L7, Cancer as a preventable disease Flashcards
1
Q
What percentage of cancers are supposedly preventable? List 6 key actions
A
- WHO: ‘30-50% of cancers are preventable’
- Not smoking
- Healthy weight
- UV safety
- Avoiding substances at work
- Protecting against certain diseases
- Low alcohol intake
2
Q
Tobacco mortality:
A
- Causes 22% of all cancer deaths (biggest preventable cause of cancer)
3
Q
Carcinogenesis by smoking:
A
- Cigarette smoking introduces carcinogens
- Metabolisis activates further carcinogens -> DNA adducts
- DNA adducts introduce persistent miscoding, leading to apoptosis and mutations in critical oncogenes and TSGs (KRAS, TP53 etc)
- Alternatively, other chemicals enhance carcinogenesis by causing inflammation, ROS, gene promoter methylation (epigenetic dysregulation)
- Receptor binding of nicotine activates Akt, PKA -> decreases apoptosis, increase angiogenesis etc (also enhancing carcinogenesis)
4
Q
Nicotine receptors:
A
- NNK
- nAChRs
5
Q
Main types of lung cancer:
A
- Non-small cell (85-90%) - related to smoking
- Small cell (10-15%) - extremely related to cigarette smoking; most aggressive
6
Q
Obesity and inactivity in cancer
A
- WHO estimate almost half a million cases caused per year
- Females much more affected (hormone link)
- Skewed towards high income countries; poor diets
7
Q
How does obesity cause cancer?
A
- Exanded and reprogrammed metabolically active adipose tissue
- Direct effects on cancer cell via estrogen (due to increased aromatase activity), Insulin-signalling, JAK-STAT pathway, NFKb pathway as well as metabolic effects
- Indirect effects on tumour microenvironment such as increased inflammatory cells, increased leptins, ECM proteins, cytokines and inflammatory markers. Also, increased adipocyte progenitors
- Altered systemic physiology, cancer cells overproduced
8
Q
Sex differences in cancer susceptibility due to obesity:
A
- Overall: Skewed towards women (those cancers highly impacted by hormones) -> endometrium, breast, gallbladder
- Male skew: Oesophagus, kidney, pancreas, colorectal
9
Q
Cancer prevention strategies (2 methods and 2 case studies):
A
- Australia: Slip slap slop (effective)
- UK: Cigarette anti-smoking packaging (less effective)
- Vaccination
- Screening
10
Q
Infectious agents and cancer -> Stats, who it affects
A
- Chronic infections cause 20% of cancers
- These disproportionately affect low and medium income countries (LMIC)
11
Q
Vaccines in use for cancerous infectious disease:
A
- HPV: Gardasil followed by Gardasil9, Cervarix HPV
- HBV: Engerix -B
- Various in development for EBV, HCV, H.pylori
12
Q
Vaccine hesitancy example:
A
- Japanese government suspended recommendation of vaccination programme for HPV
- Eventually found to be spurious
- Currently estimated to cause around 4000 deaths/year from cervical cancer in Japan
- WHO listed vaccine hesitancy as one of the top 10 threats to human health
13
Q
Liver cancer causes:
A
Multifactorial:
- HBV (50% of cases worldwide)
- HCV (15%)
- Aflatoxin contamination of food
- Alcohol abuse
- Overweight/obesity (e.g. non-alcoholic fatty liver disease)
14
Q
HBV and HCV causing cancer:
A
- Multifactorial
- Chronic inflammation is key
15
Q
Aflatoxin B1 and liver cancer:
A
- Produced by fungi
- Activated in liver (epoxide formation), reacts with DNA -> DNA damage (becomes carcinogenic)
- Possibly an intercalation mediated process
- Mutage, particularly associated with mutations in p53 and HRAS
16
Q
Steatosis: Types, progression
A
- Alcoholic fatty liver disease and non-alcoholic fatty liver disease (associated with obesity)
- Can progress to an inflammatory state -> steatohepatisis
- 80-90% of HCC cases are associated with cirrhosis
17
Q
Mechanism for HCC progression:
A
- Carcinogenic agents cause tissue damage, inducing cell death (necrosis)
- Higher proliferation rate enforced to replace lost tissue
- Stellate cells become activated, generating collagen/scarring
- Hyperplastic and subsequently dysplastic nodule induced ultimately resulting in HCC
- This progresses to neoplasia if inflammation and other characteristics persist
18
Q
2 key measures taken to prevent liver cancer:
A
Reducing HBV and HCV infection rates…
- HBV vaccination (e.g. Taiwan HBV vaccination programme from 1986 -> dramatic fall in liver cancer in vaccinated groups)
- Elimination of HCV iatrogenic sources (e.g. contaminated blood)
- -> historically poor screening of donated blood in Japan
Education…
- Discourage sharing of needles by IDUs
- Food storage/diet changes
- Reduce alcohol intake
19
Q
Methods for oestrogen based breast cancer prevention:
A
Signalling targeted via…
- Selective oestrogen receptor modulators (SERMs e.g. tamoxifen, raloxifene)
- Aromatase inhibitors (e.g. exemestane, letrozole)
20
Q
Role of oestrogen signalling in breast cancer:
A
- 75% of breast cancers are positive for the oestrogen receptor; strong link between oestrogen levels and breast cancer risk
- ER and oestraiol coactivate ER target genes (proliferative) by binding ERE
- Oestradiol is synthesised in the ovaries of pre-menopausal women
21
Q
SERMs: Mechanism and side effects
A
- Act as ER antagonists in breast tissue
- However, they can also act as ER agonists in other tissues (bone and endometrium)
- Greater side effects than aromatase inhibitors -> increased risk of stroke and endometrial cancer
22
Q
Aromatase inhibitors: Mechanism and side effects
A
- Preventing oestrogen synthesis in peripheral fat
- Aromatase typically converts testosterone to oestradiol and androstenedione to oestrone
- Aromatase inhibition means no transcription of ER target genes -> menopausal symptoms, joint pain and osteoporosis
23
Q
+ Potential drugs for colorectal cancer prevention:
A
- NSAIDs shown to reduce risk of polyps, mostly by cyclooxygenase-2 inhibition
- Examples include aspirin, sulindac, celecoxib
- COX inhibition is thought to suppress prostaglandin synthesis -> decreased angiogenesis, cell proliferation, increased apoptosis
- Prostaglandins: Inflammatory mediators
- Not appropriate in long-term (5+ yrs) due to associated cardiovascular risk of NSAIDs
- ‘Cancer prevention, early diagnosis, surgical and adjuvant treatment should constitute a complete anticancer strategy’
24
Q
+ List the common aetological factors for HCC:
A
- Chronic HBV and HVC infection
- Chronic alcohol consumption
- Aflatoxin-B1 contaminated food
- Cirrhosis inducing conditions
25
Q
+ Key differences between HBV and HCV
A
- HCV has a much higher propensity to become a chronic infection
- HCV has a higher propensity to promote liver cirrhosis (~10 to 20x)
- HCV does not have a DNA intermediate form and cannot integrate into host genomes
26
Q
+ How does alcohol exposure promote carcinogenesis?
A
- Causes production of inflammatory cytokines
- Increases concentration of circulating endotoxin
- Sensitizes hepatocytes to TNFalpha -> chronic hepatocyte destruction, cycle of regeneration and stellate cell activation -> cirrhosis -> HCC
- Oxidative stress mechanisms -> fibrosis and cirrhosis
27
Q
+ What are finasteride and dutasteride examples of?
A
- 5-alpha-reductase inhibitors for treatment of prostate cancer
