Oncology Workshop 1 Flashcards
1
Q
Slide 14 start from here
A
2
Q
What are apoptosis triggers?
A
- 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
3
Q
What is autophagy and explain it
A
- 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
- When is this clinically relevant?
4
Q
What is necrosis and explain it
A
- 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!
5
Q
Explain sustaining proliferative signalling and why it is important
A
-
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
6
Q
What are the mechanisms for cancer cells to acquire sustained proliferation capacity?
A
4 mechanisms cancer cells acquire sustained proliferation capacity:
- Overproduction of growth factor ligands
- Overproduction of growth factor receptors
- Altering receptor structure, so they can signal without ligand binding
- Activating of intracellular signalling pathways independent of ligand binding
7
Q
Explain the cell cycle
A
Comprised of 4 phases:
- G1 (gap 1)
- S (DNA synthesis)
- G2 (gap 2)
- M (mitosis/meiosis)
8
Q
Explain cell cycle regulation
A
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
9
Q
Explain the stimulation of the cell cycle
A
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
10
Q
Explain evading growth suppressors
A
- 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
11
Q
Explain enabling replicative mortality
A
- 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
12
Q
Explain inducing angiogenesis (and in cancer)
A
- Formation of new blood vessels
- Blood vessels produced by tumour-mediated angiogenesis are abnormal±±They are characterised by:
- Precocious capillary sprouting
- Increased vessel branching
- Distorted and enlarged vessels
- Microhaemorrhage and leakiness
- 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)
13
Q
Explain activating invasion and metastasis in tumours
A
- 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)
- Gastric
- Breast
- Colorectal (always check if they have a Ras mutation)
- Thyroid
- Ovarian
14
Q
Explain cancer energy metabolism (changes)
A
- 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
15
Q
Explain tumour promoting inflammation in cancer
A
- Inflammatory vasodilation results in increased blood flow
- Increased permeability of the blood vessels
- Leads to exudation of plasma proteins and fluid into tissues
17
Q
Explain the hallmarks of cancer and their treatments
A
