Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BIOL3043 - Cellular and molecular pathology > Lectures 11&12 - The Tumour microenvironment > Flashcards

Lectures 11&12 - The Tumour microenvironment Flashcards

1
Q

What is intracellular communication driven by

A

complex and dynamic network of cytokines, chemokines, growth factors and inflammatory and matric remodeling enzymes (autocrine, paracrine, juxtacrine (cell contact), endocrine)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

The evolution, structure and activities in the cells in the TME have many parallels with what?

A

wound healing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are CAFs?

A

Cancer associated fibroblasts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are TILs?

A

Tumour infiltrating lymphocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What do the different levels of CAFs and TILs mean for survival rate

A

% of survival decreases as CAFs increase and TILs decrease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What do lots of fibroblasts infer about cancer prognosis

A

Bad prognosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What do lots of CD8 cells infer about cancer prognosis

A

Good prognosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the major types of cells in the TME

A

Cancer-associated fibroblasts

Adipocytes

Cells of the vasculature - Vascular endothelial cells

                                           - Pericytes

Immune cells:

Tumour-associated macrophages

T lymphocytes – eg CD8+, CD4+, CD4/FoxP3+

B lymphocytes

Natural Killer cells and Natural Killer T cells

Dendritic cells

Myeloid-derived suppressor cells

Tumour-associated neutrophils

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is a fibroblast

A

Ubiquitous cell - most common cell of connective tissue

Typically mesenchymal origin

Structural cell – maintain structural integrity of connective tissue

Produce extracellular matrix - collagen, glycosaminoglycans, reticular & elastin fibres

Involved in organ homeostasis – inflammation (switch on and off) , wound healing and fibrosis – produce scar tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Explain fibroblasts role in inflammation

A

Can be present as specialised types of fibroblasts

Can also be present in non-lymphoid tissue

Also involved on switching inflammation off once wound has healed

Produce cytokines ans chemokines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are some cytokines and chemokines fibroblasts produce?

A

Cytokines - TGFβ1, IL1β, IL6, IL33

Chemokines - CXCL12, CXCL13, CCL2,

ECM proteins – collagens, fibronectin, tenascin

In cancer- they protect cancer from the immune system

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What does a fibroblast become when its activated

A

Myofibroblast

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Explain the process of a fibroblast turning into a myofibroblast

A

Fibroblast encounters mechanical stress -> turns into a proto-myofibroblast with focal adhesions and Filamentous actin

proto-myofibroblast encounters mechanical strss cytokines e.g. TGF-b -> tuns into myofibroblast with FAs, Filamentous actin and a-SMA

Both proto-myofibroblasts and myofibroblasts have ED-A fibronectin (Fibroblasts have fibronectin only)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are myofibroblasts

A

Typically ‘activated’ through TGF-beta signaling (also need tissue tension/mechanical stress)

Contractile, secretory cells that produce ECM

Function to contract a wound and produce scar tissue (resolve the wound)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

how can you test for the upregulation of collagen in fibroblasts with TGF-b added

A

Gel contraction assay

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are some features of CAFs

A

A fibroblast in a cancer

The major stromal type in most solid cancers

Historically, the term cancer associated fibroblast has referred to cells resembling ‘activated’ myofibroblasts as found in wound healing

Contractile cells expressing α-smooth muscle actin (SMA) stress fibres

Generated through TGF-β1 signalling

Produce and secrete large amounts of ECM proteins

Secrete growth factors and cytokines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

True or false: CAF are plastic cell type population and can change phenotype

A

TRUE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Why do fibroblasts change phenotype

A

Don’t want fibroblasts to keep producing ECM once wound has healed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Explain the different CAFs in cancer

A

myCAFs : tend to work through justocrine interactions, so would ususially find myCAF cell lying up against the tumour as ist cell-cell interactions that the myCAF is communicating through

Also a population of iCAFs - inflammatory CAFs : usually found further from the tumour cell, they have secreting factors such as IL-6/IL-11, there are then having an effect on the tumor cells (not the iCAF itself – paracrine)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Explain the triggers for Quiescent plutipotent stem cells to turn into myCAFs and iCAFs

A

myCAF – TGF-β, blocks IL-1 signaling (immunosuppressive)

ICAF – NF-kB signaling and JAK/STAT signaling (promoting immune system)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What are myofibroblastic CAFs associated with

A

aggressive cancers and poor prognosis, they promote metastiasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Often when there’s many CAFs there will be little…

A

T cells (due to immune suppression)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What does the ECM consist of

A

fibronectin, collagens, periostin, tenascin, proteoglycans, MMPs

24
Q

What are Haematogenous vs Lymphatic metasiasis

A

Metastasis – No longer connected to surface epithelium, spread of tumour to distant organs

 Haematogenous – via bloodstream 

 Lymphatic – to lymph nodes
25
What does Transcoelomic mean in terms of cancer spread
across body cavities
26
What does Implantation/transplantation mean in terms of cancer spread
normally due to tumour gets accidentally inserted to somewhere else by a surgeon (rare)
27
What percentage of cells entering circulation develop into metastasis?
<0.01%
28
How do CAFs promote invasion and metastasis
Secretion of cytokines (TGF-β1, HGF, CXCL12) – induction of tumour cell EMT Secretion of ECM (collagens, cross-linking collagen [LOX enzymes]) – increasing tissue stiffness and activatIng tumour cell mechanotransduction signaling pathways Remodeling ECM (secreting enzymes such as matrix metalloproteinases [MMPs] – creating tracks for tumour cells Secretion of other factors – IL6, 1L32
29
How can tumour invasion be studied in the lab?
Plating tumour ells onto gels containing fibroblasts - feed with medium and at end and take gel and process it and take sections - can see in cancer surface epethilum and island of tumour cells invading
30
How can metastasis be studied in the lab?
4T1 grows in immunocompetent mice Can co-inject tumour cells with finroblasts or CAFs When we do this we can see in the primary tumours when we stain for smooth muscle actin, can see SMA positive stroma, also tumours grow much bigger, much quicker
31
What does CAF promote in the lungs
Metastatic deposits
32
What do high T cell levels infer about cancer survival?
Better survival chance
33
Explain the process of immunoediting, three Es: elimination, equilibrium and escape
Elimination - any potential cancer cells are eliminated, immunosurveillance and adaptive and innate immunity active Equilibrium - persistance, genetic instability and immunoselection. mmune system no longer able tp kill off tumour cells, but the tumour is not getting any larger escape - progression, chronic inflammation and cancer progression
34
What specific T cell type is associated with better survival?
CD8 T cells
35
What do Tumour-infiltrating lymophocytes (TILs) recognise?
Viral antigens in HPV+ in oropharyngeal cancer
36
What is oropharyngeal cancer
Cancer of the head and neck, caused by smoking and drinking, can also be caused by HPV virus
37
Is surival higher in people with HPV causing head and neck cancer, or HPV -ve
Survival higher in HPV causing cancer (T cells recognise virus specific antigens)
38
Compare the transcriptomics of HPV+ and HPV-ve oropharyngeal cancer
Transcriptomics are different In HPV+ there were lots of immune genes that were unregulated Looking at T cell levels in HPV+ cancers - much higher levels About 15% of HPV+ don’t have high levels of T cells and their prognosis was much poorer
39
How do CAF promote tumour immune evasion?
No one single mechanism responsible: lots of things that inhibit its of types of immune cells Inhibit CD8 T-cells Exclude CD8 T-cells Kill CD8 T-cells Inhibit dendritic cells Inhibit NK cells Promote suppressive T-regs Promote MDSCs Promote M2 macrophages
40
Explain how cytotoxic (CD8) T-lymphocytes are tumour killer cells
Focus on these as these are the soldiersof the imune system Recognise specific antigens bound to Class I MHC Activation requires 2 signals - TCR (T-cell) & antigen-bound MHC Class I (APC) -Costimulation CD28 (T-cell) by CD80/86 (APC) Expansion – IL-2 Express perforin, granzyme, Granulysin, FasL
41
What are the tumour antigens?
Mutated proteins - neoantigens Oncofetal antigens – eg CEA Testis antigens – eg MAGE Highly overexpressed antigens – eg tyrosinase Viral antigens – eg HPV
42
Describe immune hot vs immune cold tumours
Immune hot – got lots of T cells within them Immune cold – 2 different patterns Excluded – CD8T cells stuck around edge of tumour and can't get at tumour cells Desert – doesn't seem to be an immune response at all
43
Whats a proposed way that immune therapy could work more effectively to treat cancer
The T cells are there and want to try destroy the tumour, so If you could get a drug for eg, and it could get T cells into the tumour – perhaps that would be a way of getting immune therapy to work more effectivly
44
Explain the dysfunction of CD8-T cells in tumours
Immunosuppressive immune infiltrate and tumour cells – Tregs, MDSCs, TAMs, TANs etc. Hostile environment – hypotoxic, acidic, nutrient depleted, toxic metabolites Suppressive receptors – PD-L1/L2, VISTA etc. Inhibitory enzymes – Arginase, IDO-1 Lack of Co-stimulation – T cell intrinsic dysfunction, PD-1, LAG-3, Tim-3 etc. Upregulation and suppressive signaling : Suppressive molecules – IL-10, TGFβ, adenosine, PGE2
45
Describe the regulation of T cells through different receptors present on them
Activating: CD28, OX40, CD40, CD27 Inhibatory: LAG3, PDL1, CTLA4 (PD1 and CTLA4 both have drugs that interact)
46
What are the two different types of TAMs
M1 expressed - MHC class II, CD14, CD80 (inflammatory M2 expressed - CD36, CD163 anti-inflammatory - promote angiogenesis Now been seen that these two categories not totally correct as seen to be mixed expression
47
What analysis is carried out to ensure precision medicine is precise
'omic' analysis - but sequencmg DNA by itself doesnt give you that much useful info analysis expensive - if a pathology test could be created would be much cheaper
48
What happens if you group data according to DNA mutations
no pattern, messy, however if you look at gene expression pattern, subgroups start to appear
49
How is it decided who gets immunotherapy treatment
stain cancer for PD-L1 scoring system, if scoring is high enough, patient is eligible for anti-PD-L1 treatment Problem: - many pharmaceutical companies have developed drugs against PD1, so systems have become very complex - test not hugely accurate of predictive, patients who test negative for this can still benefit from drug - PDL1 expression is heterogenous
50
Explain why higher mutation rates lead to better immunotherapy response
Immunotherapy uses mechanism of recognising tumour as non-self, so higher the mutations, more likely it is to express mutated MHC I antigens
51
Explain what studies showed about patients who don't respond well to immunotherapy
patients with high levels of fibroblasts (CAFs) in tumours tend to be associated with non-response, therefore this is a target area for getting immunotherapy to work better
52
What are the 4 subtypes of the pan-cancer microenvironment, which one is associated with immunotherapy resistance
immune-enriched, fibrotic immune enriched, non-fibrotic fibrotic depelted immunotherapy resistance - fibrotic (Bagaev 2021)
53
How could you target a CAF
'Normalise' CAF - TGFb inhibition, NOX4 inhibition Kill CAF population - CAF directed vaccination Block CAF function - target CXCl12
54
How could you target a CAF
'Normalise' CAF - TGFb inhibition, NOX4 inhibition Kill CAF population - CAF directed vaccination Block CAF function - target CXCl12
55
What would be the problem with blocking TGFb to target CAFs
TGFb involved in tissue homeostasis and in early stages of cancer development TGFb helps supress cancer development small molecules developed showed cardiac toxicities
56
What are ways of localising inhibition of TGFb
- neutralising antibodies - small molecule inhibators
57
Whats a another way that CAF is regulated
NOX4 - enzyme that produces ROS can block NOX4 - CAF goes from myofibroblatoc phenotype to normal quiescent like cell (tested with SMA staning) tumours grew much smaller and CD8T cells infiltate

BIOL3043 - Cellular and molecular pathology (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions