Macrophages in the tumour microenvironment Flashcards
What cells does the tumour microenvironment consist of?
The Tumour Microenvironment consists of many different cells: •Tumour cells •Macrophages •Monocytes •T-cells •BMDCs (Bone-marrow derived dendritic cells) •Neutrophils •Fibroblasts •Stromal cells •Endothelial cells
Why would you target the tumour microenvironment?
Normal cells co-opted by tumour cells can promote cancer progression. Co-opted normal cells are genetically stable and so should not acquire mutations that contribute to therapeutic resistance. Cancer therapies could be enhanced by simultaneously targeting the tumour-promoting functions of cells in the microenvironment.
How are macrophages attracted to tumour sites?
Macrophages are attracted to tumour sites by cytokines and chemokines. E.g. MCP-1, CSF-1 SDF-1, IL-4. They follow the gradient of these cytokines, the closer to the tumour, the higher the concentration
What the difference between tumour blood vessels and normal blood vessels?
Tumour blood vessels are very messy and curly, while normal blood vessels are straight and orderly.
What are the homeostatic functions of macrophages?
They have homeostatic functions:
•Tissue formation during development
•Phagocytosing or eating microorganisms, foreign particles and clearing dead or abnormal cells.
•Releasing chemical signals that recruit other types of immune cells to sites of injury/ infection.
•Patrolling and specialized tissue-specific macrophages.
How are macrophages replenished?
Macrophage are replenished by monocytes.
What are the three theories on the embryological origin of macrophages
Model 1:
Labelling at d7.5 or 8.5 in Tie2-Cre mouse: hemogenic endothelial progeny cells are labelled
Tissue resident macrophages in the brain, liver and skin are foetal and adult macrophages arise from yolk sac progenitors, seeded before d9.5
Model 2:
Labelling at d7.5 or 8.5 in Runx1-Cre mouse: 2 waves of EMPs- primitive progenitors and definitive progenitors.
Tissue resident macrophages in the brain, the microglia, are separate populations.
The other tissue resident macrophages derive from a late EMP progenitor, which outcompete early
EMPs and transition through a foetal liver monocyte stage.
Model 3:
Using another tracing model, tissue resident macrophages have been shown to derive from a foetal haematopoietic stem cells, with the exception of brain microglia
What marker can you use to see the difference between microglia and tissue macrophages?
Microglia are F4/80 high and tissue macrophages are F4/80 low
Is the presence of a lot of macrophages a good sign in cancer?
More macrophages in cancer are a sign of worse prognosis in (almost) every cancer except colorectal cancer.
Is every tissue resident macrophage the same in terms of transcriptional profile?
Tissue resident macrophages show diverse transcriptional profiles driven by tissue specific transcription factors. Environmental signals sculpt macrophage enhancer and gene expression. Transplant studies show tissue specific acquisition for newly arriving cells
What do angiogenic macrophages express/secrete?
Angiogenic macrophages express/secrete VEGR1, CXCR4, TIE2, CtsB and CtsS
What do activated macrophages express/secrete? (inflammation)
Activated macrophages express/secrete IL-12, MHCII, iNOS and CD80
What do immunosuppressive macrophages express/secrete? (immune regulation)
Immunosuppressive macrophages express/secrete arginase, IL-10 and CCL22
What do perivascular and invasive macrophages express/secrete? (intravasion, invasion)
Perivascular and invasive macrophages express/secrete CtsB, CtsS, CtsZ and EGF
How do cancer cells exit the tumour bulk?
Cancer cells exit the tumour bulk using “tracks” made by macrophages.
- Hypoxia recruits new vessels and allows immune influx of macrophages
- Macrophages release proteases to degrade ECM and basement membrane
- This allows for the influx of additional immune cells which pave the way from vessels to tumour
- Cells exposed to hypoxia change their behaviour (motile) in an attempt to find nutrients
