CAN Overview

Question 1

What is cancer?

Answer 1

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

Question 2

Global nature of cancer

Answer 2

Different cancers are more prevalent in different countries.
Due to different life styles factors of each country and the environment they are exposed to.
High processed food diets in western countries U.K. - higher colorectal cancers
Areas higher sunlight per day - Australia higher incidences of melanomas

Question 3

Is cancer contagious?

Answer 3

No, aberrations in cells cannot be passed from person to person.
Some viruses can be carcinogenic and act to cause cancer was a result of the virus it is not the cancer that is contagious it is the virus which can cause cancer.

Question 4

Origins of cancer - common origins

Answer 4

Most common origin of cancer is in epithelial tissue more than mesenchymal tissue.
Epithelial tissues cancer - adenocarcinomas or small cell carcinomas
Mesenchymal tissues - sarcomas, bone - osteosarcoma
Haematopoietic cells and immune system cells - named differently depending on their origin.
Leukaemia, lymphoma, myeloid tumours
Neuroectodermal cells - central and peripheral NS - glioma in glial cells, end in -Oma and have different recipes dependent on where originated from

Benign and malignant tumours
Benign tumours are benign from the onset cannot become malignant.

Question 5

How is cancer studied?

Answer 5

Cell cultures
Animal models
Computer models
Human -clinical trials

Question 6

Cancer is a genetic disease, types of cells can occur in and the difference

Answer 6

Dependent on mutations
Germline cells 
Somatic cells 
Process of micro evolution
Leads to the accumulation of 5-10 critical mutations and requires many years

Question 7

Different types of gene that may initiate cancer

Answer 7

Genes that normally control:

• growth
• passing on if 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 and maintenance

Question 8

How do mutations arise?

Answer 8

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

Question 9

Cancer growth is it monoclonal or polyclonal?

Answer 9

Monoclonal - the cells all originate from one cells that has a mutation. Even if other surrounding cells had a different mutation one of the mutations would still outcompete the other leading to the formation of a tumour that in monoclonal
X inactivation occurs which causes mosaicism - a pattern of different expression. Migration of G6PD tumour from heterozygous patients even though they express both forms of the enzyme the tumour patients only ever show one form of enzyme in their tumour.

Question 10

Tumour progression

Answer 10

Progressive development of cancer -

Premalignant to malignant

Question 11

Genetics single or multiple

Answer 11

For a cancer to become invasive more than one gene needs to be affected. There are multiple genetic steps to malignancy many things need to be deregulated before it can invade and spread.
Driver mutation has conferred growth advantage has been positively selected in the microenvironment

Question 12

Cancer development requires multiple genetic steps - what are they?

Answer 12

Going to need multiple genes to become mutated for each step to occur. Different genes control different aspects of the cell function that has become aberrant.
Tumour cell growth - growth factors
Adhesion - between cells become weaker
Signalling - growth and survival so tumour cells are not killed
More growth - GF
Apoptosis - other cells that are normal as they become starved of nutrients, and tumour cells that aren’t contributing to survival
Angiogenesis - acquisition of nutrients and leaky vessels to allow for invasion and spread

Question 13

Main genes involved in cancer development and what goes wrong with them?

Answer 13

Oncogenes - activated

Tumour suppressor genes - deactivated

Question 14

Tumour suppressor gene (protein)

Answer 14

Normal function: negative regulator of cell growth (prevent cell growth)
Protein from one allele is enough for it to continue functioning
Need to lose both alleles to lose its suppressor effect
Inc chance if one allele is already lost at birth due to inheritable genetic factor.
Examples are APC, PTEN, p53, pRB

Question 15

Oncogenes

Answer 15

Positive regulator of cell growth - makes cells grow
Only one allele mutation is necessary
These genes are important in normal cells esp. during development. And their control is strict usually. However, in cancer there are mutations which prevent this control and become constitutively active (all the time)
Examples c-myc, Raf kinase and and Ras

Question 16

Name the hallmarks of cancer

Answer 16

1) self sufficiency in growth signals - sustaining proliferative signalling
2) insensitivity to anti-growth signals - evade growth suppressors
3) evasion of apoptosis- resisting cell death
4) limitless replicative potential - enabling replicative immortality
5) sustained angiogenesis - inducing angiogenesis
6) tissue invasion and metastasis

Question 17

Hallmark 1: self sufficiency in growth signals

Answer 17

Alterations of:
Extracellular growth
Transmembrane inducers
Intracellular circuits that translate those signals
1) normally cells receive growth signals extracellularly to activate RTK. In cancer the cells can be activated with no ligand binding constitutively activated receptor.
2)they can produce their own growth signals which activated the RTK.
3) there can be mutations down stream in the signalling pathway sustaining the signal even in the absence of extracellular signals.
Example, Ras protein mutations which are found in the majority of tumours. It is an ATPase protein. Enable the cell to become self sufficiency in cell signalling can fire without extracellular input.

Question 18

Hallmark 2: insensitivity to anti-growth signals

Answer 18

Loss of TSG function means loss of growth suppressive functions and/or cell cycle checkpoint control, resulting in enhanced proliferative potential.
Disruptions of pRB (TSG) pathway - loss of control over progression from G1 into S phase.
After mitosis cells enter G1 phase (where the cells is responsive to mitogenic GFs and TGF-beta) Before S phase DNA damage checkpoint: blocked continuation if genome is damaged. pRB is the guardian of the restriction-point, this is then lost so there can be proliferation when the genome is damaged and uncontrolled so can increase in proliferative number.

Question 19

Hallmark 3: evasion of apoptosis

Answer 19

Loss or mutation of p53 (TSG) - proapoptotic regulator
Disruptions in DNA repair, when damage is non-repairable apoptosis is induced by p53
P53 is usually activated by: lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription. Mutations in or loss of p53 mean these stimulants don’t cause a reaction to induce cell death so the damage persists.

Question 20

Hallmark 4: limitless replicative potential

Answer 20

Circumvention of senescence
Increased expression and activity of telomerase
Telomeres protect from chromosomal damage, each division some telomere is lost, and proliferation is limited by the amount of telomere left. In cancer cells they express telomerase which act to extend the telomeres of the chromosomes extending the proliferative potential.

Question 21

Hallmark 5: sustained angiogenesis

Answer 21

Angiogenic switch
Control of transcription of pro-angiogenic inducers
Downregulation of angiogenic inhibitors
Crucial for tumour metastasis
Vasculature important for growth and survival of normal and neoplastic cells
Inhibitors are downregulated leading to a counterbalance of increased activators in proportion so leading to increased activation.

Question 22

Hallmark 6: tissue invasion and metastasis

Answer 22

Changes in expression of adhesion receptors:
Cadherins Integrins: down regulated to allow cells to become less structured and mobile. Allow the movement needed for invasion and metastasis
Activation of extracellular proteases - matrix metalloproteases MMPs breakdown the ECM.
EMT - endothelial mesenchymal transition, morphological changes to the epithelial like cancer cells to fibroblast like which allows the invasion a and metastasis of the cells
Role of the premetastatic niche tumour metastasis. Seed and soil hypothesis and by anatomical location.

Question 23

What are the additional hallmarks ?

Answer 23

1) reprogramming the energy metabolism of cells in cancer

2) evading immune detection