Lecture 1: What is cancer and how does it develop?

Question 1

What is the main characteristic of cancer?

Answer 1

abnormally proliferating cells capable of spreading surrounding tissue an other part s of the body

Question 2

80% of all cancers are what type?

Answer 2

Carcinomas (derived from epithelial tissue)

Question 3

How are cancers named?

Answer 3

After their cells of origin

Question 4

What type of cancer is derived from epithelial cells?

Answer 4

Carcinoma

Question 5

What type of cancer is derived from mesenchymal cells?

Answer 5

sarcoma

Question 6

What type of cancer is derived from haematopoietic cells?

Answer 6

Leukaemia

Question 7

What type of cancer is derived from melanocytes?

Answer 7

melanoma

Question 8

What is the biggest risk factor for the majority of cancers?

Answer 8

Age (more likely to acquire mutations that lead to cancer - mutations in proto-oncogenes and tumour suppressor genes)

Question 9

Which type of cancer peaks in early age, drops, and then increases with age again?

Answer 9

Leukaemia (peaks at early age due to inherited mutations)

Question 10

True or false: cancers are genetically stable?

Answer 10

False - cancers are genetically unstable with some tumour karyotypes consisting of severe aneuploidy and chromosomal rearrangements

Question 11

What is the model that describes the progression of colorectal cancer?

Answer 11

The Vogelstein model (integrates molecular changes with phenotypic changes)

Question 12

Describe the progression of colorectal cancer with reference to the associated genetic changes

Answer 12

• normal epithelium
  (genetic change: loss of APC)
• hyperplastic epithelium that forms early adenomatous crypts
  (genetic change: DNA hypermethylation)
• formation of adenomas (early stages associated with activation of K-Ras and late stages associated with loss of 18q TSG
  (genetic change: loss of p53)
• formation of carcinoma
• other genetic changes result in metastatic and invasive phenotype

Question 13

What is a major factor that influences continued tumour growth?

Answer 13

access to vascularisation

Question 14

Without growth of new blood vessels, what is the maximum size a tumour will grow? why is this?

Answer 14

1 mm

This is because the growth is limited by how far oxygen can diffuse

Question 15

Describe the angiogenic switch

Answer 15

• pericytes loosen to allow for blood vessel dilation near proliferating cells
• if this process goes unchecked then can result in angiogenic sprouting in which new blood vessels form and mature in areas of low oxygen so proliferating cells can take up oxygen, recruiting pericytes.

Question 16

What are the mediators of angiogenesis (give 3 activators and 3 inhibitors)?

Answer 16

Activators:
- VEGF-A, -B, -C
- FGF1
- FGF2

Inhibitors:
- Thrombospondin-1, -2
- Interferon α/β
- Angiostatin
- Collagen IV fragments

Question 17

Describe the major differences in organisation of tumour vasculature

Answer 17

• vessels more dilated and disorganised
• fewer tight junctions leads to holes in tumour vasculature that may aid invasion and metastasis

Question 18

What is metastasis?

Answer 18

The escape of cancer cells from the primary site and establishment at distant secondary sites.

Question 19

What percentage of cancer mortality is metastasis responsible for?

Answer 19

90%

Question 20

What structure normally separates epithelial cells from the stroma (underlying cells)?

Answer 20

The basement membrane

Question 21

What proteins are involved in formation of tight junctions between adjacent epithelial cells?

Answer 21

E-cadherins

Question 22

Describe the steps involved in metastasis of tumour cells

Answer 22

1. local invasion:
   - secretion of proteases (such as matrix metalloproteases MMPs) by tumour cells or adjacent stroma to breach the basement membrane - no longer a benign tumour as invading
   - EMT - expression of transcription factors (Twist, Snail, Slug) so cells adopt a motile fibroblastic phenotype and become more resistant to apoptosis - cells repress expression of E-cadherin and upregulate N-cadherin which forms weaker links
2. Intravasation and transport through circulation
   - intravasation not completely understood
   - many cancer cells die through transport by anoikis or hydfrodynamic stress
3. Arrest and extravasation
   - cells become lodged in microvessel and can extravasate
   - cancer cells begin proliferating at new site, typically involving mesenchymal to epithelial transition (MET)
4. Colonisation - cells must adapt to environment of new site. Some tissues offer a more ‘friendly’ environment.

Question 23

Which step of metastasis is the least efficient and why?

Answer 23

Colonisation
- the new site likely has different growth and survival factors impeding the ability of cancer cells to form a new tumour

Question 24

What is Paget’s seed and soil hypothesis?

Answer 24

The seed and soil hypothesis states that metastatic tumor cells will metastasize to a site where the local microenvironment is favorable, just like a seed will only grow if it lands on fertile soil

Question 25

What are four common sites of metastases?

Answer 25

1. brain
2. lungs
3. liver
4. bone marrow

Question 26

Describe how cancers are stages using the TNM system

Answer 26

T refers to tumour size:
T1 (small) - T4 (large)

N refers to local spread to lymph nodes:
N0 (no lymph nodes containing cancer cells) - N3 (many lymph nodes contain cancer cells)

M refers to metastasis:
M0 (no metastasis) - M1 (cancer has spread to other parts of the body)

Question 27

True or false: the presence of any metastasis regardless of the T or N characterisation makes little difference to a patient’s survival?

Answer 27

False: the presence of any metastasis significantly reduces survival rate

Question 28

What are the 6 hallmarks of cancer?

Answer 28

1. Sustaining proliferative signalling
2. evading growth suppressors
3. activating invasion and metastasis
4. enabling replicative machinery
5. Inducing angiogenesis
6. resisting cell death

Question 29

Give an example of a method that can be used to detect metastases?

Answer 29

CT-PET imaging of radiolabelled glucose to show regions of high glucose uptake in yellow

Question 30

Why do tumour cells show up as bright white/yellow on combined CT-PET imaging of radiolabelled glucose?

Answer 30

High glucose consumption/uptake of cancer cells is due to a phenomenon known as the Warburg effect and increased metabolic activity which indicates metastasis

Question 31

How can lymph nodes be examined to observe for cancer spread?

Answer 31

Lymph node biopsy = Injection of dye into a tumour can show whether fluid (and potentially cancer cells) is draining from the tumour into a particular node (i.e. the sentinel node)

Immunohistochemical staining of lymph nodes