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Cellular and Molecular pathology > 14. The Tumour Microenvironment and Metastasis 1 > Flashcards

14. The Tumour Microenvironment and Metastasis 1 Flashcards

1. Describe steps of cancer invasion and metastasis 2. Role of cell-cell and cell-ECM adhesions in metastasis 3. How new blood vessels affect cancer growth and metastasis 4. Understand how hypoxia induces VEGF production 5. Explain how VEGF and other factors stimulate angiogenesis 6. Describe how angiogenesis can be inhibited

1
Q

What are genetic mutations?

A
  1. caused by mutagens or mistakes in replication
  2. mostly repaired by DNA repair
  3. mutations are random and don’t target specific genes
  4. some rare mutations can give rise to cancer
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2
Q

What is cancer?

A

An accumulation of genetic mutations that can give a cell selective advantage over its neighbours

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3
Q

Mutations and cancer

A
  1. different mutations can cause different cancers in different tissues
  2. some mutations are selective for specific cancer
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4
Q

Why would we sequence a patient’s tumour?

A

To identify what genetic mutations they have and what mutations define that cancer

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5
Q

Oncogene mutation

A

make the protein more active

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6
Q

Tumour suppressor mutation

A

loss of a protein gives a selective advantage

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7
Q

What are the hallmarks of cancer?

A
  1. Resisting cell death
  2. Inducing angiogenesis
  3. Enabling replicative immortality
  4. Activating invasion and metastasis
  5. Evading growth suppressors
  6. Sustaining proliferative signalling
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8
Q

What do the hallmarks of cancer allow cancer cells to do?

A

makes the cells grow better and accumulate more mutations than their neighbours

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9
Q

What are 90% of cancers?

A

epithelial cell derived like CRC, lung, breast, skin, breast

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10
Q

What are the principles of metastasis?

A
  1. primary tumour grows in the epithelium and the cells have a selective advantage over their neighbours. But is still contained in the epithelium.
  2. It continues to grow and breaches the basement membrane and ECM it can enter the blood and circulate in the body.
  3. The circulating cells can leave the blood at anytime at a different tissue and form a secondary tumour
  4. common sites of metastasis are the liver, lungs, brain and bone
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11
Q

How do the cancer cells go round the blood?

A

as single invasive cells which have lost their adhesion to the epithelium

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12
Q

What are the 3 types of cell-cell junctions?

A
  1. tight junctions
  2. Adherence junctions
  3. gap junctions
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13
Q

What are tight junctions?

A
  1. made of claudins
  2. they stop fluids getting in and out of the gut so everything has to go through the cell
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14
Q

What are adherence junctions?

A
  1. made of cadherins
  2. Tells cells there are other cells near so they don’t need to divide
  3. usually involved in wound healing when neighbours as lost
  4. E-cadherin is the epithelial cadherin
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15
Q

What are gap junctions?

A
  1. made of connexins
  2. passes messages between cells
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16
Q

What is E-cadherin?

A

a transmembrane adhesion protein

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17
Q

What does a loss of E-cadherin cause?

A
  1. it allows for cell proliferation because the cells are not receiving signals to stop dividing
  2. The cells think there is a wound to they keep dividing to try and repair it
  3. This is very common in metastatic tumours as it enables migration
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18
Q

How do benign tumours become malignant?

A
  1. they acquire new genetic changes that allow them to invade
  2. The surrounding tumour microenvironment can induce the transformation to malignant
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19
Q

What are the stages of colorectal cancer?

A
  1. hyperplasia
  2. polyps
  3. adenoma
  4. adenocarcinoma
  5. carcinoma
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20
Q

Stages of CRC: hyperplasia

A

The cells are just dividing rapidly. They haven’t formed a specific tumour that can be removed.

21
Q

Stages of CRC: polyps

A

They have more cells and can be removed

22
Q

Stages of CRC: adenoma

A

Still benign with some cells that are pre-malignant with additional genetic changes

23
Q

Stages of CRC: Adenocarcinoma

A
  1. Still contained in 1 area looking like a polyp.
  2. Starting to breach the basement membrane
  3. can be removed but there is a high chance of invasion
24
Q

Stages of CRC: Carcinoma

A
  1. Flatter, still has a polyp like protrusion but has invaded the muscle and surrounding tissues
  2. cannot just remove what you can see
  3. need to remove a large section
  4. very high chance of metastasis
25
Q

What are matrix attachments?

A
  1. signal for cell survival and migration
  2. attachments are integrins
  3. alpha and beta subunits
26
Q

What is Anoikis?

A
  1. ‘state of being without a home’
  2. A type of apoptosis
  3. this is what happens when normal cells lose integrin-mediated adhesion to ECM
27
Q

Metastatic cells and anoikis

A

they usually are resistant to anoikis and this is essential to be able to spread around the body.

28
Q

What percentage of circulating cancer cells survive to form metastatic tumours?

A

<1%

29
Q

What are most metastatic cells killed by?

A
  1. The mechanical forces and pressure in the blood vessels which fragment the cancer cells
  2. Anoikis - loss of attachment
  3. Destructions of circulating natural killer cells
30
Q

What causes the most cancer deaths (90%)?

A

metastases and secondary tumours.

31
Q

Why is early screening and treatment important?

A

to catch tumours before the metastasis

32
Q

What cancers have screening programs?

A
  1. cervical
  2. breast
  3. CRC
33
Q

When can metastasis occur?

A

Can happen when tumours are very small - about 10^9 cells

34
Q

What else can be detected to indicate cancer?

A

circulating cancer cells can be detected in the blood stream

35
Q

What is angiogenesis?

A

The formation of new blood vessels by endothelial cells

36
Q

What is the process of angiogenesis?

A
  1. 1 endothelial cell will receive a signal and will form a capillary branch
  2. A psuedopodial process to probe the surrounding connective tissue and starts the formation of a new blood vessel
  3. other cells follow to form a capillary sprout
  4. Then hollows out and forms a tube
  5. endothelial cells divide as they move to form a new capillary
37
Q

What can trigger angiogenesis?

A
  1. embryonic development
  2. adaptive response to hypoxia in adults
  3. wound healing as lots of oxygen and nutrients are needed for prolieration
38
Q

What blood supply do different tumours need?

A
  1. small tumours survive on pre-existing blood supply
  2. larger tumours become hypoxic which triggers angiogenesis
  3. the onset of angiogenesis = more aggressive tumour = grows faster, invades and metastasises
39
Q

How do tumours induce angiogenesis?

A

they become hypoxic due to the number of cells which triggers the innate signalling mechanism.
It is not due to any mutations.

40
Q

What is hypoxia inducible factor?

A
  1. HIF-1a and HIF-1ß
  2. HIF-1a is always made but is very unstable. This allows for rapid response to hypoxia
  3. HIF-1a is stabilised by hypoxia which allows the HIF-1 complex to form
  4. HIF-1ß is constitutively expressed
  5. The HIF-1 complex enters the nucleus and induces gene expression of many genes including VEGF
41
Q

What is VEGF?

A

Vascular endothelial growth factor

42
Q

What does VEGF do?

A

stimulate the growth and movement of vascular endothelium.
ONLY endothelial cells

43
Q

How does VEGF work?

A
  1. VEGF diffuses away from the tumour towards the blood vessels and binds to the VEGF receptor
  2. VEGFR is a tyrosine kinase receptor. When VEGF binds to VEGFR and triggers a kinase signalling pathway which leads to the formation of new blood vessels
  3. it is directional and grows towards where the VEGF is being secreted.
  4. They grow into the tumour and form a proper blood vessels for circulation
44
Q

What would inhibiting angiogenesis do?

A

inhibit tumour growth and wound healing

45
Q

What else can stimulate angiogenesis?

A
  1. Fibroblast growth factor (FGF1/2) activates FGFR- tyrosine kinase receptor
  2. hepatocyte growth factor (HGF) activates HGFR/Met tyrosine kinase receptor
  3. Angiogenin doesn’t have an obvious receptor and is related to RNase. Has multiple signalling roles and localises to the nucleus to promote transcription
46
Q

What are Anti-angiogenic factors?

A

most are natural to prevent the over formation of new blood vessels.
1. Thrombospondin (TSP-1) is an ECM glycoprotein that binds membrane proteins to induce cell signalling to inhibit angiogenic signals.
2. Angiostatin is a cleavage product of plasminogen that binds to membrane proteins like integrins to induce signalling.

47
Q

Where are anti-angiogenic factors expressed?

A

Expressed in all normal cells and reduce in tumours

48
Q

What are cancer therapies that target VEGF and VEGFR?

A
  1. antibodies that block VEGF binding to VEGFR
  2. Chemicals that inhibit tyrosine kinase function
49
Q

What do VEGF cancer therapies do?

A

they prevent angiogenesis and can starve the tumour of oxygen and nutrients.

Cellular and Molecular pathology (25 decks)

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