Lecture 6 Flashcards Preview

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Flashcards in Lecture 6 Deck (36):
1

What two mechanisms can cancers use to spread?

Invasion - Migration and penetration into neighbouring tissues

Metastasis - Penetration of lymphatic or blood vessels, circulation and colonization of normal tissue at a distant site

2

Outline the basic steps of the metastatic cascade

  1. Primary tumour formation by transformed cells
  2. Proliferation and angiogenesis 
  3. Detachment and invasion in circulatory system
  4. Embolism/ciculation
  5. Extravasion 
  6. Proliferation and angiogenesis at distant site to form a metastatic tumour

3

Why is metastasis a problem?

Large decrease in survival rate 

90% of cancer deaths due to metastasis 

4

Why are metastatic cancer cells a large area of study?

Due to decrease in survival rate 

Also when in transport may be easier to target so possible treatment route

5

What are the three main theories for how metasis can occur?

  1. A minortity of tumour cells are able to metastasis (supported by stem cell theory)
  2. All tumour cells in population can metastasis (supported by gene expression profiling) 
  3. Subpopulations within tumours have potential to metastasis to specific places

6

What type of cells exist in a heterogenous tumour environment?

  • Cancer cells
  • Immune-inflammatory cells
  • Cancer associated fibroblasts 
  • Endothelial cells and pericytes (for blood vessels)
  • Cancer stem cells 
  • Invasive cancer cells

7

What does heterogenous tomour population give rise to?

How was it first shown?

Heterotypic signalling

By Van Scott and Reinertson in 1962

Transplanted skin tumours to different sites on body. Only tumour cells transplanted with carcinoma-associated stromal cells were able to form new tumour at distant site

8

Give two examples of how cancer cells use positive feedback loops for their growth 

  1. Release signals with stimualte mesenchymal stem cells to release CCL5 which will stimulate cancer cell invasion 
  2. Release chemotactic factors to cause circulating monocytes to become tumour-associated macrophages, whcih release:
  • EGF to promote cancell cell survival and proliferation 
  • Proteases to disrupt ECM ctreating more space and releasing angiogenic factors 
  • Angiogenic factors to cause angiogenesis 

9

What is the implication of the cross-talk and feedback between cancer and non-cancer cells?

Tumours are not dependent on new mutations to allow them to metastasis, but can use cross-talk with other cells to lead to their ability to metastasis 

10

What are the consequences of being too far from a blood vessel?

Hypoxic and anoxic areas

  • Low pH
  • Low O2
  • Low ATP
  • Low Glucose 
  • High lactic acid 

11

Outline the basic process of angiogenesis

  1. Cells lacking Orelease angiogenic factors
  2. Recruited cells can then orchestrate an inflammatory response
  3. Release of TNF-α and prostoglandins will promote angiogenesis 
  4. Endothelial cells then release PDGF and HB-EGF to attract pericytes and smooth muscle cells to build the blood vessel

12

What factor of sodium channels has been shown to be important for angiogenesis?

ß1 factor which has been to cause increased angiogenesis and increased levels of VEGF

13

What was thought to be a major advantage of anti-angiogenesis therapy?

Targeting normal cells which would be more susceptible to treatment

14

What drugs are in use to target angiogenesis?

Bevacizumab - which targets VEGF

15

Why is bevacizumab thought to not be as successful as hoped?

Although stops angiogenesis initially and hence stops tumour growth leads to hypoxia which may stimulate endothelial to mesenchymal transition and save angiogenesis. May also lead to intravasation, extravasiation, vessel co-option or thrombosis. All of which cause increased invasive ability of the tumour. 

16

What cell adhesion molecules are commonly expressed on cancer cells?

  • Intergins 
  • Ig superfamily adhesion molecules 
  • Cadherins 

17

Outline the basic structure of integrins

An α and ß subunit which bind to the ECM and can signal in the cell via FAK and RAS

18

What are the functional roles of adhesion molecules?

  • Regulate cell shape 
  • Alter adhesion
    • Loss of attachment to other cells
    • Loss of attachment to ECM
    • Loss of anti-growth signalling
    • Facilitates migration 
    • Facilitate anchorage at new sites 

19

When is the endothelial to mesenchymal transition usually seen?

During embryonic morphogensis and wound healing

But is also co-opted cancer cells

20

What controls EMT in non-cancer cells?

E-cadherin which blocks ß-catenin 

21

How can cancer cells stop E-cadherin?

What is the outcome?

  • Mutation of E-cadherin or ß-catenin genes
  • Transcriptional repression
  • Proteolysis of extracellular cadherin domain

Loss of adhesion 

22

Outline the basic EMT program 

  • Dissolution of cell-cell junctions
    • Loss of E-cadherin or acquisition of N-cadherin
  • Acquistion of mesenchymal phenotype
    • Actin reorganisation
    • Stress fiber formation
    • Migration and invasion 

23

What are the outcomes of EMT?

  • Increased motility
  • Increased resistance to apoptosis
  • Enablisation of invasion and metastasis

24

What is the reverse of EMT?

MET

E-cadherin expression causes transtion back to epithelial cell

25

How do cancer cells hijack heterotypic signalling to allow EMT and MET?

  • Tumour associated macrophages in reactive stroma cause EMT
  • At new site lack of TAMs will lead to MET

26

What must cancer cells be able to do in order to invade?

Cause reorganisation and proteolysis of the ECM

  • Protease genes are upregulated
  • Protease inhibitor genes are downregulated
  • Inactive proteases activated 

27

What are the two main types of invasion?

Invasion - into tissues

Intravasation - invasion into vessels

28

What familys of proteases have been shown to be important for invasion? 

Matrix metalloproteinases (MMPs) - Family of zinc- or calcium- dependent proteases which can degrade all components of the ECM

Cathepsins - Degrade collagen

29

Outline the structure of MMPs

 

Secreted and membrane bound exist 

Membrane bound via type 1, c-terminus anchor, type 2, n terminus anchor, or GPI-membrane domain

Both secreted and membrane bound have propeptide and catalytic domains 

30

What upregulates MMPs in cancer cells?

Oncogenes, e.g. c-myc and c-ras

31

Why is it thought that MMP inhibitors have, so far, had little success?

The inhibitors are selective for a specific MMPs

  • Not all MMPs are equal
  • Some have anti-tumour activity
  • Produced by reactive stroma, not the tumour cells

32

Where are cathepsins expressed in normal and cancer cells?

In normal cells they are expressed in lysosomes, whereas in cancer cells they are expressed on the cell surface

33

What do cancer cells use cathepsins for?

Degradation of the basal lamina and stroma to exit organs and undergo intravasation 

34

How is heterotypic singalling hijacked for ECM degradation?

Macrophages at tumour periphary can supply MMPs and cathepsins 

35

How can you observe ECM degradation?

In vivo zymography

36

What are the patterns of invasion?

Mesenchymal - regulated by EMT

Collective- groups of cells advance into new tissue

Amoeboid invasion - tumour cells attract cells which secrete ECM degrading enzymes and squeeze between cells due to morphological plasticity