PED1003/L26 Cancer Therapeutics Flashcards
Describe the two methods of ATP synthesis in healthy cells.
Some by glycolysis in cytoplasm
More by oxidative phosphorylation in mithchondria
What is the Warburg effect?
Shift towards glycolysis associated with immune cell activation, cancer and age-related diseases
Why do cancer cells switch to favour glycolysis? (3)
Scarcity of oxygen
Faster ATP production (100x)
Intermediates used for DNA synthesis, proteins and lipids
How do cancer cells speed up their energy production?
Uptake more glucose through GLUT1-4
Elevate expression of glycolytic enzymes
Name 2 glycolysis enzymes.
HK2
PFK1
PK-M2
LDHA
Give 2 roles of lactate inside cancer cells.
Regeneration of NADH
Reduction of ROS production
Give a role of lactate outside cancer cells.
Lactate lower pH of microenvironment (pro-invasive)
What is the role of lactate in metabolic symbiosis? (3)
Lactate converted to pyruvate in normoxic cells
Enters TCA cycle
Energetic source for these cells
What is the role of lactate in immunosuppression? (3)
Promotes TME acidification
Lower pH within immune cells affecting signalling pathways
Inhibit CD4, CD8 T cells NK cells dendritic cells by lowering pH
Apoptosis of CD8 T cells and NK cells
Explain how immune destruction is avoided. (4)
When tumours arise, immune cells recognise and eliminate them
Variant tumour cells arise that are more resistant to being killed
Over time a variety of different cancer cells develop
One variant may escape killing mechanism or recruit regulatory cells to protect it so can spread unchallenged
Give the 5 main mechanisms by which immune destruction is avoided.
Low immunogenicity
Tumour treated as self antigen
Antigenic modulation
Tumour-induced immune suppression
Tumour-induced privileged site
Describe low immunogenicity. (3)
No peptide:MHC ligand
No adhesion molecules
No co-stimulatory molecules
Describe tumour treated as self antigen.
Tumour antigens taken up and presented by APCs in absence of co-stimulation tolerize T cells
Describe antigenic modulation.
T cells may eliminate tumours expressing immunogenic antigens but not tumours that have lost such antigens
Describe tumour-induced immune suppression. (2)
Factors secreted by tumour cells inhibit T cells directly
Expression of PD-L1 tumours