Oncology Workshop 1

Question 1

Slide 14 start from here

Question 2

What are apoptosis triggers?

Answer 2

• Removal of survival factors such as IL-3 or IGF-1
• Or by activation of cyclin E without cyclin D
• TP53 is a tumour suppressor gene that can induce apoptosis°If sufficient levels of genomic damage
• TP53 gene produces the p53 protein
• Loss of p53 linked to breast and colorectal cancer (poor prognosis)
• Fun Fact!
• Genomic damage can occur due to chemotherapy and radiotherapy
• TP53 loss can occur due to:
  
  • Increased expression of anti-apoptotic regulators
  • Down-regulation of pro-apoptotic factors
  • .Short-circuiting of extrinsic ligand-induced death pathway

Question 3

What is autophagy and explain it

Answer 3

• Is a catabolic process
• Cell constituents are degraded by lysosomal machinery
• Induced by environmental stresses and nutrient deficiency
• Radiotherapy and chemotherapy can result in nutrient starvation and increase autophagy
• Paradoxically can by cytoprotective for malignant cells?!
  
  • They increase nutrient availability for the malignant cell to grow
• Severely stressed cells have been shown to shrink via autophagy to a state of reversible dormancy
  
  • When is this clinically relevant?
    
    • Decrease symptoms and delay prognosis but, the cancer will reactivate at some time

Question 4

What is necrosis and explain it

Answer 4

• Is the premature death of cells±Release of cellular contents into the local tissue microenvironment
• Contrast to apoptosis which is dismantling in a step by step fashion resulting in phagocytosis
• Necrotic cell death results in the recruitment of inflammatory immune cells to the site of tissue damage
  
  • Paradoxically necrosis can lead to increased angiogenesis?!
  • Leads to proliferation and tissue invasion in neighbouring cells
  • Promoting cancer cell populations rather than inhibiting carcinogenesis

±Is this clinically relevant?

NO!

Question 5

Explain sustaining proliferative signalling and why it is important

Answer 5

• Is a defining feature of a cancer cell±
  
  • Growth-promoting signalling pathways involve growth factors
• Growth factor ligands bind to cell surface-bound growth factors receptors°
• Activates an intracellular tyrosine kinase-mediated signalling cascade±
• Changes gene expression
  
  • Promoting cellular proliferation and growth

Question 6

What are the mechanisms for cancer cells to acquire sustained proliferation capacity?

Answer 6

4 mechanisms cancer cells acquire sustained proliferation capacity:

1. Overproduction of growth factor ligands
2. Overproduction of growth factor receptors
3. Altering receptor structure, so they can signal without ligand binding
4. Activating of intracellular signalling pathways independent of ligand binding

Question 7

Explain the cell cycle

Answer 7

Comprised of 4 phases:

1. G1 (gap 1)
2. S (DNA synthesis)
3. G2 (gap 2)
4. M (mitosis/meiosis)

Question 8

Explain cell cycle regulation

Answer 8

Cell cycle regulation

• Key regulatory elements are cyclins and cyclin-dependent kinases
• Regulated by activating and inactivating phosphorylation
• Tumour suppressor genes (TP53, TP21 and TP16)
• Proteins deactivate cyclin-CDK complexes and halt the cell cycle
• Malignant phenotypes lack restrictions

Question 9

Explain the stimulation of the cell cycle

Answer 9

Stimulation of the cell cycle

• Cancer cells can produce growth factors to drive self-proliferation
  
  • transforming growth factor-alpha (TGF-α)
  • platelet-derived growth factor (PDGF)°
• EGFR (lung cancer and bowel cancer) and HER2 (breast cancer) overexpression
  
  • Activates the Ras-Raf-MAP kinase pathway causing cell proliferation°
• RAS mutations cause ligand-independent signalling
  
  • Leads to MAP kinase signalling and cell abnormal cell growth

Question 10

Explain evading growth suppressors

Answer 10

• Tumour suppressor genes are central to cellular regulatory networks
• Cancer cells proliferate independently to their inhibitory signals
• Normal growth-inhibitory factors modulate the cell cycle to activate CDK inhibitors
• Mutations in inhibitory proteins are common
• Loss of restriction pathways produces loss of restraint on the transition from G1 to S phase

Question 11

Explain enabling replicative mortality

Answer 11

• Normally telomeres shorten progressively with successive cycles
• Preventing cells from dividing past a certain point
• Absent in normal cells, cancer cells express high levels of telomerase enzyme
• Telomerase enzyme adds nucleotides to telomeres extending their life

Question 12

Explain inducing angiogenesis (and in cancer)

Answer 12

• Formation of new blood vessels
• Blood vessels produced by tumour-mediated angiogenesis are abnormal±±They are characterised by:

1. Precocious capillary sprouting
2. Increased vessel branching
3. Distorted and enlarged vessels
4. Microhaemorrhage and leakiness
5. Abnormal levels of endothelial cell proliferation and apoptosis

• Angiogenesis is dependent on angiogenic growth factors such as VEGF and PDGF
  
  • E.g. anti-VEGF (e.g. bevacizumab)

Question 13

Explain activating invasion and metastasis in tumours

Answer 13

• Cancer cells undergo a number of modifications so they can metastasise±
• Cadherin-1 facilitates assembly of organised cell sheets in tissues
• Increased expression of cadherin-1 is recognised as an antagonist to metastasising
• Cancer cells lose expression of cadherin-1±
• Mutations of CDH1 gene are associated with: (usually don’t check as wont affect treatment → test for things that are treatable)

1. Gastric
2. Breast
3. Colorectal (always check if they have a Ras mutation)
4. Thyroid
5. Ovarian

Question 14

Explain cancer energy metabolism (changes)

Answer 14

• Cancer cells upregulate GLUT1 (glucose transporter) to favour aerobic glycolysis±
• Though 18 fold more inefficient than normal oxidative phosphorylation
  
  • Done at significantly high levels able to maintain metabolism

Question 15

Explain tumour promoting inflammation in cancer

Answer 15

• Inflammatory vasodilation results in increased blood flow
• Increased permeability of the blood vessels
• Leads to exudation of plasma proteins and fluid into tissues

Question 16

Explain evading immune destruction in cancer

Answer 16

• Chemotherapy can cause neutropenia and then cause neutropenic sepsis
  
  • Hence, do immunotherapy instead
• ±Deficiencies in the development or function of: (these can be low because of HIV, Organ transplant because of tacrolimus etc.)
  
  • CD8+ cytotoxic T lymphocytes:
  • CD4+ Th1 helper T cells
  • Natural killer cells
• Lead to increase cancer rates
• Cancer cells recruit T Cells and myeloid-derived suppressor cells
• As these are immunosuppressive against cancer

Question 17

Explain the hallmarks of cancer and their treatments

Answer 17

Question 18

What are the side effects of immunotherpy?

Answer 18

• Increases risk of autoimmune diseases (as can attack healthy tissue)
• Common symptoms:
  
  • Myocarditis (very low but if have it very high)
  • Diarrhoea
  • Rash
  • Muscle aches and pains
  • SOB
  • etc many more

Question 19

What are the treatment principles?

Answer 19

• Neo-adjuvant = treatment before surgery
• Adjuvant - treatment that comes after surgery (surgery = curative treatment)
  
  • E.g. immunotherapy, chemotherapy, radiotherpy
• Curative - most commonly means surgery (not always)
• Radical - curative treatment (e.g. radiotherapy)
• Palliative - improve symptoms, decrease cancer size, live longer