Edmead - L1 - molecular basis for cancer

Question 1

Cancer = a group of diseases characterised by ______ cell growth & ______ & spread of cells from ______/_____ to other sites in the body (_______)

Answer 1

Unregulated
Invasion
Site of origin/1ry site
Metastasis

Question 2

Name 4 broad classes of cancer…

Answer 2

1) Epithelial cells = carcinomas
2) Mesoderm cells (bone, muscle) = sarcomas
3) Glandular tissue (breast) = adenocarcomas
4) Blood cell derived sarcomas = leukaemia

Question 3

Hallmarks of cancer: 10 of them!

List them.

Answer 3

1) Growth signal autonomy (sustain proliferative signalling)
2) Evasion of growth inhibitory signals
3) Avoiding immune destruction
4) Unlimited proliferative potential
5) Tumor promoting inflammation
6) Invasion and metastasis
7) Angiogenesis
8) Genome instability and mutation
9) Evasion of cell death
10) Reprogramming energy metabolism

Question 4

One of the hallmarks of cancer = Growth signal autonomy (sustains proliferative signalling) - explain

Give an example of a treatment that targets this hallmark.

Answer 4

1) Normal cells require signals from growth factors to stimulate proliferation and growth
2) Cancer cells are not depended on growth factor signalling
3) Mutations alter growth factor pathways causing unregulated growth

Treat: EGFR inhibitor e.g Gefitinib (IRESSA) small molecule inhibitor

Question 5

Another hallmark is evasion of growth inhibitory signals - explain this
Treatment?

Answer 5

1) Normal cells respond to inhibitory signals to maintain homeostasis (most cells not actively dividing)
2) Cancer cells x respond to growth inhibitory signals
3) Acquired mutations or gene silencing interfere with inhibitory pathways

Treat: cyclin dependent kinase inhibitors

Question 6

Another hallmark is avoiding immune destruction - explain this
Treatment?

Answer 6

1) ‘Immune surveillance’ theory is that immune cells can recognise and eliminate cancer cells
2) Successful cancer cells x simulate immune response (evade detection) or can interfere with immune response to avoid destruction

Treat: e.g. immune activating anti CTLA-4 mab

Question 7

Another hallmark is unlimited replicative potential
explain this
Treatment?

Answer 7

1) normal cells have a finite no of cell doublings after which they become senescent
2) This is due to the shortening of chromosomal ends (telomeres) which occurs during every round of DNA replication
3) Cancerous cells maintain the length of their telomeres so continue to replicate

Treat: telomerase inhibitors (ends can then shorten)

Question 8

Another hallmark of cancer is tumour promoting inflammation
explain this
Treatment?

Answer 8

1) Virtually all tumours contain inflammatory immune cells
2) Inflammation = immune response that can facilitate ability of acquiring core hallmarks of cancer e.g. provide growth factors & enzymes that promote angiogenesis and invasion
3) inflammatory cells also release oxygen species that are mutagenic

Treat: certain anti-inflammatory drugs

Question 9

Another cancer hallmark is invasion and metastasis
explain this
treatment?

Answer 9

1) Normal cells generally maintain location in body and don’t migrate to other regions
2) Cancerous cells can move to other parts of the body (metastasise) and this is a major cause of death
3) alterations to the genome can alter activity &/or levels of enzymes involved in invasion of molecule involved in cell-cell or cell-extracellular adhesion

Treat: inhibitors of HGF/c-met

Question 10

Another hallmark of cancer is angiogenesis
explain this
treatment?

Answer 10

1) Normal cells depend on blood vessels to supply O2 and nutrients to cells but vascular architecture more or less constant in adults
2) Cancerous cells induce angiogenesis (formation of new blood vessels) needed for tumour survival and expansion
3) Altering the balance between angiogenesis inducers and inhibitors can activate the angiogenic switch

Treat: VEGF inhibitors e.g. bevacizumab

Question 11

Another hallmark of cancer is genetic instability and mutation
explain this
treatment?

Answer 11

1) Acquiring the hallmarks of cancer often depends on genomic alterations
2) Faulty DNA repair pathways can contribute to genomic instability

TREAT: PARP inhibitors

Question 12

Another hallmark of cancer is evasion of cell death (apoptosis)
explain this
Treatment?

Answer 12

1) Normal cell death occurs to remove cells often in response to DNA damage
2) Cancer cells evade apoptotic signals and can turn off apoptotic pathways

TREAT: proapoptotic BH3 mimetics

Question 13

Another hallmark of cancer is reprogramming energy metabolism
explain this
treatment?

Answer 13

1) uncontrolled cell division demands increase in fuels and biosynthetic precursors - this is obtained by adjusting energy metab
2) unlike normal cells, cancer cells carry out glycolysis even in presence of O2
3) glycolysis intermediates used in biosynthetic pathways so cancer cells grown more

TREAT: aerobic glycolysis inhibitors

Question 14

Define ‘benign tumour’

Answer 14

• Resemble normal cells
• Tend to be localised (x metastasise)
• Often surrounded by fibrous capsule (easy to define edges and remove)
• Usually require little treatment e.g. warts
• Surgical removal IF appropriate

Question 15

Define ‘malignant tumour’

Answer 15

• Often less well differentiated than normal cells - fewer specialised structures
• Grow and divide more rapidly
• Lose morphology, functionalisation
• More difficult to treat, less definition as to where tumour mass ends (not encapsulated)
• Involves surrounding tissues and metastasis (enter circulation and seed at different site)

Question 16

Normally cells grow in single layer (monolayer) in petri dish. This is due to _____ _____.
Transformed cells (cancer cells) acquire following phenotypes:
1) Don’t exhibit ____ ____ & grow in pile of cells against monolayer of normal cells
2) Can grow in conditions of low _____
3) Adopt a round morphology rather than flat extended one
4) Able to grow w/o attaching to substrate - _____ ______

e.g. viral transformed fibroblasts transformed with RAS create fragile tumour mass that can break apart due to reduced contact growth

Answer 16

Contact inhibition
Contact inhibition
Serum
Anchor independence

Question 17

List 3 different types of DNA mutation that can lead to cancer.

Accumulation of mutations in cells over time underlies carcinogenesis (increases with age)

Answer 17

1) Point mutation (single nucleotide base substitution, insertion or deletion)
2) Chromosomal translocation
3) Gene amplification

Question 18

List 3 processes that contribute to net cell numbers

Answer 18

1) Cell proliferation (cell division and growth)
2) elimination of cells by programmed cell death
3) during differentiation cells can enter inactive phase of cell growth

Question 19

Proto-oncogenes normal function is to… 1
They are converted to oncogenes by ____ of ____ ____.
List three types of mutation

Answer 19

Control cell growth
Gain of function mutation
Point mutation e.g. constitutively active RAS
Gene amplification = more protein e.g. template slip
Chromosomal translocation - gene moves from level of low transcript to high transcription for example

Question 20

Oncogenes are genes that encode proteins that are able to transform cells (make cancerous)
They are derived from normal cellular gene (_______)

Answer 20

Proto-oncogene

Question 21

Tumour suppressor genes code for proteins that play a role in _____ _____ and ____ _____.
Mutations occur that cause a ____ __ _____ of these genes so cells grow.
Both _____ must be mutated before loss of function seen (mainly recessive)

If Tumour suppressor genes function is lost then excessive, unregulated growth of damaged cells occurs which leads to cancer

Can screen for mutations in TS genes to see if there’s an increased tendency for developing cancer

Answer 21

inhibiting growth and tumour formation
Loss of function
Alleles

Question 22

_____ Two hit hypothesis states what?

Answer 22

• Require mutations in both tumour suppressor alleles to have a loss of function
• This will then lead to excessive, unregulated growth of damaged cells
• Can inherit one mutation then have a ‘head start’ for developing cancer as only need mutation in other allele for loss of function to occur
• Can screen for inherited mutations in tumour suppressor genes to see who is more susceptible for developing cancer

Question 23

Knudson & Vogelstein:
Cancer cells usually have to mutations that accumulate
These are all on diff ____ and _____ pathways
Cells undergoing mutations must survive long enough to sustain subsequent mutations
Malignant transformation of a single cell is enough to give risk to a tumour
____ tissues surrounding malignancies freq contain all but one of these mutations and retain morphology and function until they acquire more mutations

Answer 23

1 to 3
growth and survival
benign

Question 24

Name 5 causes of mutations that can lead to cancer

Answer 24

Environment - work place - exposure to radiation, UVB from sun causes direct DNA mutation by forming pyrimidine dimes and causing mutations

Smoking - a least 81 carcinogens detected in cig smoke (mutates DNA)

Reproduction - nuns more likely BC but less likely cervical (as less likely to get transmission virally HPV) having a child and breastfeeding reduces BC risk

Alcohol - identified as carcinogen, mouth, oesophageal and liver cancer - alcohol and smoking = synergistic effect

Diet - japanese diet inc risk stomach cancer and med diet decreased risk