Cancer Pathology

Question 1

Definition of cancer

Answer 1

• collection of related diseases, where in all types some of the body’s cells begin to undergo uncontrolled proliferation and spread into surrounding tissues
• there are >200 different types and they are highly heterogeneous (between types and between individuals)
• cancers are highly genetically divergent (mutations perpetuate mutations)

Question 2

Causes of cancer: mutations and familial/sporadic, environmental causes

Answer 2

• 90-95% of cancers arise from sporadic mutations, only 5-10% could be considered familial
• environmental causes: UV light, pyrolysed food, nuclear radiation, smoking
• mutations: some are silent (i.e in intergenic regions and have no effect), others could affect coding sequence (altering protein function) or affectinf regulatory sequence (altering control of processes i.e transcription/splicing), these are cancerous mutations

Question 3

Types of mutations in cancer

Answer 3

• mutations in tumour suppressor genes: such as Rb1 (inhibits cell cycle by binding eIF2 to stop movement to S phase, implicated in variety of cancers such as retinoblastoma, where Knudson discovered the 2 hit hypothesis), p53, p16 (inhibits cell cycle)
• mutations in proto-oncogenes causing activation to oncogenes: over-expression of EGFR (cells can then proliferate without finding of growth signal), Her2, Ras, myc

Question 4

Genetic evolution of cancers

Answer 4

• tumours are highly heterogeneous, and will mutate depending on selective pressures
• mutations will give rise to other mutations which will divide quicker and cell cycle even more dysfunctional
• different clonal variants will have different phenotypes i.e those at center of tumor are more hypoxic and will activate VEGF for angiogenesis
• TRACERX experiment found 1-10 driver mutations in most tumors

Question 5

Implications of genetic heterogeneity of tumors

Answer 5

1. Means that biopsies are not representative of the whole tumor
2. Difficult to distinguish causal mutations from collateral damage (difficult to target treatment?)
3. Different parts of tumor may respond differently to therapy
4. Tumor behaviour and drug response will change over time

Question 6

The 6 hallmarks of cancer

Answer 6

1. Self-sufficiency in growth signals: Activating mutations in oncogenes (EGFR, Her2, Ras, myc)
2. Insensitivity to anti-growth signals: need inactivating mutations to tumor suppressor genes (Rb1, p53, p16)
3. Evasion of apoptosis: increasing anti-apoptotic signals to prevent cell death, p53 loss/mutation or down regulation of Fas/CD95
4. Limitless replicative potential: evasion of the hayflick limit (50-70 cell cycles) for telomere shortening. 90% activate telomerase, 10% have homologous recombination for telomere repair
5. Sustained angiogenesis: if tumor more than 1-2mm will become hypoxic which activates VEGF for angiogenesis. Angiogenic factors can also be activated by ras, myc, p53
6. Increased invasion and metastasis: invasive tumors need mutations in adhesions and morphology. They loosen intracellular junctions, attach to cell layer through fibronectin and laminin receptors (loss of E-cadherin, activation of N-cadherin), degrade the extracellular matrix through type IV collagenase/matrix metalloprotease, secrete chemokines/cytokines, and slip through ECM into blood stream through autocrine motility factors

Question 7

Additional hallmarks of cancer (added in 2011)

Answer 7

• avoiding immune destruction
• deregulation of cellular energetics (altered metabolism)
• genome instability and mutation
• tumour promoting inflammation