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Cancer & The Cell Cycle > Lecture 6 - Tumour microenvironment, invasion and metastasis > Flashcards

Lecture 6 - Tumour microenvironment, invasion and metastasis Flashcards

1
Q

What percentage of cancer deaths are caused by secondary tumours?

A

90%

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2
Q

What is the process of metastasis?

A
  • Invasion into capilaries
  • arrest in organs
  • adherence to vessel wall
  • extravasation
  • metastasis
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3
Q

What cells are tumours made up of?

A

Many different ones but endothelial cells and pericytes definitely (blood vessels)

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4
Q

What are the features of cells in tumours?

A
  • Biologically heterogeneous

- Contain genotypically and phenotypically diverse subpopulations as they have arisen from different places

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5
Q

How did Van Scott and Reinerston (1961) investigate heterotypic signalling?

A
  • Took autologous transplantations of skin tumours
  • Transplanted onto back
  • Found that if transplanted with carcinoma-associated stromal cells they profliferated but with out they did not grow
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6
Q

What did Van Scott and Reinsterston conclude?

A
  • Stromal cells required to support growth of tumour

- Signalling occurs between different cell types within same tumour

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7
Q

What is an example of crosstalk and feedback in tumours?

A

Mesenchymal stem cells in tumours secrete CCL5 in response to signals released by cancer cells.
CCL5 then acts on cancer cells stimulating invasive behaviour

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8
Q

How does malignancy arise and what is it’s implication?

A

Not in a cell-autonomous manner.
The invasion-metastasis cascade may be acquired without additional mutations beyond those that were needed for primary tumour formation

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9
Q

Why does analyses of tumour cell genomes only reveal part of the story?

A

Invasion metastasis cascade happens with only a few starting mutations and a lot of cross talk between cell types

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10
Q

How far from a vessel is hypoxic (oxygen under 2.5mmHg)

A

60 microns

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11
Q

How far from a vessel is anoxic? (no oxygen)

A

90 microns

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12
Q

What do recruited cells (responding to angiogenic factors from cancer) to promote angiogensis?

A

Release TNF-a and prostaglandins

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13
Q

What do endothelial cells recruited to the tumour do to promote angiogenesis?

A

Release PDGF and HB-EGF to attract pericytes and vascular smooth muscle cells to build up structure of vessels

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14
Q

What is the advantage of anti-angiogenic therapy?

A

Targetting genetically normal cells

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15
Q

What is an approved anti-angiogenic drug treatment?

A

Bevacizimab, an anti-VEGF-A antibody which reduces tumour growth

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16
Q

What is a possible explanation as to why anti-angiogenic drugs only moderately improve survival?

A

By producing a hypoxic environment you are inducing invasion

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17
Q

What are the 3 classes of cell adhesion molecules expressed on cancer cells?

A

Cadherins
Integrins
IgSF CAMs

18
Q

What changes does altered adhesion result in?

A
  • loss of attachment to other cells
  • loss of attachment to ECM
  • loss of anti-growth signalling
  • facilitates migration
19
Q

What is the epithelial to mesenchymal transition (EMT) due to?

A

Change in adhesion molecules

20
Q

What usually happens in EMT?

A

During embryonic morphogenesis and wound healing signals from neighbouring cells trigger expression of TFs that promote EMT

21
Q

How do cancer cells do EMT?

A

epithelial cell to cell adhesion molecule E-cadherin maintains quiescent state and suppresses invasion and metastasis
Cancer cells downregulate E-cadherin

22
Q

How does cancer downregulate E-cadherin?

A
  • Mutation of E-cadherin
  • Transcriptional repressson
  • Proteolysis of extracellular cadherin domain
23
Q

What does cancer do at the same time as downregulating E-cadherin?

A

Upregulates adhesion molecules associated with mesenchymal cell migration such as N-cadherin

24
Q

What changes with EMT?

A

Increased motility
Increased resistance to apoptosis
Enables invasion and metastasis
Dissolution of cell-cell junctions

25
Q

What is different in the mesenchymal phenotype?

A

Actin reorganisation
Stress fibre formation
Different shape

26
Q

What occurs with dissolution of cell-cell junctions in EMT?

A
  1. tight junction dissociation

2. adherens and desmosome dissociation

27
Q

What can sometimes activate EMT?

A

heterotypic signals from TAMs in reactive stroma

28
Q

When may tumour cells revert to MET?

A

in absence of reactive stoma (eg at a distant site)

29
Q

Why is acquisition of many mutant genes not necessarily required for malignancy?

A

EMT-TFs are pleiotropic

30
Q

What is the cycle of cancer cels in metastasis (plasticity)

A
  1. Carcinoma on basement membrane
  2. Invasion into stroma by EMT
  3. Intravasation
  4. Transport and extravasation
  5. MET into basement membrane
  6. Colonisation
31
Q

What does the invasion of cancer require?

A

Reorganisation and proteolysis of ECM

32
Q

How does cancer reorganise the ECM?

A

Upregulates proteases and downregulates protease inhibitors. Inactive proteases convrted into active.

33
Q

Features of matrix metalloproteinases (MMPs)

A
  • Upregulated in almost all cancers
  • break down all ECM
  • expression inducedby oncogenes (c-myc)
34
Q

Why do MMPs not work as drug targets?

A
  • Not all MMPs are equal
  • Some have antitumour activity
  • produced by reactive stroma not tumour cells
  • selective MMP inhibitors may hold more promise
35
Q

What do cathepsin proteases do when expressed by cancer cells?

A

degrade collagens in connective tissue allow penetration and intrravasation

36
Q

What are the advantages and disadvantages of 2D in vitro cell culture models?

A 
Adv: - easy to perform
- repeatable
- well defined parameters easy to interpret
Disadv: - Monoculture
- 3D environment significantly different
37
Q

What are the features of cancer cell lines?

A
  • Difficult to adapt to in vitro
  • Many cells lines derived from effusions (loss of stromal support requirement
  • In vitro conditons (high serum, no stroma) very different to in vivo so interpret with caution
38
Q

What are the features of collective invasion?

A
  • Groups of cells advance into adjacent tissues
  • Usually not metastatic
  • Typical of squamuous cell carcinomas
39
Q

How does amoeboid invasion work?

A

Tumours attract cells that secrete ECM degrading enzymes

40
Q

Have a look at intravital imaging

A

See how to do it

Cancer & The Cell Cycle (8 decks)

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