tumour microenvironment Flashcards
tissue
tissue is a cooperative assembly of cells and extracellular matrix woven together to form a multicellular fabric with a distinctive function
changes in tissues in cancer
in cancer, sometimes that’s slightly different and the organization can sometimes starts to degrade.
- in tumours this organization changes and how cells interact with each other changes in a tumor.”
different cell types in lining of gut that work together in a normal tissue
- Epithelial cells - cells butting up against each other tightly connected forming these sheet-like structures that enable organs and tissues to be self-contained.
- Beneath that we’ve got this connective tissue layer. That’s really dominated by fibroblasts. So these are important molecules for secreting extracellular Matrix,
we’ve also got this smooth muscle layer that’s important for regulating tension and contractility.
where are carcinomas derived from
epithelial tissues
stromal fibroblasts in cancer
the cancer cells are still clustered together but they’re surrounded by fibroblasts
- And these fibroblasts are not the cancer cells. They’re the other part of the tumor and we call that the stroma
○ So these are stromal fibroblasts.”
proportion of epithelial tumour to stroma
the proportion of epithelial tumor to stroma varies across a lot of different cancers, but actually in many cancers you can get up to 90% of the tumor is actually not the cancer cells but the stroma
so that means understanding how cancer cells interact with the stroma is really important because the stroma dominates a lot of different cancer types.
single-cell RNA sequencing to try and understand what different cell types are part of a tumour
this is a way where you can get cancer tissue from a patient and you can analyze the gene expression.
- so you can end up with tens of thousands or hundreds of thousands of cells and for each one of those cells you know the gene expression profile.
- different cell types Express different signatures of genes or different markers.
- So immune cells will Express different Gene profile to a fibroblast. For example.
- And so because we know these markers and signatures we can say Well this cell expresses this Gene profile. So it must be a fibroblast
And you can use bioinformatic approaches then to Cluster all the cell’s together that have a similar gene expression profile and then you can label it with a certain cell type.”
what is in the stroma
-when fibroblasts are activated to make lots more extracellular Matrix, then they can be termed myofibroblast. So these are active fibroblasts. They’re churning out lots more Matrix into the micro environment.
- We’ve got stem cells.
- We’ve got blood vessel vasculature cells,
- got all sorts of different immune cells,
-the extracellular Matrix non cellular components.”
immune cells
- in some cases, immune cells can recognise and destroy cancer cells
- in other cases, the tumour microenvironment can suppress the anti-tumour immune response, allowing cancer cells to grow and spread
- immunotherapy is a type of cancer treatment that harnesses the power of the immune system system to dight certain types of cancer
anti tumour immune microenvironment
if you for example take a patient tumor sample, and it’s enriched for cytotoxic T cells such as cd8 positive T cells, you know, that’s generally going to be linked to a positive prognosis for the patient because you’ve got these killer T cells in there that can recognize and clear the tumor.
immune suppressive microenvironment
If however there’s a patient sample that has a lot of T-Regs that’s usually less good news for the patient because the anti-tumor immune response has been suppressed and you get this suppressive microenvironment.
fibroblasts
- key component of the tumour stroma
- secrete growth factors, cytokines and ECM components that change the properties of the microenvironment and promote tumour growth
- create a physical barrier around the tumour, blocking immune cell entry
- communicate with cancer cells to promote survival and growth of cancer cell
- cancer and stromal cells secrete tgf-BETA, pGDF and fibroblast growth factor 2 to convert fibroblasts to cancer associated fibroblasts”
different types of fibroblasts and treatment responses
fibroblasts are not just a single cell type.
- They are a collection of different cells that can have different functional outputs as well.
- when those different fibroblasts are transformed with the same oncogenes it is a vastly different invasive response of these fibroblasts
- and this is essentially because different fibroblasts from different tissues from different parts of the body have different functions because they are driven by different expression profiles of genes.
- And this is a challenge Because it means it’s part of the reason why cancers in different parts of the body in different tissues respond, very differently to treatment
myofibroblasts and prognosis
a patient with a high density of cancer Associated fibroblasts, This would be associated with a much poorer prognosis.
extracellular matrix
- complex network of proteins, glycoproteins and proteoglycans that surround cells - provides structural support
- sequesters growth factors and other soluble molecules
- continuously remodelled by proteases, which liberates tethered molecules, generating localised high concentrations
- in the tumour microenvironment, ECM can promote tumour growth and progression
- create a physical barrier around the tumour, blocking immune cell entry
- glycan modification is implicated in cancer progression”
