Neoplasia

Question 1

How do cancers invade the extracellular matrix?

Answer 1

1. Detachment - tumour cells resist apoptosis when loss of attachment to ECM, or reduce cellular cohesion by down-regulation of epithelial cadherins
2. ECM degradation: tumour cells can migrate between fibres (ameboid migration) or produce proteases to degrade ECM allowing passage for migration
3. ECM attachment: invading tumour cells express adhesion molecules to allow interaction with ECM
4. Migration: tumour cells have increased locomotion, and also migrate in response to stromal cell chemotactic factor, degraded ECM components and liberated stromal growth factors

Question 2

How do tumour cells metastasise (at a cellular level)

Answer 2

1. Invasion of extracellular matrix
2. Vascular dissemination and homing: tumour cells embolize in the bloodstream as self-aggregates and by adhering to circulating leukocytes and platelets

Question 3

What determines where tumour cells embolise and begin growing?

Answer 3

1. Vascular and lymphatic drainage from the site of the primary tumour
2. Interaction with specific receptors, e.g. CD44 adhesion molecules that bind endothelial venules in lymph nodes, chemokine receptors that bind to ligands in certain vascular beds
3. The microenvironment of the organ or site

Question 4

What is a paraneoplastic syndrome?

Answer 4

A complex of symptoms that cannot be readily explained by the local or distant spread of a tumour or by elaboration of hormones from the tissue in which the tumour arose

Question 5

What are the main types of paraneoplastic syndromes?

Answer 5

1. Endocrinopathies
2. Nerve and muscle syndromes
3. Dermatological
4. HPOA

Question 6

What factors influence the development of cancer in individuals?

Answer 6

1. Geographic & environmental: UV radiation, air pollution, obesity, alcohol and smoking
2. Age: >55, accumulation of somatic mutations and decline in immune surveillance
3. Genetic predisposition:
   a) Autosomal dominant inherited cancer syndromes - characterised by a single mutant gene, e.g. RB in retinoblastoma, APC in familial adenomatous polyposis
   b) Defective DNA repair (autosomal recessive) - predispose to DNA instability in the face of environmental carcinogens, e.g. hereditary nonpolyposis colony cancer
   c) Familial cancers - familial clustering of cases, e.g. breast, ovarian, pancreatic cancers
4. Nonhereditary predisposing conditions - proliferation, chronic inflammation

Question 7

What the environmental agents that cause genetic damage and how do they induce neoplastic transformation? (1/3)

Answer 7

1. Chemical carcinogens:
   Typically electrophilic compounds that are highly reactive with nucleophilic targets, especially DNA, and induce mutations by altering primary sequence (oncogenes, tumour suppressors)
   a) Initiation - induction of certain irreversible changes (mutations) in the genome, giving rise to tumours when stimulated by promoting agents (direct-acting agents, e.g. alkylating agents, or indirect-acting agents requiring metabolic conversion via cytochrome P-450 MFOs, e.g. smoking)
   b) Promotion - process of tumour induction in previously initiated cells (short-lived, reversible)
   Unrepaired DNA alterations > initiation where carcinogen-altered cells must undergo at least one cycle of replication > subsequent exposure to promoters in order to induce cellular proliferation

Question 8

What the environmental agents that cause genetic damage and how do they induce neoplastic transformation? (2/3)

Answer 8

2. Radiation carcinogenesis:
   a) UV radiation from sun (UVB) causes skin cancers - carcinomas and melanomas. Damage to DNA occurs through formation of pyrimidine dimers
   b) Ionizing radiation from electromagnetic (x-rays) & particulate (∂/ß particles and neutrons) sources which induce DNA mutations by generating free radicals from oxygen or water

Question 9

What the environmental agents that cause genetic damage and how do they induce neoplastic transformation? (3/3)

Answer 9

3. Microbial carcinogenesis:
   • Oncogenic RNA viruses - HTLV-1 retrovirus causing T cell leukaemia/lymphoma
   • Oncogenic DNA viruses - HPV can cause cervical carcinomas which requires interaction with smoking, other infections, dietary deficiencies or hormones
   • EBV - herpesvirus that infects B cells and oropharyngeal epithelium, associated with Burkitt lymphoma, B-cell lymphomas in immunosuppressed patients, Hodgkins lymphoma and nasopharyngeal carcinoma
   • Hepatitis B & C viruses - cause HCC through immunologically mediated chronic inflammation
   • H pylori - can cause gastric carcinomas (prolonged chronic inflammation) or gastric lymphomas (MALTomas)