W8.4_Basic Cancer Biology

Question 1

What are cancer cells and how are they arisen from normal cells? Define the hallmarks of cancer.

Answer 1

• Cancer cells: require a series of mutations/cell damage
• Normal cell ⇌initiation/DNA repair⇌ Initiated cell -promotion-> Preneoplastic cell -progression-> Neoplastic cell -metastasis-> Malignant tumour
• Hallmarks of cancer: what makes cancer cells distinguishable from normal cells

Question 2

Explain intrinsic, endogenous, and exogenous risk factors of cancer with examples.

Answer 2

• Intrinsic risk factors: unmodifiable (random errors in DNA replication)
• Endogenous risk factors: partially modifiable (non-intrinsic) (ex. ageing, genetic susceptibility, DNA repair machinery, hormones, growth factors, inflammation)
• Exogenous risk factors: modifiable (non-intrinsic) (ex. radiation, chemical carcinogens, tumour-causing viruses, bad lifestyles)

Question 3

In terms of self-sufficiency in growth signals, explain how normal cells respond to growth factors and contrast it with how cancer cells operate. Describe the three types of mutated signalling pathways in cancer cells.

Answer 3

• Normal cells need growth factors (GF) as signals to proliferate (especially in hair follicles, inner lining of GI tract)
• GF are components in extracellular matrix (ECM) which influences cell-cell adhesion
• Normal cells cannot grow in absence of these stimuli, but cancer cells can grow independently
• Heterotypic signalling (normal receptor): GF -> receptor -> normal expression -> physiological signalling
• Autocrine signalling: cancer cells generate GF on itself -> overexpress message & messenger (ex. PDGF in glioblastoma)
• Overexpression: cancer cells stop regulating the number of receptors -> hyper-responsive to normal levels of GF (ex. EGFR in stomach/brain/breast, HER2 in stomach/breast/lung)
• Ligand-independent signalling: direct mutation of receptor -> allow uncontrolled signalling in absence of GF (ex. EGFR in lung)

Question 4

In terms of insensitivity to growth signals, describe which checkpoints in the cell cycle are ignored and why.

Answer 4

• Sensed by retinoblastoma protein (Rb), mutations in it causes checkpoints to be ignored in cell cycle
• During G1: external signals -> cell decides to proliferate or not
• During G1/S: cell look for DNA damage -> try to fix themselves before progressing (managed by p53)
• During G2: assess whether chromosome replication was successful, decides whether to continue with cell cycle
• After metaphase: determines whether all sister chromatids are correctly attached to spindle microtubules

Question 5

In terms of evading apoptosis, define apoptosis and how it relates to p53 gene.

Answer 5

• Apoptosis: programmed cell death, cancer cells evade it by mutating/losing p53 gene -> cell division > cell death
• Caused by mutagens/inherited gene mutation/pathogens (HPV virus)
• p53: tumour suppressor gene that identifies DNA damage and halts cell cycle (G1/S) -> activate DNA repair proteins -> initiates apoptosis when damage cannot be repaired

Question 6

In terms of limitless replicative potential, explain how it relates to pRb/p53 gene and the consequences of it.

Answer 6

• Mutated pRb/p53 -> lose senescence (lost of power of division and growth) -> become immortal -> crisis
• Abnormal telomere maintenance -> up-regulation of telomerase -> increase copies of 6bp repeats onto the ends -> unlimited replication
• Massive cell death, karyotypic disarray

Question 7

In terms of sustained angiogenesis, explain how this process is different in cancer cells from normal cells and describe the process of it.

Answer 7

• Cells require oxygen and nutrients for cell function, growth, survival (<150-200µm from blood vessel)
• Angiogenesis is very carefully regulated in normal tissue, tumours hijack it to support tumour growth
• Secretion of angiogenic factors -> proteolytic destruction of ECM -> endothelial cell proliferation and migration (growth & extension) -> appearance of new tumour vasculature -> intravasation (can start metastasis)

Question 8

In terms of tissue invasion and metastasis, define invasion and describe the process of how metastasis works. What are the example gene mutations that could cause metastasis?

Answer 8

• Tumour cells invade beyond tumour margin: invasion
• Move away from primary site and colonise a distant secondary site: metastasis
• Primary tumour -> invasion -> intravasation -> circulation -> extravasation at target sites -> micrometastasis at pre-metastatic niche -> colonisation
• Loss of cell adhesion molecules can be responsible for metastasis
• Examples in gene mutation that causes metastasis: KRAS, BRAF, APC, SMADA, PIK3CA