Cancer Biology & Clinical Concepts

Definition & General Concepts

• Cancer = group of diseases in which abnormal cells divide uncontrollably and may invade adjacent tissues or spread (metastasize) through the vasculature.
• Cancer is predominantly a disease of aging; sequential accumulation of mutations is required.
• Two basic tumor categories
  • Benign: named for tissue of origin + “-oma” (lipoma, leiomyoma, meningioma).
  • Malignant: name reflects tissue line
  – Carcinoma → epithelial tissue.
  – Adenocarcinoma → gland/duct epithelium.
  – Sarcoma → mesenchymal tissue.
  – Lymphoma → lymphatic tissue.
  – Leukemia → blood-forming cells.
• Carcinoma in situ (CIS) = pre-invasive malignant epithelial growth that has not crossed basement membrane or invaded stroma.

Clonal Evolution & Multistep Carcinogenesis

• Clonal proliferation/expansion: a mutated cell acquires growth advantage and forms a clone; further mutations drive progression from benign lesion → CIS → invasive/metastatic cancer.
• Classic colon model
  • Earliest event: loss of tumor-suppressor $APC$.
  • Followed by oncogenic $RAS$ activation, $COX2$ up-regulation, and loss of $DCC$ & $TP53$ ➔ benign polyp → invasive carcinoma.
  • Expressed sequentially: $APC \rightarrow RAS \rightarrow COX2 \rightarrow DCC, TP53$.

Molecular Categories of Cancer Genes

• Proto-oncogenes: normal genes that stimulate growth; activated (gain-of-function) → oncogenes.
• Tumor-suppressor genes (TSGs): encode proteins that restrain proliferation; loss/inactivation (e.g., $RB$, $TP53$) removes brakes.
• Caretaker genes: maintain genomic integrity via DNA repair (mismatch, nucleotide/base excision, double-strand break repair).

Hallmarks & Enabling Characteristics (2011 revision)

• Sustained proliferative signaling.
• Evading growth suppressors.
• Enabling replicative immortality.
• Activating invasion & metastasis.
• Inducing angiogenesis.
• Resisting cell death (apoptosis).
• Reprogramming cellular energetics (Warburg effect).
• Avoiding immune destruction.
• Tumor-promoting inflammation (enabler).
• Genomic instability & mutation (enabler).

Oncogene Activation Mechanisms

• Point mutation: e.g., single nucleotide change converts RAS to constitutively active form.
• Chromosomal translocation:
  • $t(8;14)$ in Burkitt lymphoma.
  • $t(9;22)$ Philadelphia chromosome (BCR-ABL) in CML.
• Gene amplification: multiple copies elevate oncogene expression (e.g., MYCN in neuroblastoma).

Tumor-Suppressor Inactivation

• Two-hit hypothesis (Knudson): both alleles must be inactivated.
• Mechanisms: point mutations, deletions, epigenetic silencing (promoter hyper-methylation), dominant-negative mutant proteins.

Genomic Instability & Chromosome Abnormalities

• Increased mutation rate ➔ higher cancer risk.
• Chromosome instability (CIN): loss, duplication, or fragmentation ➔ aneuploidy, loss of heterozygosity, gene amplification.

Telomeres & Replicative Immortality

• Normal somatic cells: telomeres shorten each division; critically short telomeres trigger senescence/apoptosis.
• Cancer cells activate telomerase ➔ maintain telomere length ➔ $\text{unlimited divisions}$.

Angiogenesis (Neovascularization)

• Tumor growth >1–2 mm requires own blood supply.
• Cancers secrete pro-angiogenic factors & suppress inhibitors
  • Vascular Endothelial Growth Factor (VEGF)
  • Platelet-Derived Growth Factor (PDGF)
  • Basic Fibroblast Growth Factor (bFGF)

Metabolic Reprogramming

• Warburg effect: preferential use of aerobic glycolysis even under normoxia; generates biosynthetic precursors.
• Reverse Warburg effect: cancer-associated stromal cells perform glycolysis, supplying high-energy metabolites to oxidative tumor cells.

Apoptosis & Cancer Cell Survival

• Intrinsic (mitochondrial) pathway senses DNA damage, oncogenic stress, detachment, etc.
• Extrinsic pathway: death-receptor mediated.
• Tumors acquire mutations in pro-apoptotic genes (e.g., BAX, BIM) or overexpress anti-apoptotic proteins (BCL-2, IAPs).

Inflammation & Tumor Microenvironment

• Chronic inflammation (e.g., $Helicobacter\ pylori$ gastritis) increases risk of stomach carcinoma & MALT lymphoma.
• Tumor-Associated Macrophages (TAM)
  • Often polarised to M2 phenotype (anti-inflammatory, pro-healing).
  • Secrete cytokines, growth factors, proteases that enhance angiogenesis, invasion, suppress cytotoxic T/NK cells.

Invasion, EMT & Metastasis

• Local invasion: tumor breaks through basement membrane by
  • Mitotic rate > cell loss rate.
  • Secretion of lytic enzymes (proteases, collagenases).
  • Down-regulation of cell–cell adhesion molecules (E-cadherin).
  • Increased motility via autocrine motility factors.
• Epithelial–Mesenchymal Transition (EMT)
  • Loss of epithelial traits (polarity, adhesion) & gain of mesenchymal traits (motility, stem-like state).
  • Confers resistance to apoptosis & favors colonization of distant sites.
• Routes
  • Direct contiguous spread.
  • Lymphatic dissemination.
  • Hematogenous spread (veins ➔ liver, lungs, bone marrow, brain).
• Organotropism examples: breast → bone, prostate → bone, colon → liver, lymphoma → spleen.
• Dormancy: micrometastases may remain clinically silent for years.

Clinical Manifestations

• Pain: seldom in early disease; mechanisms include pressure, obstruction, nerve invasion, visceral stretch, tissue destruction, inflammation.
• Fatigue: multifactorial—sleep loss, metabolic changes, treatment effects, psychosocial stress, anemia, cachexia.
• Cachexia: "wasting" syndrome—anorexia, early satiety, weight loss, asthenia, anemia, altered metabolism of carbs/lipids/proteins.
• Anemia: ↓Hb from chronic bleeding, nutritional deficiency, marrow infiltration, therapy toxicity.
• Leukopenia & Thrombocytopenia: marrow invasion or chemo toxicity ➔ infection & bleeding risk.
• Infection risk correlates with ↓absolute neutrophil / lymphocyte counts.
• Gastrointestinal: mucositis (oral ulcers), malabsorption, diarrhea, chemo-induced nausea.
• Hair/Skin: alopecia (reversible), dryness, breakdown.

Staging & Classification

• Anatomic stage (AJCC):
  1. Stage 1 – confined to organ (no metastasis).
  2. Stage 2 – locally invasive.
  3. Stage 3 – spread to regional lymph nodes/structures.
  4. Stage 4 – distant metastasis.
• TNM (WHO) system
  • $T$ = tumor size/extent.
  • $N$ = regional lymph node involvement.
  • $M$ = distant metastasis.
• Histologic grading via immunohistochemistry & molecular profiling (e.g., ER/PR/HER2 in breast, IDH1 in glioma) refines prognosis & therapy.

Tumor (Biologic) Markers

• Substances produced by tumor or host in response; detected in serum, CSF, urine.
  • Hormones (hCG, calcitonin, catecholamines)
  • Enzymes (PSA, LDH, acid phosphatase)
  • Oncofetal antigens (AFP, CEA)
  • Genetic changes (BCR-ABL, EGFR mutations)
  • Antibodies (M-protein in myeloma)
• Uses: screening high-risk groups, aiding diagnosis, monitoring response/recurrence.

Therapeutic Modalities

• Surgery
  • Prevention (colectomy for FAP)
  • Diagnosis/staging (biopsy, sentinel node).
  • Curative resection for localized disease.
  • Palliation (debulking, obstruction relief).
• Radiation Therapy
  • Ionizing radiation damages DNA (double-strand breaks).
  • Goal: eradicate tumor while sparing normal tissues.
• Chemotherapy
  • Combination regimens target multiple pathways/phases (e.g., $M!_\text{phase}$ specific + non-specific).
  • Aim: eliminate micro-metastases & shrink primary.
• Immunotherapy
  • Prophylactic vaccines vs oncogenic viruses (HBV, HPV).
  • Therapeutic strategies (checkpoint inhibitors, CAR-T, cytokines) under intense research; to date variable success.

Key Numbers, Equations & Terms

• Telomere shortening per division ≈ $50\text{–}200$ bp.
• Philadelphia chromosome: $t(9;22)(q34;q11)$ produces $BCR\text{–}ABL$ fusion tyrosine kinase.
• Warburg effect depicted: $\text{Glucose} \xrightarrow[O_2]{\text{aerobic}} \text{Lactate} + 2\ ATP\ (\text{fast})$ vs $\text{OXPHOS}:\ 36\ ATP$ (slow).
• Two-hit model: $TSG^{+/-} \xrightarrow{2^{nd}\ hit} TSG^{-/-} \Rightarrow \text{cancer predisposition}$.

Practical / Ethical / Real-World Points

• Screening must balance benefit (early detection) vs harm (false positives, over-diagnosis).
• Understanding molecular drivers (e.g., EGFR, ALK) enables targeted therapy but raises cost/availability issues.
• Chronic inflammatory diseases (colitis, H. pylori gastritis) warrant surveillance to prevent cancer.
• Decisions on aggressive therapy vs quality of life require patient-centered ethical considerations.