Lecture 7: Cancer as a preventable disease Flashcards
The WHO describes that what percentage of cancers are preventable?
30-50% (smoking is the most important cause of cancer that can be prevented)
Which cancer is the top cause of death in a large number of countries?
Lung cancer
How has changes in tobacco consumption related to prevalence of lung cancer deaths?
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)
How does cigarette smoking drive the development of lung cancer?
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
True or false: nicotine is a carcinogen?
False: but facilitates cancer progression due to addictive properties
What are the two main types of lung cancer?
Non-small cell lung cancer (more common)
Small cell lung cancer (less common and very strongly related to smoking)
What lifestyle factors are strongly associated with cancer development?
obesity/inactivity
sun exposure
Describe the global distribution of obesity-related cancer
more prevalent in America and europe
Which 4 cancers are especially linked to obesity/being overweight?
Breast, kidney, bowel, womb
How does obesity increase risk of developing cancer?
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)
Why is obesity-related cancer more prevalent in females?
Cancers that are influenced by hormones such as beast and endometrial cancer are more common in females
How can the incidence of preventable cancers be reduced?
Increase in Education - campaigns that increase awareness (eating more fruit and veg - lower fat diet, cigarette packaging) but difficult to change people’s behaviour
Chronic infections cause what percentage of all cancers worldwide?
20% (with H. pylori and HPV most common)
which vaccination/eradication strategies are in use or in development to prevent cancer development?
Vaccines in use: HPV protects against a number of HPV subtypes, HBV (hepatitis B)
Vaccines in development: EBV, Hepatitis C and H. pylori
How has HPV vaccination hesitancy affected incidence of cervical cancer in Japan?
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.
Hepatocellular carcinoma is multifactorial and is associated with what risk factors (there are 5)?
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)
How do HBV and HCV viruses cause liver cancer?
causes chronic inflammation
- lymphocytic infiltration of liver tissue promotes inflammation
how and why does Japan differ in the proportion of HCC caused by HBV and HCV?
Unlike the res of the population, HCV causes more cancer than HBV in Japan
why?
poorer medical practices - contaminated blood and drug use
What is Aflatoxin B1 and how does it cause liver cancer?
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
What is steatosis and how is it linked to development of liver cancer?
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
How does HCC develop?
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
How can liver cancer be prevented?
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
What are 8 steps individuals can take for cancer prevention?
- avoid smoking and tobacco products
- eat healthy diet
- maintain healthy weight
- protect skin (use SPF)
- Get vaccinated
- Exercise regularly
- Limit alcohol consumption
- regular check-ups and cancer screenings
give 2 examples of chemoprevention as a new strategy for cancer prevention?
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)
How can oestogen increase the risk of developing breast cancer?
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
There is a strong link between (1) levels and (2) risk
- oestrogen
- breast cancer
women that experience ___?____ have shown to have a decrease in breast cancer risk … why?
Early menopause
why?
due to decrease in oestrogen production
How does the location of oestrogen synthesis differ between pre-menopausal and post-menopausal women?
in pre-menopausal women, oestrogen is largely synthesised in the ovaries
in post-menopausal women, oestrogen is largely synthesised by the adipose tissues
What is the role of aromatase in oestrogen synthesis in peripheral adipose tissue?
Aromatase produced by adipocytes converts testosterone/androgens to oestradiol
What can be side effects of aromatase inhibitors?
Aromatase inhibitors result in no transcription of ER target genes so can have effects such as menopausal symptoms, joint pain, osteoporosis
What can be side effects of SERMs?
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
Cancer risk is determined by both ____(1)____ and ____(2)____ that interact?
genetics and environmental factors
(any order)
