Lecture 1 - What is Cancer?

Question 1

What is cancer?

Answer 1

uncontrolled growth of abnormal cells in a tissue, invasive and spreading

Question 2

Is cancer contagious?

Answer 2

No but some viruses are carcinogenic

e.g. HPV and cervical cancer

Question 3

Where does cancer originate from?

Answer 3

majority of tumours originate from epithelial tissues but also from other tissue types
the morphology of epithelial cells changes

Question 4

What is the origin of sarcomas?
What is the origin of carcinomas?
What is the origin of leukaemia and lymphomas?
What is the origin of neuroectodermal tumours?
What is the origin of brain tumours?

Answer 4

sarcomas = mesenchymal cels
carcinomas = epithelial cells
leukaemia/lymphoma = haematopoetic tissue and cells of the immune system
neuroectodermal tumours = cells from the CNS and ONS
brain tumours = neuroblastoma, glioma

Question 5

In what four ways can cancer be studied?

Answer 5

cell cultures
animal models
computer models
human

Question 6

Mutations causing cancer occur in what two places?

Answer 6

germline and somatic cells
Germline = predisposes someone to cancer
somatic = the actual cause of cancer

Question 7

What is microevolution?

Answer 7

The process leading to the accumulation of 5-10 critical mutations and lead to cancer.
Each mutation provides that cell line with a survival advantage over normal cells

Question 8

What kinds of genes may initiate cancer?

Answer 8

Genes that normally control:

• growth
• passing on of signals from outside the cell (receptors) across the cytoplasm to the nucleus
• programmed cell death
• the cell cycle
• stemness
• the integrity of the genome - repair

Question 9

In what three ways can mutations arise?

Answer 9

Copying errors during DNA replication
Spontaneous deprivation
Exposure to different agents e.g. radiation, UV light, tobacco products

Question 10

Describe an experiment that helped to prove that cancers were monoclonal growths

Answer 10

Certain enzymes e.g G6PD are only carried on the X chromosome
So heterogenous females carry two different alleles of the gene for G6PD.
Tumours from heterozygous patients were found to only carry one on the alleles, so therefore could only have originated from one original cell

Question 11

What is tumour progression?

Answer 11

the progressive development of cancer from premalignant to malignant stages
- multistep in terms of genetic changes

Question 12

Cancer can be described as a disorder resulting from multiple genetic steps.
What is the first genetic step called?
What are the subsequent steps called?

Answer 12

1st = gate keeper mutation

2nd end onwards = driver mutations

Question 13

What are oncogenes?
What are tumour suppressor genes?
How many alleles need to be mutated to cause cancer?

Answer 13

oncogene = postive regulator of cell growth - makes cells grow, even when only one allele mutated
tumour suppressor genes = normally a negative regulator of cell growth, need to lose both alleles to lose suppressor effect

Question 14

Define a hallmark of cancer

What are the 6 original hallmarks of cancer?

Answer 14

A characteristic the tumour cell should acquire to become malignant

1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis

Question 15

Describe hallmark 1 - self sufficiency in growth signals

Answer 15

1st = extracellular growth signals --> mutations in receptors mean that they can fire in the absence of GF 
2nd = transmembrane transducers of growth signals, some tumour cells produce growth factors that are ligands to their own receptors (autocrine signalling) 
3rd = intracellular circuits that translate these signals, Ras protein initiates three major downstream signalling cascades, mutations in Ras can cause many changes in cell behaviour

Question 16

What is Ras?

Answer 16

A GTPase - molecular switch found on majority of tumours
If mutated it can be constitutively active
Ras initiates three major downstream signalling cascades, mutations cause many changes in cell behaviour

Question 17

Describe hallmark 2 - insensitivity to anti-growth signals

Answer 17

• disruption of pRB (TSG) pathway - loss of control over progression from G1 into S phase

Question 18

What is the cell cycle clock? (hallmark 2)

Answer 18

the central governor of growth and proliferation
in response to signals accumulating (e.g. tyrosine kinase receptors, GPCRs, integrins, nutrients) makes a decision about response
–> entre in G0 or active cell cycle

Question 19

What does pRB do?

Answer 19

pRB serves as a guardian of the restriction point gate

It normally stops cells entering the cell cycle at the restriction point (between G1 and S)

Question 20

Describe hallmark 3 - evasion of apoptosis

Answer 20

loss or mutation of p53 (TSG) - proapoptotic regulator

disruptions in DNA repair

Question 21

What activates p53?

What can p53 do? x4

Answer 21

p53 activated by physiological stresses e.g.
- lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription
p53 can cause:
- cell cycle arrest, DNA repair, block of angiogenesis, apoptosis

Question 22

What are 2 of the anti-apoptotic mechanisms used by cancer cells?

Answer 22

increase in activity of anti-apoptotic proteins

decrease in activity of pro-apoptotic proteins

Question 23

Describe hallmark 4 - limitless replicative potential

Answer 23

• circumvention of senescence and crisis. Increased expression and activity of telomerase
• normally proliferation of cultured cells is limited by the telomeres of their chromosomes, cancer cells can escape this criss by expressing telomeres

Question 24

Describe hallmark 5 - sustained angiogenesis

Answer 24

angiogenic switch
control of transcription of pro-angiogenic inducers
Downregulation of angiogenic inhibitors

Question 25

Vasculature is important for growth and survival of normal and neoplastic cells. Name some inhibitors and activators of angiogenesis

Answer 25

activators = VEGF and FGF
inhibitors = thromobospondin. interferon angio/endostatin

Question 26

What is angiogenesis normally initiated by?

Answer 26

hypoxia

Question 27

Describe hallmark 6 - tissue invasion and metastasis

Answer 27

changes in expression of adhesion receptors e.g. cadherins, integrins, activation of extracellular proteases, epithelial mesangial transition

Question 28

Describe the role of the pre-metastatic niche in the promotion of tumour metastasis

Answer 28

tumours release factors into the bloodstream that travel to prepare the secondary site. This ensures the microenbironment is ready

Question 29

Where do the following cancers usually metastasise to?

1. prostate
2. breast
3. colon
4. pancreas

Answer 29

1. prostate –> bone marrow, liver, brain, lungs
2. breast –> bone marrow, lungs, liver, brain
3. colon –> liver, bone marrow, lungs
4. pancreas –> liver, lungs

Question 30

What are the 2 new hallmarks of cancer?

Answer 30

deregulating cellular energetics - alter metabolism

avoiding immune destruction - cancer cells require immune cells to survive/proliferate but also tries to suppress them

Question 31

What are the 2 new enabling characteristics of cancer?

Answer 31

genome instability and mutation

tumour-promoting inflammation - immune system beneficial to tumour