Tumour microenvironment Lecture 16 Flashcards
What are parenchymal and stromal cells?
Parenchymal - function tissues of an organ
Stromal - supportive cells
What are the non cellular components associated with the tumour?
pH
- Hypoxia causes angiogenesis to occur
- Tumour cells and low O2 favour anaerobic metabolism
- This produces lactic acid which accumulates due to poor vasculature -> lowering pH
Pressure
- Interstitial fluid pressure (IFP) is increased in solid tumours
- Caused by vascular abnormalities reducing lymphatic function and increasing vessel permeability
- High IFP reduces drug concentration in tumours
Extracellular Matrix
- ECM remodelled in tumours, allowing furthe dissemination
- MMPs break down ECM to allows remodelling
What are the other cellular components associated with the tumour?
Cancer associated fibroblasts (CAFs)
Lymphocytes (CD4, CD8, NK)
Monocytes (macrophages) Endothelial cells
What are cancer associated fibroblasts?
-High CAF abundance correlates with worse outcome in pancreatic and colorectal cancer
Function by:
Direct: produce angiogenic factors
Indirectly: attract macrophages which stimulate cancer cell division
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
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 are the types of tumour immune microenvironments?
Infiltrate excluded: Immune cells trapped at tumour-stroma interface
Infiltrated-inflamed: May respond well to anti-immune mechanisms
What do Tumour Associated Macrophages (TAMs) do in a tumour?
Tumour hypoxia promotes release of chemoattractants that recruit macrophages to the tumour
- TAMs then promote angiogenesis by releasing VEGF and MMP9: this triggers the angiogenic switch, allowing the tumour to grow beyond small size
- TAMs also supress other immune cells by releasing IL-10 which interferes with T and Dendritic cells
How can Myeloid Derived Supressor Cells aid cancer development?
Interfere with innate and adaptive immunity
- Inhibit Natural Killer and DC function
- Induce Treg cells
- Produce arginase, depleting arginine thereby interfering with T cell function
Describe the types of T cell in the tumour
CD8+ = cytotoxic T effector cells, have granules containing perforin and granzymes that trigger apoptosis in tumour cells
CD4 Th1 cells = activate macrophages, kill tumour cells
CD4 Th2 = nomrally defence against parasites, but may be involved in activating eosinophils
CD4 Th17 = express IL17, may be involved in cancer delveopment
CD4 Treg = express FoxP3 and CD25, increaed number are benefical
How do Tregs aid cancer immunosupression?
Enriched in tumours because:
- Tumours secrete CCL22 and CCL28, attracting them
- Hypoxia further increases CCL28
Mechanism of suppression:
- Tregs produce TGF-beta and IL-10
- Tregs express high levels of CD25 so starve effector T cells of IL2
- Produce adenosine, suppressing T cells
Treg have marker CD39 which breaks down ATP to AMP to adenosine which can surpess T cells in tumour
How might the immune system be used to treat cancer?
Reawakening naturally occurring anti-tumour T cells Boosting number of anti-tumour T cells Use genetically engineered T cells that recognise the cancer
