Mechanisms of Cancer & Anti-Cancer Pharmacology

Acknowledgement of Country

  • We acknowledge the Kaurna people as the original custodians of the Adelaide Plains and the land on which the University of Adelaide’s North Terrace, Waite, and Roseworthy campuses are built.

Key Learning Objectives

  • Understand definition, genesis, and progression of neoplasms.
  • Comprehend the role of genetic mutations in neoplastic development (proto-oncogenes vs tumour-suppressor genes).
  • Grasp the two-step model of carcinogenesis (initiation → promotion).
  • Distinguish benign vs malignant tumours and define “cancer”.
  • Describe metastasis: requirements, routes, and common sites.
  • Apply concepts of grading (microscopic) and staging (macroscopic) to prognosis.
  • Become familiar with major classes of anti-cancer drugs, their cellular targets, side-effects, resistance, and rationale for combination therapy.

Cellular Plasticity & Pre-Neoplastic Change

  • Plasticity = ability of a tissue to alter form/function in adaptation or regeneration.
  • Progressive spectrum (reversible → irreversible):
    • Normal
    • Hyperplasia – ↑ cell number (e.g. endometrium).
    • Metaplasia – conversion of one differentiated cell type to another (e.g. bronchial epithelium after long-term smoking).
    • Dysplasia – disordered cell growth with loss of uniformity; reversible if stimulus withdrawn (e.g. cervical dysplasia).
    • Neoplasia – uncontrolled, irreversible proliferation forming a mass.

Neoplasia Defined

  • “Neo” = new, “plasia” = growth.
  • Tumours/neoplasms arise from genomic alterations → failure of normal controls → excessive, poorly regulated proliferation.
  • THREE P’s summarise behaviour:
    • Progressive – growth independent of normal cues.
    • Purposeless – no physiological function.
    • Parasitic – diverts host nutrients without contributory benefit.

Normal Cell Turnover vs Tumour Formation

  • Homeostasis: Cell Proliferation=Apoptosis\text{Cell Proliferation} = \text{Apoptosis} (no net change).
  • Neoplasia: ↑ proliferation + ↓ apoptosis → net cellular gain → mass.

Genetic Regulation of Proliferation

  • Two gene groups maintain balance:
    1. Proto-oncogenes (dominant):
    • Code for growth-promoting proteins.
    • Mutation/over-expression of ONE allele → oncogene → uncontrolled growth, checkpoint bypass.
    • Examples: HER2, PRAD1.
    1. Tumour-suppressor genes (recessive):
    • “Apply the brakes” via apoptosis/DNA repair.
    • BOTH alleles must be inactivated to lose restraint.
    • Examples: p53, BRCA1.

Nature of Mutations

  • DNA replication ≈ 3×1093\times10^{9} base pairs per division; ≈ 2 trillion divisions/day.
  • Most replication errors corrected; single mutations rarely sufficient for cancer.
  • Mutagenic sources: chance, inherited germline defects, environmental carcinogens (chemicals, radiation, viruses).
  • Mutations can be beneficial, neutral, or harmful, depending on gene context.

Carcinogenesis (Cancer Initiation & Promotion)

  • Carcinogenesis = process by which normal cell → cancer cell.
  • Two-step model:
    1. Initiation – rapid, irreversible DNA damage by “initiators” (mutagens)
    • Alkylating drugs, hydrocarbons (smoked food), aromatic amines, nitrosamines, tobacco-specific nitrosamines, UV sunlight.
    1. Promotion – prolonged, reversible proliferation stimuli “promoters” amplify initiated clone
    • Hormones (oestrogen), chronic inflammation (cirrhosis, ulcers), cyclamates, viruses (EBV, HPV).
  • Chemical carcinogenesis pathway: DNA damage → (repair failure) → genomic instability ± loss of tumour-suppressors → pre-cancer → cancer; apoptosis may abort process.

Classification of Neoplasms

  • Benign: Localised, do not invade or metastasise, usually encapsulated, slow-growing, well-differentiated.
  • Malignant (Cancer): Invasive, can metastasise, poorly defined margins, fast growth, variable differentiation.

Differentiation (Histologic Grade)

  • Well-differentiated: resembles parent tissue, minimal atypia, low mitoses → better prognosis.
  • Moderately: retains some architecture, pleomorphism begins.
  • Poorly-differentiated: little resemblance, marked atypia, hyperchromasia, high mitotic rate, central necrosis → aggressive.

Benign Tumours – Clinical Considerations

  • Not cancerous yet can cause harm via:
    • Obstruction or compression (nerves/blood vessels).
    • Space-occupying mass → ↑ICP, organ dysfunction.
    • Ulceration/haemorrhage → blood loss.
  • Usually curable by excision, low recurrence, never progress to malignancy.

Malignant Tumours – Clinical & Pathologic Features

  • Gross: non-capsulated, irregular/ill-defined, infiltrative.
  • Microscopic: large dark pleomorphic nuclei, abundant mitoses, central necrosis.
  • Consequences: tissue destruction, organ failure, ulceration/bleeding, perforation, cachexia.

Cancer Terminology & Nomenclature

  • Suffixes:
    • Benign: “-oma” (e.g. adenoma, leiomyoma).
    • Malignant of epithelial origin: “carcinoma” (adenocarcinoma, squamous cell carcinoma).
    • Malignant of mesenchymal origin: “sarcoma” (osteosarcoma, leiomyosarcoma).
  • Exceptions (malignant despite “-oma”): melanoma, lymphoma, mesothelioma.
  • Primary tumour named by site of origin; secondary (metastatic) retains primary’s name (e.g. melanoma metastasis in brain ≠ brain cancer).

Dysplasia & Carcinoma In Situ (CIS)

  • Dysplasia: pre-neoplastic, confined to epithelium above basement membrane, potentially reversible, stimulus-dependent.
  • Carcinoma in situ: high-grade dysplasia extending full epithelial thickness, has NOT breached basement membrane, low likelihood of regression.
  • Many invasive cancers evolve from progression of pre-existing dysplasia/CIS.

Metastasis

  • Definition: spread of malignant cells from primary site to distant site forming a secondary tumour.
  • Late-stage event requiring multiple mutations → phenotypic capabilities:
    • Detach → motility → invade ECM → intravasate → survive circulation → extravasate → induce angiogenesis → colonise new niche.

Routes of Spread

  1. Haematogenous (blood) – common in sarcomas.
  2. Lymphatic – common in carcinomas.
  3. Transcoelomic (direct seeding) – peritoneum, pleura, joint spaces.

Common Metastatic Sites (high blood flow)

  • Liver, lung, brain, bone, adrenal glands.
  • Grossly multifocal; microscopically resemble primary (e.g. melanotic deposits in brain metastasis).

Grading vs Staging – Prognostic Tools

  • Grade (microscopic): extent of differentiation (1 = well; 4 = poorly). Lower grade → better prognosis.
  • Stage (macroscopic): size, depth, nodal status, distant spread (e.g. TNM). Lower stage → better prognosis.
  • Determined via imaging, surgical pathology, sentinel node biopsy.

Traditional Cancer Management

  • Surgery: curative for localised disease; limited in systemic/metastatic forms.
  • Radiotherapy: local photon (γ) delivery; adjunct to surgery/chemo.
  • Chemotherapy: systemic cytotoxics; adjunct or primary in disseminated disease.
  • Limitations: invasiveness, cost, duration, significant side-effects (because all rapidly dividing cells targeted).

Epidemiology & Survival

  • Estimated lifetime probability of cancer death by age 85: overall ≈15%\approx 15\%; males ≈17%\approx 17\%, females ≈13%\approx 13\% (Australia).
  • 5-year relative survival (all cancers): improved from 52%52\% (1989-93) → 70%70\% (2014-18).

Anti-Cancer Pharmacology Overview

  • Majority are non-specific cytotoxics interfering with DNA/mitosis; newer agents target specific molecular pathways or immune checkpoints.
  • Cell-cycle knowledge crucial: some drugs act phase-specifically (e.g. S-phase antimetabolites, M-phase spindle poisons) while others are non-phase-specific (alkylators).

Major Drug Classes & Mechanisms

  1. Alkylating Agents (e.g. cyclophosphamide)
    • Highly reactive; form DNA crosslinks → strand breakage; not cell-cycle specific.
  2. Antimetabolites (S phase)
    • Folate antagonist: methotrexate mimics folic acid → blocks nucleotide synthesis.
    • Pyrimidine analogues: 5-fluorouracil → inhibits thymidylate synthetase.
    • Purine analogues: pentostatin → inhibits adenosine deaminase → ↓ purines.
  3. Cytotoxic Antibiotics (e.g. bleomycin)
    • Bacterial glycopeptides chelating metal ions; cause DNA fragmentation; G2 phase active.
  4. Spindle/Mitotic Poisons (vinca alkaloids: vincristine, vinblastine)
    • Bind tubulin → prevent microtubule assembly → metaphase arrest; side-effects include myelosuppression and neurotoxicity.
  5. Tyrosine Kinase Inhibitors
    • Small molecules (imatinib) block oncogenic kinases (Bcr-Abl in CML); monoclonal antibodies (trastuzumab → HER2) hinder growth-factor signalling.
  6. Hormonal Therapies
    • Agonists: high-dose corticosteroids (prednisone) suppress lymphoid lineage.
    • Antagonists: tamoxifen (ER blocker) in breast cancer; flutamide (androgen receptor blocker) in prostate cancer.
  7. Immunotherapies
    • Monoclonal antibodies: rituximab (CD20 for B-cell lymphoma), trastuzumab (HER2).
    • Immune checkpoint inhibitors: pembrolizumab (PD-1), atezolizumab (PD-L1) unleash T-cell attack by blocking inhibitory signals.

Combination Therapy Rationale

  • Regimens (e.g. CHOP, ABVD) combine drugs with distinct mechanisms → synergistic kill, reduced individual toxicity, diminished resistance likelihood.
  • Intermittent high-dose courses (2–3 weeks apart) allow marrow recovery.

Adverse Effects & Management

  • Emesis/diarrhoea: gut epithelium damage; treat with anti-emetics/loperamide.
  • Bone marrow suppression: dose-limiting; strategies – autologous marrow reinfusion, growth-factor stimulation (G-CSF, EPO).
  • Neurotoxicity, alopecia, mucositis reflect collateral damage to rapidly dividing/MT-dependent cells.
  • Immunotherapy-specific: autoimmune-type toxicities due to target overlap on normal cells.

Drug Resistance Mechanisms

  • Efflux pumps (P-glycoprotein) expel drug.
  • ↓ Drug uptake (loss of transporters).
  • Altered target enzymes (isoforms of topoisomerase).
  • Enhanced detoxification (↑ glutathione conjugation).
  • Overcome by combination therapy, novel agents, and dose scheduling.

Ethical, Practical & Societal Considerations

  • Balancing life-prolongation vs quality of life given side-effects.
  • Cost and access to advanced therapies (checkpoint inhibitors) can create disparities.
  • Recognition of Indigenous health inequities (link to acknowledgement) vital in cancer prevention, screening, and treatment outreach.

Recap of Essential Concepts

  • Neoplasia arises from genetic imbalance: proto-oncogene activation and tumour-suppressor loss.
  • Carcinogenesis requires initiating mutation plus promoting proliferation.
  • Benign vs malignant defined by invasive & metastatic potential, not solely morphology.
  • Metastasis depends on tumour acquiring motility, invasiveness, intravasation, survival, and colonisation capabilities.
  • Grade (microscopy) and stage (macroscopy) together inform prognosis and guide therapy.
  • Cancer therapy ranges from local (surgery, radiation) to systemic pharmacotherapy; modern trends emphasise targeted and immune-based treatments.
  • Side-effects and resistance remain major hurdles, mandating personalised, combination, and supportive care strategies.