Cancer cells Flashcards
Why is cancer metabolism different?
Increased proliferation- need nucleotides, AAs, lipids, ATP, redox active molecules
Mutations in signalling pathways
Detoxification of anticancer therapies
Survival in an inhospitable environment
What is the Warburg effect?
High lactate production even in the presence of oxygen- aerobic respiration
Produces an acidic environment and can increase invasion
Can be used for tumour diagnosis- FDG-PET imaging
What are the possible explanations for high rates of glycolysis in normoxic conditions in cancer cells?
Mitochondrial energy generation is irreversibly damaged- mitochondrial defects seen in phaeochromocytoma, paraganglioma, leiomyoma
Changes in enzyme expression due to differential signalling- c-myc increases glutamate uptake, p53 increases redox, HIF1 increase glycolysis, PTEN increase glucose transporters and therefore glycolysis
Changes in requirements for macromolecule synthesis
Describe 5-FU
5-fluorouracil disrupts nucleotide synthesis by blocking thymidylate synthase
Which is also part of the pathway to synthesis dTTP
May also ellicit a DNA damage response by being incorporated into DNA and RNA
But has side effects
Describe the hypoxia phenotype in cancer cells
Slower proliferation
Increased cell migration
Increase survival factors (in non-severe hypoxia)
Chromatin silencing in areas
Change in cellular metabolism (autophagy)
Reduced differentiation profile
Can result in therapy resistance
Describe pyruvate kinase as a novel therapeutic target
Conversion of phosphoenolpyruvate to pyruvate
Isoform M2 is expressed in proliferating embryonic cells
Helps tumours
Can be targeted but tumours find away around it
Could lactate dehydrogenase be a therapeutic target?
Required for NAD regeneration
LDH5 often observed in cancer cells
Tumours stop proliferating
What are the other cellular components associated with the tumour?
Cancer associated fibroblasts (CAFs)
Lymphocytes (CD4, CD8, NK)
Monocytes (macrophages)
Endothelial cells
What are the non cellular components associated with the tumour?
Hypoxia
Extracellular pH changes
Oedema
Extracellular matrix changes
Describe the typical vasculature that you are likely to see in a tumour
Inappropriately functional vascular bed resulting in hypoxia
Contains blunt ends, AV shunts and bends that provide a pro-thrombotic environment
Dysfunctional vasculature allowsthe cancer cells to intravasate
What cellular phenotypes does HIF control
Hypoxia inducable factor Proliferation and survival Metabolism Invasion and metastasis Angiogenesis pH regulation Stem cell maintainence
Describe the role of cancer associated fibroblasts in cancer
CAF provide supports for all tumour types
Remodel the ECM- rebalancing of components, degradation, stiffening
Release of previously inaccessible compounds
Produce TGF-beta➡ fibroblasta➡ desmoplasia
Evidence they could be irreversibly modified- epigenetics +mutations)
Their metabolism can support that of the cancer cells- lactastre swapping, AA synthesis
Secrete paracrine factors that change the phenotype of the tumour
They can also permit increased tumour cell migration
List the positive and negative influences immune cells can have on a cancer
CD8 T Cells present is a postive indicator for a good prognosis
Immunosuppression, CD4 Foxp3 regulatory T cela, cytokines production giving an inflammatory phenotype increased cell numbers give a larger metabolic demand give a bad prognosis
What novel treatments target the stroma?
Targeting tumour infiltrating lymphocytes
Ipilimumab- reactivates CD8 T cells approved for melanoma
What is the evidence for immune system involvement in cancer?
Immunodeficiency leads to an increased risk of cancer- genetic disorders can increase cancer risk by 4-25% eg. SCID predispose to lymphoma, leukaemia, renalk carcinoma, immunosuppressive drugs, via virus infection eg. EBV➡ lymphoma and non-virus associated cancer eg. Lymphoma, colon, lung, bladder, prostate, skin
Immune activation by infection can lead to cancer regression- BCG vaccine into the bladder is still used as the first line treatment appears to stimulate immune activation in the lining of the bladder which can lead to an anticancer response
Increased numbers of immune cells can improve survival
