Neoplasia & Cancer Fundamentals – Vocabulary Flashcards

Definition and Terminology

• Neoplasia: literally “new growth”; proliferation of cells/tissue without physiological purpose.
  • Examples: moles, warts.
• Tumour (Latin "swelling")
  • Historically linked to inflammation.
  • May be benign (no direct threat to life) or malignant (tending toward death/deterioration).
• Cancer
  • Word origin: Greek karkinos (“crab”) – refers to projecting, infiltrative growth pattern.
  • Used almost exclusively for malignant tumours.
• Oncology: study/treatment of cancer (onkos = mass).
• Clonal origin: most tumours arise from a single mutated cell.
• Pleomorphism: tumour ends up containing cells of different types/sizes/shapes due to additional mutations.
  • Extreme example: teratomas (“monstrous tumours”) from totipotent germ cells; may contain hair, teeth, bone, neuronal tissue, etc.

Normal Cell Development: Growth, Regulation & Differentiation

• Normal cells:
  • Grow, divide, differentiate into specialised forms (myocyte, erythrocyte, neuron, etc.).
  • Maintain contact inhibition & neighbour awareness.
  • Monitor DNA integrity; activate repair systems.
  • Undergo apoptosis when irreparable damage occurs.
• Replicative capacity: average somatic cell divides $50\text{--}60$ times before senescence.
  • Governed by telomere shortening.
  • Tumour-suppressor proteins (e.g., p53, RB) reinforce growth arrest.
• Apoptotic cascade example:
  • Mitochondrial damage ➜ release of cytochrome-c ➜ downstream caspase activation ➜ controlled cell death.

Carcinogenesis: Breaking the Three Fundamental Rules

A cell must violate all three rules to become malignant:

1. Divide only when appropriately signalled.
2. Commit apoptosis when severely damaged.
3. Divide a finite number of times.

• Success requires:
  • Constitutive activation of growth pathways.
  • Inactivation/mutation of tumour-suppressor genes (e.g., $RB1$, $TP53$).
  • Reactivation of telomerase to maintain telomere length.
• Result = Unrestrained, signal-independent, apoptosis-resistant, immortal growth that can encroach on neighbours & migrate (metastasise).

Molecular & Cellular Mechanisms Promoting Cancer

• Autocrine signalling loops: tumour makes its own growth factors (e.g., PDGF, TGF-α in glioblastoma, sarcoma).
• Growth-factor receptor alteration: EGFR over-expression/constitutive activity (stomach, brain, breast cancers).
• Intracellular signalling mutation:
  • RAS family: mutated in >$30\%$ of cancers (≈$95\%$ pancreatic, $45\%$ colon, $35\%$ lung adenocarcinoma).
• Epigenetic changes (DNA methylation, histone modification) can silence tumour-suppressors without altering DNA sequence.
  • Example: histone de-acetylation around $RB$ gene ➜ pRB inaccessible.
  • Caffeine increases SC35 splicing factor → may enhance/restore KLF6 tumour-suppressor variants (possible protective role).
• Inflammation & ROS: chronic inflammation (hepatitis, ulcerative colitis) → TNF-α, inducible NOS, COX-2, LOX enzymes → DNA damage via reactive oxygen/nitrogen species. Reduced antioxidant (vitamin-E) levels worsen risk.

Characteristics of Cancer Cells

• Rate of growth: usually rapid, but some benign tumours can grow quickly, some malignancies slowly (impacting drug efficacy).
• Differentiation state:
  • Malignant = poorly differentiated/anaplastic.
  • Anaplasia = loss of specialised features.
• Plasticity: potential to transdifferentiate (e.g., nerve-to-muscle phenotype).
• Pleomorphism: heterogeneity in size/shape within tumour.
• Tumour markers: substances released into blood (e.g., PSA).
  • Helpful for screening/monitoring but limited by false-negatives and lack of specificity between benign vs malignant.
• Cancer stem cells: only sub-population truly immortal; therapy must eradicate every malignant stem cell to avoid relapse.

Hallmarks of Cancer (Hanahan & Weinberg)

• Genomic instability & mutation
• Tumour-promoting inflammation
• Sustained proliferative signalling
• Evading growth suppressors
• Resisting apoptosis
• Enabling replicative immortality
• Inducing angiogenesis
• Activating invasion & metastasis
• Deregulating cellular energetics (Warburg-like increased glucose demand)
• Avoiding immune destruction

Risk Factors & Prevention

• Up to $\frac{2}{3}$ cancers may originate from random replication errors (controversial).
• Five leading modifiable factors (>$1/3$ of deaths):
  1. Tobacco ($>8$ million deaths).
  2. Alcohol.
  3. High body-mass index.
  4. Low fruit/vegetable intake.
  5. Physical inactivity.
• WHO focuses on $7$ major preventable risks (Fig 1.5): tobacco, diet/obesity, alcohol, infections, environmental pollution, occupational carcinogens, ionising radiation.
  • Preventive strategies: smoking cessation; balanced diet with ample produce; weight control & exercise; vaccination (HBV, HPV); reduce exposures; PPE in workplaces; limit radiation.

Inherited vs Sporadic Cancers & Two-Hit Hypothesis

• Two-hit model (Knudson): both alleles of a tumour-suppressor must be inactivated.
  • In hereditary cases, first “hit” is germline; only one additional somatic hit needed.
• Proto-oncogenes ➜ Oncogenes: single gain-of-function mutation sufficient (dominant).
• Most common cancers require $4\text{--}7$ cooperative mutations accumulated over time.
• Mendelian (single-gene) cancers:
  • Tumour-suppressor loss: autosomal recessive in effect, but inheritance often autosomal dominant with reduced penetrance (e.g., retinoblastoma $RB$, Lynch syndrome mismatch-repair genes).
  • Oncogene gain-of-function: autosomal dominant (e.g., EGFR mutations).
• Penetrance variability illustrated by Lynch syndrome family: same germline mutation; grandfather & granddaughter affected, mother phenotypically normal.
• Sporadic cancers: majority; driven by environment, lifestyle, random errors.

Carcinogens: Environmental, Lifestyle, Biological

Natural & synthetic sources:

• Natural organic toxins: aflatoxin-B$_1$ from _Aspergillus flavus_ on peanuts, corn; converted by CYP-450 to DNA-damaging epoxide → liver cancer.
• Cooking by-products: heterocyclic amines & PAHs from high-temperature meat cooking → prostate risk (OR $1.26$ for any PC, $1.97$ for advanced).
• Radiation: UV (pyrimidine dimers), background ionising (radon, cosmic), medical imaging, nuclear accidents.
• Viruses: HPV (cervical), EBV (Burkitt, Hodgkin, nasopharyngeal), HBV/HCV (hepatoma), HHV-8 (Kaposi).
• Cigarette smoke: polycyclic aromates, aldehydes, nitrosamines, heavy metals, $^{210}\text{Po}$ → “complete carcinogen”; accounts for $22\%$ of all cancer deaths & $90\%$ lung cancer.
• Asbestos: ~$10\%$ lung cancers in AU (high mesothelioma rates).

Tumour Invasion & Metastasis

• Requirements:
  • Loss of adhesion (down-regulate fibronectin, cadherin).
  • Expression of basement-membrane receptors (laminin-R).
  • Secretion of proteases (collagenase, MMPs) to degrade ECM.
  • Acquisition of motility structures (filopodia, pseudopodia).
• Sequence:
  1. Detachment ➜ 2. ECM degradation ➜ 3. Intravasation into blood/lymph ➜ 4. Survival in circulation ➜ 5. Extravasation ➜ 6. Colonisation & angiogenesis at distant site.

Classification & Grading

• Nomenclature: root identifies tissue; suffix –oma = tumour.
  • Examples:
  • Lipoma (benign fat), Fibroma (benign fibrous tissue), Carcinoma (malignant epithelium), Sarcoma (malignant mesenchyme), Adenocarcinoma (malignant glandular epithelium), Blastoma (embryonic origin, malignant).
• Benign vs Malignant
  • Benign: encapsulated, slow-growing, well-differentiated, non-invasive.
  • Malignant: poorly differentiated, invasive, metastatic potential.
• TNM staging (UICC)
  • T$_{0-4}$: tumour size/extent (T$0$ = in situ).
  • N$_{0-3}$: regional lymph-node involvement.
  • M$_{0-2}$: absence/presence of metastases.
• AJCC Stages $0\text{--}IV$ map onto TNM combinations.

Clinical Manifestations & Paraneoplastic Syndromes

• Common systemic effects (Fig 1.8):
  • Pain, pressure, fatigue, cachexia, anaemia, infection.
  • Management strategies include analgesia, nutrition, EPO, transfusion, antibiotics, rest, psychosocial support.
• Paraneoplastic syndromes (Fig 1.9):
  • Endocrine: ectopic ACTH, ADH (hyponatraemia), PTH-rP (hypercalcaemia), insulin-like → hypoglycaemia.
  • Neuro: peripheral neuropathy, cerebellar degeneration, encephalitis (auto-antibody cross-reaction).
  • Haematologic: anaemia, erythrocytosis via EPO mimic/block.
  • Renal: immune-complex glomerulonephritis.
  • Rheumatologic: polymyalgia, polyarthritis.
  • Cutaneous: flushing (prostaglandins), hyperpigmentation, pruritus.
  • GI: secretory diarrhoea (VIP).

Indigenous Health Disparities & Cultural Considerations (AU/NZ)

• Aboriginal & Torres Strait Islander people: higher age-standardised incidence for liver ($\times2.8$), cervical ($\times2.2$), lung ($\times2$), uterine ($\times1.7$), pancreatic ($\times1.4$). Lower for colorectal, breast, lymphoma, prostate.
• Māori: overall incidence $\times1.7$, mortality $\times2$ vs European NZers.
  • Female Māori: higher melanoma ($\times4.6$), stomach ($\times4.5$), lung ($\times3.8$), uterine ($\times16.2$); lower colorectal.
  • Male Māori: higher lung ($\times3$), pancreatic ($\times1.9$), lymphoma ($\times1.2$); lower colorectal, prostate.
• Cancer mortality gap widening: non-Indigenous deaths ↓ $10\%$; Indigenous deaths ↑ $16\%$.
• Contributing factors: higher prevalence of smoking ($\times3.1$), alcohol ($\times1.6$), obesity ($\times1.6$), low screening uptake, delayed diagnosis/treatment.
• Culturally competent, community-driven, multidisciplinary approaches essential to reduce disparities.