Hypoxic cancer microenvironment

Question 1

What is the morphology of metastisized tumounr reminiscent of?

Answer 1

the tissue of origin if cancers are from differentiated cells.

Question 2

what stromal cells are there in the tumour?

Answer 2

macrophages, fibroblasts and endothelial cells.

Question 3

What cells and products contribute to the hardness of tumours?

Answer 3

fibroblasts and the ECM they lay down.

Question 4

what surrounds the cancerous cells?

Answer 4

Blanket of stromal cells.

Question 5

How can fibroblasts benefit tumour?

Answer 5

They have an activated ‘wound healing phenotype’ and can bring nutrients and facilitate cancer growth.

Question 6

Why might cancer drug concentrations/ O2/ nutrients reaching cancer cells be low?

Answer 6

because capillaries are embedded within the stroma.

Drugs have to penetrate fibroblasts before reaching cancer cells.

Question 7

To what extent are stromal cells in tumours present in animal models?

Answer 7

More present in human slow growing tumours.

Very fast growing tumours in animal models have far fewer stromal cells.

Question 8

Why might stromal cells attentuation of drugs be a problem?

Answer 8

Only small doses of drugs delivered to cancer cells. Unlike in vitro studies.

Sub lethal doses of drugs can drive cancer resistance to drugs.

Question 9

Is vessel size good indicator of blood flow in tumours?

Answer 9

No, because lots of blind ends, clots- often means blood flow is lower in tumours.

Blood pressure is higher in these vessels which also limits flow.

Question 10

Why is pressure higher in capillaries and lymphatics in tumours?

Answer 10

Because of myofibroblasts, can collapse lympatics and contribute towards hypoxia.

Question 11

What kind of factors contribute towards angiogenesis in tumours?

Answer 11

damage and hypoxia- stimulates ‘wound healing’ angiogenesis.

VEGF, PDGF and FGF

Question 12

What is the process of angiogenesis in response to VEGF PDGF and FGF?

Answer 12

endothelial cells become active, divide and become motile, breaking away from basement membrane

Question 13

What effect can reduced lymphatic removal of lactic acid have?

Answer 13

Causes build up and decrease of pH.

Question 14

What effect can pH play on treatement of cancer?

Answer 14

Protonated durgs from pH may be less permeable, inhibiting drug entry and effects.

Question 15

What roles do activated (myo)fibroblasts play in cancer?

Answer 15

secrete ECM, changes can cause tissue remodelling that can enable motility.

VEGF and TGF-B for angiogenesis and immunosuppression.

Question 16

In which cancer have fibroblasts walls opened up after core becomes hypoxic? What does this enable?

Answer 16

Breast cancer, this enables tumour spread.

Question 17

Where do lymphocytes accumulate after exiting capillaries in the stroma?

Answer 17

NOrmally outside the edge of cancer cells.

Some can be seen infiltrating tumour.

Question 18

5 reasons why lymphocytes might be excluded from tumours?

Answer 18

1) poor blood supply
2) physical barrier (e.g. thick ECM) inhibits their entry.
3) active chemokine mechanisms keep them out.
4) macrophages retain lymphocytes outside of tumours
5) get inside TME, but its so inhospitable they dont’ have enough nutrients to survive.

Question 19

Why might T cells be incapable of killing tumour cells if in right place?

Answer 19

little nutrietns and oxgen, can’t compete with cancer cells and not enough resources for T cell function and survival.

soluble inhibitory cytokines and nitric oxide and arginine production.
Checkpoint inhibitors.

Question 20

What changes in MHC can inhibit immune responses against cancers?

Answer 20

Downregulatin of MHC I/II.

upregulation of HLA-G and E which can inhibit NK cells- like what you see in pregnancy.

Question 21

How to solve heterogenietiy of cancer?

leaky vasculature?

Answer 21

Hetergeneity overcome with combinations of drugs and different classes.

Leaky vasculature means larger drugs can be used that only exit at these large enough capillaries.

Question 22

pH?

macrophages?

Answer 22

Use liposomes that are endocytosed and release drugs into cells to overcome pH attentuation of drugs.

Express anti cancer molecules in infiltrating macrophages.