Lecture 31: Cellular and environmental basis of malignancy (review)

Question 1

What is cancer?

Answer 1

SEA RAT RIGD

and

Cells doing the wrong job at the wrong time
- De-differentiation (loose and change function)

Cells in the wrong place in the body
- Angiogenesis, invasion, metastasis -> cells in search of nutrients, oxygen and to evade the immune system

Question 2

When it comes to a single gene involved in cancer, does the pathology leading to its cancer contribution share a common pattern of events?

Answer 2

The same gene can be activated/inactivated through different mechanisms in different cancers or even in the same cancer type in different people i.e inactivating mutations in TP53

Question 3

What happens to your chance of having cancer throughout life and why?

Answer 3

Cancer prevalence increases with time

- Cumulative environmental exposures

Question 4

Write some notes on skin cancer and prevalence

Answer 4

Non-melanoma

• Basal cell carcinoma
• Squamous cell carcinoma (2-3% metastasise)

Melanoma
- 20% metastasise

Question 5

Describe how UVB damages DNA?

Answer 5

UVB-> DNA damage

• C to T transitions
• CC to TT tandem repeats
• strong initiator and promoter

Question 6

Describe how UVA damages DNA?

Answer 6

UVA->DNA damage

• Indirect DNA oxidation and damage
• Weak initiator, strong promoter

Question 7

What are environmental factors that contribute to cancer?

Answer 7

UV
Smoking
Viruses

Question 8

How does smoking result in DNA damage and potentially cancer?

Answer 8

Chemicals in the cig cause DNA adducts i.e Nicotine Derivative Nitrosaminoketone (NNK)

• Initiates via G->T and G->A transitions
• Promotes via cell signalling -> Stimulates nAChRs

Question 9

What virus’ can lead to cancer?

Answer 9

HPV
Hep B and C
Epstein barr

Question 10

Describe how hep B can lead to cancer;

Answer 10

Hep B can lead to into cirrhosis and progress to hepatocellular carcinoma

Question 11

What are the effects of cancer mutations?

Answer 11

Cells acquire survival advantages

• ‘Survival of the fittest’ - somatic tumour evolution
• SEA RAT RIGD

Question 12

What are the routes of metastasis?

Answer 12

• Hematogenous
• Lymphatic
• Transcoelomic (plural and peritoneal)

Question 13

What gives a tumour cell an invasion advantage? Part 1

Answer 13

Acquisition of invasive potential

• Modulation/mutations of TSGs/Metastatic suppressor/oncogenes
• Cells undergo epithelial-to-mesenchymal transition (EMT) - a migratory type of cells

Question 14

What gives a tumour cell an invasion advantage? Part 2

Answer 14

Expansive growth and invasion of the basement membrane

• Enhanced protease activity (i.e matrix metalloproteases MMPs)
• Enhanced cell motility and different interactions with ECM/stroma
• Decrease integrity of cell-cell contacts (i.e downregulation of E-cadherin)

Question 15

What gives a tumour cell an invasion advantage? Part 3

Answer 15

Angiogenesis, intravasation and transport in blood

• Migration/interaction through ECM
• Induction of new blood vessels (i.e through secretion of pro-angiogenic factors)
• Interaction with vascular endothelial cells
• Invasion into blood vessel (intravasation)
• Survival in circulation/immune evasion (i.e as cell clusters surrounded by protective platelets-thrombi)

Question 16

What gives a tumour cell an invasion advantage? Part 4

Answer 16

Arrest and extravasation at secondary site

• Interaction with vascular cells (similar interactions as for neutrophils during acute inflammation, like adherins of neutrophils)
• Invasion into secondary tissue (extravasation)

Question 17

What gives a tumour cell an invasion advantage? Part 5

Answer 17

Invasion of secondary tissue and formation of metastasis

• Invasion/migration into secondary tissue
• Interaction and adaption to tissue micro-environment
• Establishment of new blood vessels
• Secondary tumour establishment or dormancy
• Dormant cells can be resistant to chemotherapy and reactivate in response to external factors

Question 18

What is a solid tumour?

Answer 18

Tumour + Stroma

- Can create environment by secreting factors. Also factors can subvert normal function i.e subverting imune cells

Question 19

What cell types are found in the tumour stroma?

Answer 19

Immune
Fibroblasts
Endothelial
Pericytes

Question 20

When UV mutates the DNA in cancer what does it potentially result in?

Answer 20

Wrong/new peptides = Neoantigens

Question 21

Why arent neoantigens detected by the immune system?

Answer 21

The cancer avoids the immune system by;

• No surface antigens
• Stop immune checkpoints
• Stop elimination

Question 22

What does the stroma provide in malignant melanoma?

Answer 22

Vascular blood supply;

• Oxygen
• Nutrients
• pathways to spread and or metastasise