1.07 - Pathophysiology of Tumour Development

Question 1

What is a neoplasm?

Answer 1

An abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues and persists in the same excessive manner after the cessation of the stimuli which evoked it

Question 2

What are the requirements for Tumour Development?

Answer 2

Self sufficiency in growth signals (oncogenes)
Insensitivity to growth inhibitory signals (tumour suppressor genes)
Evasion of apoptosis
Limitless replicative potential (telomerase)
Sustained angiogenesis
Ability to invade (epithelial to mesenchymal transition)
Ability to metastasise
Defective DNA repair
Some novel requirements:
- Tumour-protmoting stroma and inflammation
- Evasion of the immune system
- Tumour reprogramming of energy metabolism
- Genomic instability

Question 3

What are the two basic components of a neoplasm?

Answer 3

Proliferating neoplastic cells - determines the behaviour and the outcome of the neoplasm
Stromal component - responsible for the growth and evolution of the neoplasm

Question 4

What are the stages in the tumour life cycle?

Answer 4

Malignant transformation in target cells
Proliferation and accumulation of transformed cell
Local invasion
Distant metastasis

Question 5

What are the two Cell Cycle Checkpoints?

Answer 5

G1: Decisions of whether the cell should divide, delay diviiosn or enter a resting stage
G2: The cell has to check a number of factors before the cell is ready for mitosis - e.g. DNA damage

Question 6

What is the doubling time a tumour?

Answer 6

The time taken for a tumour to double in size. May be similar or longer than the length of normal cell cycle

Question 7

What is the growth fraction?

Answer 7

The proportion of cells within the tumour population that are in the proliferative pool. i.e. The proportion of cells that are dividing verse those that are resting.

• By the time a tumour is clinically detectable majority of cell are not in the proliferative pool
• Varies between 5-20%

Question 8

What three factors determine the rate of tumour growth?

Answer 8

Doubling time of tumour cells
The fractions of cells in the replicative pool
The rate of cell loss from the growing tumour

Question 9

What ways can a cell leave the proliferative pool?

Answer 9

Shedding
Lack of nutrients (due to lack of blood supply)
Apoptosis
Differentiation (can become terminally differentiated)
Reversion to G0 (resting phase)

Question 10

Describe the association between chemotherapy and growth fraction

Answer 10

Anticancer agents act on cells that replicating
Good response to treatment is therefore seen in tumours with a high growth fraction (e.g. burkitt’s lymphoma)
Debulking/radiation can push cells from G0 phase to G1 and thus become susceptible to treatment

Question 11

What are some examples of some rapidly growing tumours?

Answer 11

Cell Division&raquo_space;> Cell Loss
Lymphoma
Leukaemia
Small cell carcinoma of the lung

Chemotherapy the treatment of choice

Question 12

List the steps in local invasion of malignant cells

Answer 12

Invasion is a biological hallmark of malignant tumours
Tumour cells loose their adhesion molecules
Detachment of tumour cells
Attachment to basement membrane matrix components
Degradation of ECM by production of proteolytic enzymes
Migration of tumour cells

Question 13

Define: Metastasis

Answer 13

Tumour implants at a site away from the primary tumour

Question 14

What are some common sites of Cancer metastasis and their associated symptoms/problems?

Answer 14

Brain (headaches, vertigo, seizures)
Respiratory (cough, hemoptysis, dyspnea)
Lymph Nodes (lymphadenopathy)
Liver (hepatomegaly, jaundice)
Skeletal (pain, fractures, spinal cord compression)

Question 15

What are the requirements for metastatic invasion?

Answer 15

Invasion of the ECM
Requires active enzymatic degradation of ECM components by proteolytic enzymes such as collagenase
- Invasive carcinoma, melanoma, sarcoma have high levels of collagenase
Matrix destruction leads to creation of a path for invasion of tumour cells

Question 16

What are the three routes of spread for malignant cells?

Answer 16

Lymphatics
Blood Vessels (haematogenous)
Transcoelomic (seeding of body cavities)

Question 17

Describe Lymphatic Spread of Malignant cancers

Answer 17

Will enter the lymphatic system and spread to local lymph nodes. Pattern of lymph node involvement follows route of lymphatic drainage.

Question 18

What is the Sentinel Lymph node?

Answer 18

The lymph node that a metastatic tumour first progressed to.
Is the node from which the tumour in other lymph nodes came from
Can be determined through injection a dye and assessing the intensity of the colour of the nodes
Common in carcinomas

Question 19

Describe Haematogenous spread of metastatic tumours

Answer 19

Enter directly in to the blood system.

Common in sarcomas and carcinomas

Question 20

Describe Transcoelomic spread

Answer 20

Seeding of body cavities

• Pleural
• Pericardial
• Peritoneal
• Subarachnoid

Question 21

Define: Angiogenesis

Answer 21

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels.

Question 22

Describe angiogenesis as it relates to malignancy

Answer 22

Tumours stimulate the growth of host blood vessels
It is essential for supplying nutrients to the grown tumour
- Tumour cannot enlarge beyond 1-2mm unless they are vascularised
- Hypoxia –> apoptosis

Question 23

What is the dual effect of tumour neovascularisation?

Answer 23

1. O2 and nutrients are delivered to the tumour cell

2. The newly formed endothelial cells stimulate the growth of nearby tumour cells (Insulin like growth factor, PDGF)

Question 24

How do Tumours Induce Angiogenesis?

Answer 24

Same as in physiological angiogenesis
Production of VEGF & bFGF
Recruitment of endothelial cell precursors from bone marrow
Existing capillary beds produce new capillary buds

Question 25

Describe the the link between malignant tumours and anti-angiogenic molecules

Answer 25

Tumours also produce anti-angiogenic molecules. The development of new blood vessels is a balance between these pro and anti angiogenic factors.
Inhibitors of angiogenesis are used a adjuncts to cancer therapy
- Bevacizumab (Blocks VEGF receptor 2)
- Sorafenib (Blocks angiogenic signal transduction)

Question 26

List some anti-angiogenic molecules

Answer 26

Thrombospodin-1
Angiostatin
Endostatin
Tumstation

Question 27

What is the Angiogenic Switch?

Answer 27

The point at which pro-angiogenic factors outweigh the anti-angiogenic factors → Rapid growth of tumour now possible by supplying oxygen and nutrients and removing waste. This also facilitates metastasis.

Question 28

Q. Which of the following factors is most influential in determining the doubling time of a tumour :

1. Angiogenesis
2. Apoptosis
3. Differentiation
4. Growth Fraction
5. Metastasis

Answer 28

Growth Fraction