Lecture 7: Cancer as a preventable disease

Question 1

The WHO describes that what percentage of cancers are preventable?

Answer 1

30-50% (smoking is the most important cause of cancer that can be prevented)

Question 2

Which cancer is the top cause of death in a large number of countries?

Answer 2

Lung cancer

Question 3

How has changes in tobacco consumption related to prevalence of lung cancer deaths?

Answer 3

Cigarette consumption increased at beginning of 20th century (more marketing campaigns and became easier to transport tobacco)
- about 20 years later after beginning of increase in cigarette consumption, see increase in male lung cancer deaths bc cancer development takes long term exposure
- female lung cancer deaths begins to increase more slowly and much later than males (females were initially targeted by cigarette campaigns)

Question 4

How does cigarette smoking drive the development of lung cancer?

Answer 4

carcinogens: interact with DNA forming DNA adducts that result in miscoding –> increase chance of generating mutations in KRAS, TP53 etc (mutations in proto-oncogenes and tumour suppressor genes)

Co-carcinogens: promote tumour development by inflammation, oxidative damage, gene promoter methylation (TSG inactivation)

Receptor binding: nicotine binding to its receptors activates other signalling pathways (Akt, PKA activation) that drives angiogenesis and transformation as well as decreasing apoptosis - increase mitogenic pathways

Question 5

True or false: nicotine is a carcinogen?

Answer 5

False: but facilitates cancer progression due to addictive properties

Question 6

What are the two main types of lung cancer?

Answer 6

Non-small cell lung cancer (more common)

Small cell lung cancer (less common and very strongly related to smoking)

Question 7

What lifestyle factors are strongly associated with cancer development?

Answer 7

obesity/inactivity
sun exposure

Question 8

Describe the global distribution of obesity-related cancer

Answer 8

more prevalent in America and europe

Question 9

Which 4 cancers are especially linked to obesity/being overweight?

Answer 9

Breast, kidney, bowel, womb

Question 10

How does obesity increase risk of developing cancer?

Answer 10

Adipose tissue dysfunction:
- increase in inflammatory cytokines
- increase in cancer stem cells - fat provides extra nutrients so favourable environment for growth of cancer stem cells

Systemic impacts:
increase insulin and insulin resistance
decrease adiponectin
increase eostrogen (breast cancer)

Has direct effects on cancer cells:
1. signalling pathway - eostrogen, insulin that can increase growth of cancer cell
2. metabolic effects

Indirect effects on microenvironment:
- cancer associated adipocytes
- inflammatory cells and markers that drive cancer development (pro-inflammatory microenvironment)

Question 11

Why is obesity-related cancer more prevalent in females?

Answer 11

Cancers that are influenced by hormones such as beast and endometrial cancer are more common in females

Question 12

How can the incidence of preventable cancers be reduced?

Answer 12

Increase in Education - campaigns that increase awareness (eating more fruit and veg - lower fat diet, cigarette packaging) but difficult to change people’s behaviour

Question 13

Chronic infections cause what percentage of all cancers worldwide?

Answer 13

20% (with H. pylori and HPV most common)

Question 14

which vaccination/eradication strategies are in use or in development to prevent cancer development?

Answer 14

Vaccines in use: HPV protects against a number of HPV subtypes, HBV (hepatitis B)

Vaccines in development: EBV, Hepatitis C and H. pylori

Question 15

How has HPV vaccination hesitancy affected incidence of cervical cancer in Japan?

Answer 15

Japanese government suspended the proactive recommendation of the HPV vaccine in 2013 due to potential association of the vaccination with adverse effects (which turned out to be false)
–> modelling suggests that if the government do not do anything about it, the incidence will remain high.

Question 16

Hepatocellular carcinoma is multifactorial and is associated with what risk factors (there are 5)?

Answer 16

Hepatitis B virus (causes 50% of cases in chronic infection due to inflammation)
Hepatitis C virus (causes 15 % of cases in chronic inflammation due to inflammation)
Aflatoxin (contamination of food causes 28% of cases)
Alcohol abuse (alcoholic fatty liver disease)
Obesity (non-alcoholic fatty liver disease)

Question 17

How do HBV and HCV viruses cause liver cancer?

Answer 17

causes chronic inflammation
- lymphocytic infiltration of liver tissue promotes inflammation

Question 18

how and why does Japan differ in the proportion of HCC caused by HBV and HCV?

Answer 18

Unlike the res of the population, HCV causes more cancer than HBV in Japan

why?
poorer medical practices - contaminated blood and drug use

Question 19

What is Aflatoxin B1 and how does it cause liver cancer?

Answer 19

is a mycotoxin produced by Apergillus spp of fungi

not carcinogenic but undergoes metabolic activation in the liver forming an aflatoxin B epoxide that interacts with DNA resulting in damage and mutations (missense and effects on coding) possible by being intercalated into DNA

Question 20

What is steatosis and how is it linked to development of liver cancer?

Answer 20

steatosis is fatty liver disease (alcoholic or non-alcoholic associated with obesity) - large fat-containing vacuoles within hepatocytes
- can progress to an inflammatory state called steatohepatitis

Question 21

How does HCC develop?

Answer 21

Injury to liver (caused by HBV, HCV, alcohol, obesity, Aflatoxin B1)
- results in continual cell necrosis
- forced increased proliferation occurs to replace the damaged tissue
- prolonged exposure = hepatocyte proliferative arrest (likely due to depletion of stem cells in tissue.
–> stellate cell activation results in collagen production and extensive scarring of the liver = liver cirrhosis
- progression to neoplasia due to inflammation and genomic instability
- further genomic instability and loss of tumour suppressor genes (p53) and oncogenic activation leads to de-differentiation and HCC

Question 22

How can liver cancer be prevented?

Answer 22

Reduce HBV and HCV infection rates: HBV vaccine (HCV vaccine in development), eliminate iatrogenic sources of HCV (E.g. contaminated blood - screen blood for transfusions)

Education: discourage sharing of needs by intravenous drug users, food storage (aflatoxin B1), changes in diet (less fat), reduce alcohol intake

Question 23

What are 8 steps individuals can take for cancer prevention?

Answer 23

1. avoid smoking and tobacco products
2. eat healthy diet
3. maintain healthy weight
4. protect skin (use SPF)
5. Get vaccinated
6. Exercise regularly
7. Limit alcohol consumption
8. regular check-ups and cancer screenings

Question 24

give 2 examples of chemoprevention as a new strategy for cancer prevention?

Answer 24

Target oestrogen signalling for prevention of breast cancer in high risk patients by giving:
- selective oestogen receptor modulator (SERMs) - Tamoxifen (bind to the oestogen receptor causing conformational changes so cannot recruit co-activator so gene transcription not upregulated)
- aromatase inhibitors (blocks conversion of testosterone/androgens to oestogen in peripheral adipose tissue)

Prevention of colorectal cancer using NSAIDS (aspirin)

Question 25

How can oestogen increase the risk of developing breast cancer?

Answer 25

Oestogen binds to cytosolic eotrogen receptor - the complex is translocated to the nucleus where they are bind to co-activator to promote transcription of target genes such as proliferative genes

Question 26

There is a strong link between (1) levels and (2) risk

Answer 26

1. oestrogen
2. breast cancer

Question 27

women that experience ___?____ have shown to have a decrease in breast cancer risk … why?

Answer 27

Early menopause

why?
due to decrease in oestrogen production

Question 28

How does the location of oestrogen synthesis differ between pre-menopausal and post-menopausal women?

Answer 28

in pre-menopausal women, oestrogen is largely synthesised in the ovaries

in post-menopausal women, oestrogen is largely synthesised by the adipose tissues

Question 29

What is the role of aromatase in oestrogen synthesis in peripheral adipose tissue?

Answer 29

Aromatase produced by adipocytes converts testosterone/androgens to oestradiol

Question 30

What can be side effects of aromatase inhibitors?

Answer 30

Aromatase inhibitors result in no transcription of ER target genes so can have effects such as menopausal symptoms, joint pain, osteoporosis

Question 31

What can be side effects of SERMs?

Answer 31

can act as eostrogen receptor agonists in other tissue types because some tissue-specific receptor subtypes are not inhibited by SERM binding so instead results in increased signalling and target gene transcription
–> this can lead to increased risk of stroke and endometrial cancer

Question 32

Cancer risk is determined by both ____(1)____ and ____(2)____ that interact?

Answer 32

genetics and environmental factors

(any order)