000 new cancer diagnoses per year in the UK
- Approximately 167,000 cancer deaths per year
- Most common cancers (UK): breast, prostate, lung, colorectal
Aetiology
- Somatic mutations: acquired during lifetime; majority of cancers
- Germline mutations: inherited predisposition (5-10% of cancers); BRCA1/2, Lynch syndrome, Li-Fraumeni (TP53), retinoblastoma (RB1)
- Environmental carcinogens: tobacco (strongest modifiable risk factor), UV radiation, ionising radiation, aflatoxins, asbestos
- Infections: HPV (cervical), HBV/HCV (hepatocellular), H. pylori (gastric), EBV (Burkitt lymphoma, nasopharyngeal)
Pathophysiology
- Cancer arises from accumulation of genetic and epigenetic alterations in a single cell (monoclonal origin)
- Multi-step carcinogenesis: initiation (DNA damage) → promotion (clonal expansion) → progression (invasion, metastasis)
- Driver mutations: confer growth advantage; passenger mutations: neutral bystanders
- Tumour heterogeneity: intratumoral and intertumoral genetic diversity drives treatment resistance
- Cancer stem cells: self-renewing subpopulation responsible for tumour initiation, maintenance, and recurrence
Clinical Presentation
General Cancer Warning Signs
- Unexplained weight loss (>5% in 6 months)
- Persistent fatigue
- Unexplained pain
- Night sweats
- New or changing lumps
- Persistent cough or hoarseness
- Change in bowel or bladder habits
- Non-healing wounds
- Unexplained bleeding
Red Flags
- Any symptom from NICE NG12 2-week wait criteria
- Rapidly enlarging mass
- Bone pain with weight loss
- Neurological deficit with known malignancy (spinal cord compression)
- Haemoptysis, haematuria, postmenopausal bleeding
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Benign neoplasm | Slow-growing, encapsulated, no invasion | Imaging, biopsy |
| Infection | Fever, localised inflammation, response to antibiotics | Cultures, imaging |
| Autoimmune disease | Multi-system, characteristic autoantibodies | Autoantibodies, biopsy |
| Functional disorder | Normal investigations, stress-related | Exclusion diagnosis |
Diagnosis / Investigation
Bedside
- Thorough clinical examination
- Performance status assessment (WHO/ECOG, Karnofsky)
Bloods
- FBC, U&Es, LFTs, calcium (baseline)
- Tumour markers: PSA, CA-125, CEA, AFP, βhCG, CA19-9 (for monitoring, not usually diagnosis)
- LDH (prognostic in some cancers)
Imaging
- CT, MRI, PET-CT for staging
- USS for superficial lesions and guided biopsy
Special Tests
- Tissue biopsy: histological diagnosis (gold standard)
- Immunohistochemistry: protein expression patterns for classification
- Molecular profiling: next-generation sequencing (NGS) for driver mutations and targeted therapy selection
- Liquid biopsy: circulating tumour DNA (ctDNA) for monitoring
Management
Non-pharmacological
- MDT approach to cancer management
- Cancer nurse specialist support
- Psychological support and holistic needs assessment
- Lifestyle advice: smoking cessation, diet, exercise
Pharmacological
- Chemotherapy: cytotoxic agents targeting rapidly dividing cells
- Targeted therapy: agents directed at specific molecular targets (e.g. imatinib for BCR-ABL)
- Immunotherapy: checkpoint inhibitors (anti-PD-1, anti-CTLA-4), CAR-T cells
- Hormonal therapy: anti-oestrogens (tamoxifen), aromatase inhibitors, anti-androgens
- Supportive care: antiemetics, G-CSF, bisphosphonates
Surgical/Interventional
- Curative resection where possible
- Palliative surgery for symptom control
- Radiotherapy: curative and palliative
Referral Criteria
- NICE NG12 guides 2-week wait referral criteria for suspected cancer
- All confirmed cancers discussed at site-specific MDT
Prognosis
- UK cancer survival has doubled in the last 40 years
- Overall 10-year survival: approximately 50% for all cancers combined
- Highly variable by cancer type: testicular (98%), melanoma (90%), pancreatic (7%), lung (10%)
- Early-stage diagnosis is the single most important prognostic factor
- Personalised medicine and immunotherapy are improving outcomes for many cancer types
Other Relevant Information
Hallmarks of Cancer (Hanahan & Weinberg)
| Hallmark | Example Mechanism |
|---|---|
| Sustaining proliferative signalling | RAS mutations, EGFR amplification |
| Evading growth suppressors | TP53 loss, RB1 loss |
| Resisting cell death | BCL-2 overexpression |
| Enabling replicative immortality | Telomerase activation |
| Inducing angiogenesis | VEGF production |
| Activating invasion and metastasis | E-cadherin loss, MMP expression |
| Reprogramming energy metabolism | Warburg effect (aerobic glycolysis) |
| Evading immune destruction | PD-L1 expression |
| Genome instability | MMR deficiency, BRCA mutations |
| Tumour-promoting inflammation | NF-κB activation, cytokine production |
Key Oncogenes and Tumour Suppressors
| Gene | Type | Cancer Association |
|---|---|---|
| TP53 | TSG | >50% of all cancers |
| KRAS | Oncogene | Pancreatic, colorectal, lung |
| HER2 | Oncogene | Breast, gastric |
| BRCA1/2 | TSG | Breast, ovarian |
| APC | TSG | Colorectal (FAP) |
| BRAF | Oncogene | Melanoma, colorectal |
| MYC | Oncogene | Burkitt lymphoma |