Cancer as a Disease of Ageing Flashcards
What is above the basal lamina?
Basal cell layer
What is above the basal cell layer?
Differentiating cells
Describe the process of cancer formation
Basal layer cells over divide - invade differentiating cell layer above - dysplasia
Basal layer cells takeover differentiating cell layer - forms carcinoma
Basal layer cells invade connective tissue under basal lamina - forms malignant carcinoma
Malignant carcinoma invades capillaries - travels in blood - adheres to capillary walls in other tissues - escapes from capillary (extravasation) - proliferates - metastasis
Name the 4 DNA repair methods
Base-excision repair
Nucleotide-excision repair
Recombinational repair
Mismatch repair
What is base-excision repair?
Replacement of single incorrect base
What is nucleotide-excision repair?
Replacement of incorrect nucleotide
When is nucleotide-excision repair performed?
When DNA helical structure distorted by damage
When is recombinational repair performed?
When double-strand break in DNA
What are the consequences of severe DNA damage?
Senescence
Apoptosis - depletes stem cell pool - pro-ageing
Mutations - cancer, ageing
Give an example of virus that can cause cancer
Sarcoma virus
What is the normal structure of cells in a dish and what is the result of infecting them with sarcoma virus?
Normally form monolayer
After infection - become more rounded - duplicate - form cluster
Give an example of a chemical agent that can cause cancer
Coal tar
How can oncogenes be identified?
Inject DNA fragments into mouse fibroblasts - grow in dish
Cells containing oncogene form focus of morphologically-transformed cells
Inject focus cells into mice - form tumour
Define a proto-oncogene
Non-transforming DNA sequence - with mutation could become oncogene
Define an oncogene
Transforming version of same proto-oncogene DNA sequence
How can the cancer-forming mutation in an oncogene be identified?
Transfect increasingly smaller fragments of oncogene into fibroblasts
Find region causing transformation
Sequence
Compare to proto-oncogene - identify mutation
Which mutation types can cause a proto-oncogene to become an oncogene?
Point mutation Oncogene amplification (CNV) Translocations between chromosomes
Name an example of a translation between chromosomes that causes a proto-oncogene to become an oncogene
Philadelphia transformation
What is the Philadelphia transformation?
In chronic myelogenous leukemia
abl gene translocation from chromosome 9 to 22
BCR promoter now controls abl expression
Overexpression of fusion protein (BCR-abl) - tyrokine kinase
Drives cell division, inhibits DNA repair
What are the multiple hits needed for transformed cell formation in colon carcinoma?
1st hit - APC mutation - tumour suppressor gene
2nd hit - RAS mutation
3rd hit - PI3K/TGF-beta mutation
What do proto-oncogenes stimulate and what normally counterbalances this?
Growth
Counterbalanced by tumour suppressor genes
How is it determined if a cancer allele is dominant/recessive?
Cell fusion experiment - fuse normal cell and cancer cells
2 possible products - hybrid cell tumorigenic (mutation dominant), hybrid cell non-tumorigenic (mutation recessive)
What is Knudson’s two hit hypothesis?
Two hits needed for tumour development
In familial retinoblastoma - inherit one mutant allele - only one somatic mutation required - acquiring 2nd mutant allele easier - early onset
In sporadic retinoblastoma - must undergo 2 somatic mutations
Is Knudson’s two hit hypothesis correct?
No - number of hits require depends on tumour type and specific mutations acquired
What are microRNAs and how can they play a role in cancer?
Bind to 3’ UTR – inhibit mRNA translation
Dysregulated in cancer – downregulate tumour suppressor genes
How can epigenetic mechanisms be involved in cancer?
CpG methylation of tumour suppressor genes – silence
Name the cellular processes typically altered in cancer cells
Cell cycle Cellular signalling pathways for growth, differentiation, death – control cell number Cellular metabolism DNA repair Genomic stability Interaction with extracellular matrix and micro-environment Interaction with immune system Ability to metastasise
How is the cell cycle altered in cancer cells?
Damaged cell continues division – causes cells with genomic instability
How is DNA repair altered in cancer cells?
Impaired
Increases mutation rate – predisposes to cancer
What is the effect of genomic instability in cancer cells?
Required for cancer cell growth
What is the main method of ATP synthesis used by cancer cells and what is the impact of this?
Glycolysis
Use more glucose
What are the products of glycolysis in cancer cells?
Less ATP
More cellular building blocks – enables increased cell division
What does p53 enable?
Enables G1 arrest, DNA repair, senescence, apoptosis
Mutation in which cell cycle regulator is common in cancer?
p53
How is inflammation linked to cancer?
Chronic inflammation predisposes to cancer
Mutations in which inflammation-related genes are linked to cancer?
Inflammatory cytokine genes
What is intratumour heterogeneity and what is the impact on treatment aims?
Within tumour each region slightly different – different mutations
Aim to treat common mutations – in all areas of tumour
What are the hallmarks of cancer mutation effects?
Evade growth suppressors Avoid immune destruction Replicative immortality – by preventing telomere shortening Tumour-promoting inflammation Enable metastasis Induce angiogenesis – supply tumours with nutrients Cause genome mutation and instability Resist cell death Upregulated nutrient sensing Sustain proliferative signalling
Name the hallmarks of ageing
Genomic instability Telomere shortening Epigenetic alterations Loss of proteostasis Deregulated nutrient sensing Mito dysfunction Cellular senescence Stem cell exhaustion
How can ageing processes increase cancer risk?
Mutation accumulation
Tissue microenvironment changes – increase risk of malignant cell growth
Increased senescent cells
Weaker immune system
How do stem cells change with age?
Accumulate DNA damage – genomic instability
What are the 2 possible outcomes of DNA damage in stem cells?
Additional mutations – forms cancer
Apoptosis/senescence – depletes stem cell pool – ageing/degenerative disease
How could treatments to improve DNA repair help to prevent cancer and ageing?
Prevent stem cell damage accumulation
What is the effect of p53 depletion in mice?
Increases cancer incidence
Shortest lifespan
What is the effect of p53 truncation (hyperactivity) in mice and what does this suggest?
More cells sent to apoptosis – pro-ageing
Intermediate lifespan
Lowest cancer incidence
Protection from cancer could be pro-ageing
What is the effect of WT p53 in mice?
Intermediate cancer incidence
Longest lifespan
What are super-p53 mice?
3 copies of p35
Under endogenous promoter – not always active
What are the characteristics of super-p53 mice and what does this suggest?
Normal ageing
Protection from cancer
Only more p53 when needed decreases cancer – without affecting lifespan – can have cancer and ageing protection
What key trait do Daf-2 mutant C. elegans have?
Long-lived
What is the effect of crossing Daf-2 mutant with ovarian cancer model C. elegans and what does this suggest?
Offspring protected from ovarian cancer – as Daf-2 sends cancer cells to apoptosis
Mutation that increases lifespan also inhibits tumour growth
What is the effect of dietary restriction in mice?
Extends lifespan
Prevents cancer
Which type of cancer drugs also extends lifespan?
mTOR inhibitors
Which drug extends C. elegans lifespan and prevents colon cancer?
Aspirin (anti-inflammatory)
Why might aspirin not be a suitable drug to prevent ageing and cancer?
Increases bleeding risk
Why does decreasing Myc expression extend mouse lifespan?
Can be increased Myc copies in cancer cells – Myc activates more oncogenes
Which type of cancer drugs could also be anti-ageing drugs?
Drugs that inhibit growth pathways
