Cancer

Question 1

what is cancer?

Answer 1

- group of diseases characterised by unregulated growth of malignant tumours

- around 200 different types

- normally need a number of mutations to occur for cancer to occur (multi hit)

- can be solid or haemotological

Question 2

how are cancers different to normal cells regarding cell signals?

Answer 2

cancer cells can survive without cell signals - autonomous. (unlike normal cells)

Question 3

name different cells found in cancer tissues

Answer 3

complex tissue:

• functional tissue (perenchyma)
• stroma (support tissue)
• cancer cells
• stem cells
• inflammatory cells
• endothelial cells
• parasite cells
• fibroblasts

Question 4

describe the overview of carniogenesis

Answer 4

Question 5

what are the 8 hallmarks of cancer?

Answer 5

all contribute to sustaining proliferative signalling -> then to tumour developement and malignant progression

1. self sufficiency in growth signals
2. insensitivity to anti-growth signals
3. evading apoptosis
4. limitless reproductive potential
5. sustained angiogenesis
6. tissue invasion and metastasis
7. deregulating cellular energetics
8. avoiding immune detection

Question 6

explain self-suffienciency in growth signals

(what is it like in normal cells - how different in oncogenes?)

Answer 6

• normal cells need mitogenic growth signals before they can move into proliferative state
• many oncogenes can mimick normal growth signals and generate own growth signals (autocrine signalling)

Question 7

explain how cancer cells are insensitive to anti-growth signals

Answer 7

• normal cells have multiple anti-proliferative signals

- anti-growth singals block proliferation by:

a) force cells out of G0
b) cells may be induced to relinquish their proliferative potential by being induced to enter into post mitotic state associated with differentation

Question 8

1. are tumour cell populations determined just by rate of cell proliferation?
2. how is limitless replicative potential achieved by cancer cells?

Answer 8

1. NO - also by rate of apoptosis
2. maintain telomeres - so prevent apoptosis

Question 9

what are three main groups of genes that implicate cancer?

Answer 9

1. oncogenes

2. tumour supressor genes:

a) gatekeepers (regulate cell cycle)
b) care takers (DNA repair)

Question 10

what are oncogenes?

what are proto-oncogenes?

Answer 10

oncogene: gene that encodes protein capable of inducing cancer

proto-oncogene: normal gene from which oncogene derives from. many encode growth factors, growth factor receptors or signalling molecules. activated by mutations. enhanced cell signalling in uncontrolled way

Question 11

why do cancer cells want to not be differentiated?

Answer 11

once differentiated, no longer divide.

onco-genes reduce differentation

Question 12

what are the five categories of proto-oncogenes?

Answer 12

1. growth factors

2. growth factor receptors

3. signal-transduction proteins

4. transcription factors

5. anti-apoptotic proteins

mutations change structure in these proto-oncogenes -> oncogenes

Question 13

give over view of cell signalling in normal cell

Answer 13

• growth factor binds to receptor. two receptors interact (dimerization)
• intracelllar side: phosphorylation of tyrosine
• siganlling proteins bind to P-tyrosine
• causes cascade of phosphorylation events
• activates two pathways: MAPK pathway and PI3 Kinase Pathway

- once pathways are activated, activate gene expression and transcription factors occur.

Question 14

what happens if overexpress growth factors?

Answer 14

get hyperplasia (Hyperplasia, or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation)

• can be precancerious or not lead to cancer
• genes are often amplified
• autocrine loops and unregulated growth

Question 15

what are examples of hyperplasia and cancer?

Answer 15

hyperplasia leads to increased growth: can be:

benign - VEGF (vascular endothelial growth factor) - (up regulate the synthesis of blood vessels.): leads t benign prostatic hyperplasia (enlarged prostate). benign growth

malignant - platelet derived growth factor (PGDR) - leads to glioblastoma

Question 16

whats an example of overpression of growth factors?

Answer 16

HER2 or ErbB2

• tyrosine kinase receptor known as HER2 or ErbB2
• overexpression leads to: uncontrolled growth, survival of cells containing mutations, invasion of tumour cells, migration tumour cells

Question 17

explain the ras pathway and how mutation leads to kras cancer

Answer 17

• when ras switched on: (normally ras is switched on by binding to GTP) can switch on ERK and AKT pathways. (ras regulates the pathways by turning on / off the ERK and AKT pathways)
• mutated ras (kras): hydrolysis of bound GTP (first stage in pathway) occurs v slowly. GTP is bound to ras in unhydroloysed form - ras is permenantly switched on. continois proliferation and growth.

Question 18

ras oncogene - is it rare / common?

Answer 18

• one of the most frequent mutations in human tumours

- need to know stats?? see slides

Question 19

explain c-MYC proto-oncogene

Answer 19

• proto-oncogene: c-MYK (~50% of cancers)
• promotion of transcription of cyclin genes (promotes cell cycle progression)
• c-MYK is correlated with agressive tumour pattern and poor clinical outcome

( - causes increased growth, metabolism, cell adhesion, differentiation and metastasis)

• seen in: Burkitt lymphoma, breast cancer

Question 20

can c-MYC induce cancer on its own?

Answer 20

NO

need secondary mutations to occur in:

• proliferative arrest
• apoptosis
• sencescence

MYC OVEREXPRESSION ALONE DOES NOT INDUCE TUMOURIGENESIS

Question 21

how can cancer cells avoid apoptosis? (general)

Answer 21

- mutations in anti-apoptotic proteins - e.g. BCL-2

• if not directed to apoptosis -> survive with mutation, up regulation of anti-apoptotic genes

Question 22

which genes normally regulate apoptosis?

Answer 22

Bax: pro-apoptotic protein

Bcl2: anti-apopotic protein

a balance is required for normal apoptosis

(overpression of bcl-2 -> cancer)

Question 23

what are the two types of tumour suppressor genes?

Answer 23

1. gate keeepers

• directly suppress growth / restrict proliferation (e.g. check point control genes)

2. care takes

• maintains genetic stability (like DNA repair)

Question 24

what do mutations in tumour supressor genes cause?

Answer 24

- act recessively ot release cells from growth control

• increase probability of other mutations in other classes ( if DNA repair / apoptosis is not occuring - mutations)
• may prevent apoptosis

Question 25

explain three gate keeper genes

Answer 25

**_Bax (pro-apoptotic protein)_** **-** allows cancer cells to survive even when challenged with chemotheropeautic or DNA damaging compounts that normally triger cytotoxic response **_p53_** _normal function_ - transcription factor (activates transcription) - **causes cells with mutations to undergo cycle arrest, allows DNA repair or entry to apopotic pathway** - p53 activated by DNA damage, hypoxia or cell injury - p53 activation activates p21 -\> inhibits cyclin complexes (prevents cell leaving G1 / entering S-phase _mutated function_ - cell progresses with cell cycle with cell damage -\> cells accumulate mutations -\> cancer **mutated pRB (**retinoblastoma): - pRb prevents cell cycle progression past G1 phase by inhibiting expression of S-phase genes - mutation in Rb gene = retinoblastoma

Question 26

what do cartaker genes do? give e.gs and how often they occur?

Answer 26

**_DNA repair proteins_** - repair DNA damage during cell cycle arrest - maintain genomic stability _Examples:_ - BRAC1 and BRAC2 are most commonly mutated genes in familial breast (50%) and ovarian cancer (70-80%) - carriers mutant BRAC1 and BRAC2 - have a 50-70% risk of developing breast cancer before aged 70 - BRAC2 leads to more aggressive prostate cancer

Question 27

what are BRAC1 and BRAC2 directly involved in during normal function?

Answer 27

**- BRAC1 and BRAC2 repair damaged dsDNA crosslinks at the G2 / M checkpoint** - loss of BRAC1 / 2 results in **strand breaks and aneuploidy** after cell division

Question 28

describe what happens in normal / mutatted BRAC1?

Answer 28

**_BRAC1:_** - normally: triggers the activation of the CDK inhibitor: **p21WAF-1** and **p53**, so _can control cell cycle_ - also involved in DNA repair - mutations lead to **genomic instability**

Question 29

describe what BRCA2 normally does / what a mutation does

Answer 29

**_BRAC2_**: - normally facilitates HR - BRAC2 deficient cells: cant recruit **RAD51** (protein that binds to ssDNA and needed in dsDNA repair) - mutations: cant repair ss and dsb DNA breaks

Question 30

what are neoplastic cells?

Answer 30

- cells that have lost control of normal processes such as growth. once neoplasm has started, not reversible