Outline of Disease Processes

Question 1

What is cancer

Answer 1

A carcinoma or disorderly growth of cells (80% originate from epithelial cells and 20% in connective, musculoskeletal or nervous tissue) which invade adjacent tissue and spread by the lymphatics and blood vessels to other parts of the body

Question 2

Most cancers are…

Answer 2

Monoclonal

Question 3

How do cancer cells divide

Answer 3

Mitosis

Question 4

State the features of cancer cell growth

Answer 4

Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumour suppressor genes
Frequent mitoses

Question 5

State the features of normal cell growth

Answer 5

Few mitoses
Oncogene expression is rare
Intermittent or coordinated growth factor secretion
Presence of tumour suppressor genes

Question 6

Why is cancer sometimes diagnosed late

Answer 6

It cannot be detected until there is 10^9 cancer cells present

Question 7

What are the causes that initiate cancer cell growth

Answer 7

Chemical
Physical
Viral

Question 8

What are the causes that promote cancer cell growth

Answer 8

Growth factors

Oncogenes

Question 9

What are the causes of cancer cell progression

Answer 9

Metastasis

Question 10

Give examples of chemical carcinogens

Answer 10

Aniline dyes in bladder cancer
Aflatoxin in liver
Nitrogen mustard in leukaemia
Alcohol and smoking in lung, head, neck and gastrointestinal cancers

Question 11

Give examples of physical carcinogens

Answer 11

Ionising radiation

Mecanisms (e.g. chromosome translocation, gene amplification and oncogene activation)

Question 12

give examples of viral carcinogens

Answer 12

Herpes virus - Burkitt’s lymphoma
Papillomavirus - Cervical cancer
Retroviruses - Adult T-cell leukaemia/lymphoma (HTLV1), Hairy cell leukaemia (HTLV2)
Hep B - Liver cancer

Question 13

What are oncogenes

Answer 13

Transforming genes
Positive regulators of growth
Represent a gain in function to transformed cells (e.g. in follicular lymphoma, BCL2 activation prevents apoptosis and p53 a tumour suppressor gene).

Question 14

What are growth factors

Answer 14

Polypeptide molecules which regulate cell growth and function by binding to cell membrane receptors to stimulate the activation of intracellular signal transduction pathways.

Question 15

How do growth factors and oncogenes work together

Answer 15

Growth factor attaches to the growth factor receptor
Triggers a post receptor signal transduction pathway
Activates oncogenes which promote growth factor and receptor synthesis.
Receptors produced will move to the cell membrane and the receptors can either cause autocrine stimulation (self-stimulating) or paracrine stimulation (adjacent cells)

Question 16

What is autocrine stimulation

Answer 16

When the cell carries the receptor and secretes the growth factor to escape the normal control mechanism

Question 17

What is paracrine stimulation

Answer 17

When the growth factors acting on a cell are produced locally by the cell or its immediate neighbours

Question 18

What is p53

Answer 18

The most commonly altered tumour suppressor gene in human tumours (37% but higher in lung and colon cancers)

Question 19

What is p53’s normal function

Answer 19

Act as a transcriptional regulator
Promote DNA repair
Apoptosis
Differentiation

Question 20

How is p53 induced

Answer 20

By DNA damage

Hypoxia

Question 21

What checkpoint does p53 control

Answer 21

G1/S checkpoint

Question 22

State 4 details of metastasis

Answer 22

Its not random
Has a cascade of limited sequential steps
Involves tumour-host interactions
‘Survival of the fittest’ pertains

Question 23

How does a tumour metastasise

Answer 23

Tumour invades through basement membrane
Moves into the extracellular matrix/connective tissue/surrounding cells
Invades blood vessels allowing tumour cells to be ‘arrested’ in distant organs

Question 24

Which enzymes in the process are present in the ECM

Answer 24

Matrix metalloproteinases (MMPs) which has several subclasses e.g. gelatinases
Plasmin
Cathepsin

Question 25

Which enzymes in the process are present in cell adhesion

Answer 25

Cahedrins (loss correlates with tumour invasion and metastasis)
Integrins
CD44

Question 26

What is angiogenesis

Answer 26

Formation of new blood vessels

Question 27

Why is angiogenesis important for tumour growth

Answer 27

It’s a key factor in the maintenance and progression of malignant tumours
New blood vessels must form in order for a tumour mass to exceed 2 mm in diameter

Clinical correlations can be seen between vessel density, tumour malignancy and metastasis

Question 28

What is necessary for angeogenesis

Answer 28

Degradation of the extracellular matrix is necessary for new blood vessel formation to occur

Question 29

How can VEGF releated cancers be treated

Answer 29

Using an anti-VEGF antibody avastin, which binds VEGF
It prevents VEGF interacting with receptors and the activation of downstream signalling pathways Therefore it results in vascular regression and the tumour remaining dormant

Question 30

What does VEGF stand for

Answer 30

Vascular endothelial growth factor

Question 31

What does the activation of the downstream signalling pathways normally lead to

Answer 31

Endothelial cell:
Growth
Proliferation
Migration
Survival

Question 32

How does the anti-VEGF antibody cause vascular regression and the tumour remaining dormant

Answer 32

It reduces microvascular growth
inhibits the progression of metastatic disease
Reduces intratumoral pressure which may improve the delivery of cytotoxic agents

Question 33

Why does the immune system not recognise cancer cells as foreign

Answer 33

They are able to ‘hide’ from T cells
PD1, a programmed death receptor, presents on T lymphocytes
The ligand, PDL-1, on tumour cells
The interaction between these two suppresses the action of T cells

Question 34

How can the action of PD1 and PDL-1 be used to treat cancer

Answer 34

Drugs could be developed to block PD1 or PDL-1
This stops them from inhibiting the immune response and allow immune damage to occur to the cell

Nivolumab was developed to have this action and studies have shown that the overall survival of patients increased