L7, Cancer as a preventable disease

Question 1

What percentage of cancers are supposedly preventable? List 6 key actions

Answer 1

• WHO: ‘30-50% of cancers are preventable’
• Not smoking
• Healthy weight
• UV safety
• Avoiding substances at work
• Protecting against certain diseases
• Low alcohol intake

Question 2

Tobacco mortality:

Answer 2

• Causes 22% of all cancer deaths (biggest preventable cause of cancer)

Question 3

Carcinogenesis by smoking:

Answer 3

• 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)

Question 4

Nicotine receptors:

Answer 4

• NNK
• nAChRs

Question 5

Main types of lung cancer:

Answer 5

• Non-small cell (85-90%) - related to smoking
• Small cell (10-15%) - extremely related to cigarette smoking; most aggressive

Question 6

Obesity and inactivity in cancer

Answer 6

• WHO estimate almost half a million cases caused per year
• Females much more affected (hormone link)
• Skewed towards high income countries; poor diets

Question 7

How does obesity cause cancer?

Answer 7

• 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

Question 8

Sex differences in cancer susceptibility due to obesity:

Answer 8

• Overall: Skewed towards women (those cancers highly impacted by hormones) -> endometrium, breast, gallbladder
• Male skew: Oesophagus, kidney, pancreas, colorectal

Question 9

Cancer prevention strategies (2 methods and 2 case studies):

Answer 9

• Australia: Slip slap slop (effective)
• UK: Cigarette anti-smoking packaging (less effective)
• Vaccination
• Screening

Question 10

Infectious agents and cancer -> Stats, who it affects

Answer 10

• Chronic infections cause 20% of cancers
• These disproportionately affect low and medium income countries (LMIC)

Question 11

Vaccines in use for cancerous infectious disease:

Answer 11

• HPV: Gardasil followed by Gardasil9, Cervarix HPV
• HBV: Engerix -B
• Various in development for EBV, HCV, H.pylori

Question 12

Vaccine hesitancy example:

Answer 12

• 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

Question 13

Liver cancer causes:

Answer 13

Multifactorial:

• HBV (50% of cases worldwide)
• HCV (15%)
• Aflatoxin contamination of food
• Alcohol abuse
• Overweight/obesity (e.g. non-alcoholic fatty liver disease)

Question 14

HBV and HCV causing cancer:

Answer 14

• Multifactorial
• Chronic inflammation is key

Question 15

Aflatoxin B1 and liver cancer:

Answer 15

• 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

Question 16

Steatosis: Types, progression

Answer 16

• 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

Question 17

Mechanism for HCC progression:

Answer 17

• 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

Question 18

2 key measures taken to prevent liver cancer:

Answer 18

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

Question 19

Methods for oestrogen based breast cancer prevention:

Answer 19

Signalling targeted via…

• Selective oestrogen receptor modulators (SERMs e.g. tamoxifen, raloxifene)
• Aromatase inhibitors (e.g. exemestane, letrozole)

Question 20

Role of oestrogen signalling in breast cancer:

Answer 20

• 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

Question 21

SERMs: Mechanism and side effects

Answer 21

• 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

Question 22

Aromatase inhibitors: Mechanism and side effects

Answer 22

• 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

Question 23

+ Potential drugs for colorectal cancer prevention:

Answer 23

• 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’

Question 24

+ List the common aetological factors for HCC:

Answer 24

• Chronic HBV and HVC infection
• Chronic alcohol consumption
• Aflatoxin-B1 contaminated food
• Cirrhosis inducing conditions

Question 25

+ Key differences between HBV and HCV

Answer 25

• 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

Question 26

+ How does alcohol exposure promote carcinogenesis?

Answer 26

• 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

Question 27

+ What are finasteride and dutasteride examples of?

Answer 27

• 5-alpha-reductase inhibitors for treatment of prostate cancer