4 The biology of cancer

Question 1

Describe what is meant by ‘what is cancer?’

Answer 1

It is a disease caused by an uncontrolled division of abnormal cells in a part of the body

Cancerous cells are also called malignant cells.

They are able to invade other tissues and can spread to other parts of the body (benign do not spread)

• Tumour may behave in a benign way > but can become malignant (cancerous)
• Only a subset of cells can generally spread

Question 2

What type of disease is Cancer?

[sporadic or familial]

Answer 2

• Sporadic cancer is different from other sporadic ‘genetic’ disease (where mutations are in all cells)
• The only disease of somatic mutation - this is what makes cancer a single group + distinguishes from other genetic disorders
• Familial syndromes; patients inherit a predisposition to developing a cancer

Sporadic is 95%
Familial cancer is 5%

Question 3

What is cancer?

Answer 3

A proliferative growth that will, if left alone, continue to grow and spread to other organs

Question 4

Describe the stages of neoplasms for benign tumors:

Answer 4

• Hyperplasia: overproliferation of cells that appear otherwise normal
• Metaplasia: normal in appearance but in the wrong place (from adjacent tissue layer)
• Dysplasia: cells that appear abnormal; often increased nuclear:cytoplasmic ratio and loss of features of differentiation
• Adenomas/polyps/warts: larger growths of dysplastic cells

Question 5

Describe the stages of neoplasms for malignant tumours:

Answer 5

• Cancer/malignant tumour: invading other tissue, usually by breaking through the basement membrane of the epithelium

Question 6

What is a cancer cell?

Answer 6

A cell that:

• Divides continuously and inappropriately
• No longer maintain its original function
• Some cancer cells must have the ability to spread to other sites

Question 7

Explain why cancer is not a single disease

Answer 7

• Tissue-specific types of cancer

- Individuals with the same type of cancer may carry different sets of mutations

Question 8

List + describe the features of cancer

Answer 8

• Proliferation: grow independently of external signals
• Immortality: avoid senescence (avoid telomere shortening)
• Avoiding cell death: apoptosis is blocked
• Angiogenesis: need nutrients
• Metastasis: many properties required

Question 9

List the ‘hallmarks of cancer’

[6 features:]

Answer 9

• Insensitivity to anti-growth signals
• Self-sufficiency in growth signals
• Evading apoptosis
• Sustained angiogenesis
• Limitless replicative potential
• Tissue invasion and metastasis

Question 10

Describe the model of mutlistage evolution of cancer

Answer 10

Sequential mutations give clones of a cell give a growth advantage

• note; cancer is clonal: all cells share some mutations with common ancestors, but they also develop subclones (subpopulations)

Question 11

Describe how carcinogens result in many mutations

Answer 11

Carcinogens lead to a high rate of mutations

• Most mutations not in genes or doesn’t affect gene function
• Most that affect gene function do not affect features of cell that would lead to cancer
• NEED TO identify those mutations that DO affect function of genes that regulate proliferation, apoptosis, immortality etc > ‘driver’ mutations
• All other mutations that are not relevant to the promotion of cancer are ‘passenger’ mutations

Question 12

What are the 2 classes of genes that are targets for mutations (driver and passenger)

Answer 12

(Proto)-Oncogenes

• Promote cell proliferation (most regulate)
• Gain of function mutations in cancer

Tumour suppressor (TS) genes

• Inhibit events leading to cancer (most regulate proliferation, immortality + apoptosis)
• Loss of function mutations in cancer

Question 13

Describe proliferation in The Cell Cycle

Answer 13

Cell division (proliferation) progression through 2 main stages:

• M phase: mitotic phase
• S phase: DNA synthesises and replicates

They are interspersed by two ‘gap’ phases (G1 and G2)

• Cells can also enter G0 (long term inactivation of cell cycle)
• Mitogens (e.g. ESF) promote the proliferation of cells in G0 and G1

Question 14

Describe the regulation of checkpoints during the progression through the cells cycle (4 checkpoints)

Answer 14

4 checkpoints are well-characterized:

• Restriction (R) point G1 phase (beyond which a cell is committed to cell division without growth factors)
• DNA damage checkpoints in late G1 and G2
• Metaphase checkpoints (spindle attachment checkpoint) in the M phase

NOTE

• Oncogenes promote proliferation (via restriction point)
• Tumour suppressors inhibit proliferation

Question 15

Describe how a cell can become immortal

Answer 15

There is an intrinsic limit to the number of times a cell can divide.
There are two processes important to this:
- Senescence: cell into G0 don’t proliferate
- Apoptosis: programmed cell death; a response to DNA damage, cell stress, etc

Both processes:

• Severely restrict tumour growth
• Both processes must be overcome to develop cancer

Question 16

Descrie senescence

Answer 16

Cells in senescence are metabolically active but have irreversibly lost the ability to re-enter the cell cycle
- Normal cells have a finite proliferative capacity (Hayflick Limit)
> At this point, they stop dividing and go into replicative senescence

• Cancers must avoid senescence if they are to keep growing

Question 17

Describe telomere shortening

Answer 17

Normally, shortening of telomeres results in senescence
- P53 gene involved
- Cell can only bypass senescence and reach ‘crisis’ if key tumour suppressors (such as P53) are inaativated
> (When P53 detects telomere shortening, it’s signals to go into G0

Question 18

Explain how telomere loss leads to chromosomal instability

Answer 18

• Telomere loss leads to incorrect incorrect DNA repair and chromosome fusion
• Especially fusion between ends of sister chromatids which are then torn apart at anaphase
• This results in translocations

Question 19

Describe how excess telomere shortening leads to crisis and apoptosis

Answer 19

Crisis
- Damage to the chromosomes will eventually make the cell unviable
- Cells undergo apoptosis if they can
> ‘genetic catastrophe’ is so severe it triggers apoptosis even in the abscence of p53

Cancer

• In cancer, a rare cell reactivates TERT (telomerase revserse transcrpitase) to become cancerus
• Most cancers exhibit activating mutations in the TERT gene promoter

Question 20

Describe the events in the evasion of senscence and crisis by cancer cells

Answer 20

> 50 cell divisions; telomeres become too short

If p53 fails then telomeres continue to shorten

Chromosomes fuse and rearrange

TERT reactivated

Cells continue to proliferate with severely damaged chromosomes

Question 21

Breifly describe apoptosis

Answer 21

Triggered by damage to cell/DNA, stress, oncogene activation

- Uses energy to kill without releasing contents and so avoid inflammation - uses caspases

Question 22

Name the 2 key genes which control proliferation, senescence, and apoptosis

Answer 22

P53
Rb

(These genes are therefore inactivated in many cancers)

Question 23

Describe sustained angiogenesis

Answer 23

• O2 and other nutrients supplied by vasculature are essential for cell function and survival
• Newly arisen tumours must promote angiogenesis to survive

Hypoxia induced factor 1-alpha

Question 24

Describe the imperfect vasculature that cancers often acquire

Answer 24

Many cancers express VEGF (vascular endothelial growth factor)

• It induced angiogenesis (new vessel growht)
• It also promotes endothelial precursor cell formation in bone marrow (which travel to tumour)

Question 25

Explain why the vasculature to a tumour may be disorganised

Answer 25

Probably due to imbalance of signals for growth vs differentiation
- Leaky because of imperfect cell-cell junction

Question 26

Describe the stages of tissue invasion and metastasis

Answer 26

Cells grow as a benign tumour in the epithelium

Cells become invasive and enter capillary (through the basement membrane, by activating metalloproteinases)

They travel through the bloodstream (fewer than 1/1000 survive immune response, and form metastases, by clotting)

They adhere to the blood vessel wall in liver

They escape from blood vessel to form micrometastasis

They colonise liver, forming full-blown metasasis

Question 27

Describe secondary tumors

Answer 27

2 types of tumors

• Seed and soil theory: cells move to a part of the body where the environment is suitable (e.g. stomach > liver, breasts > lung > anywhere)
• Capillary beds: tumour cells are larger and tend to get stuck in the capillary bed of the next organ in the circulatory system

In reality, it is probably a mix of these two;

• if the environment in the first organ is more favourable then tumour will form
• if not, a small proportion of cancer cells will escape and move on