Week 10 lecture - Cancer Flashcards
What is cancer?
- Cancer is a mass of cells that grow rapidly, refuse to die, and spread to a secondary site
- Cancer is a genetic disorder
- Mutations give cancer cells a survival advantage
- Mutations cause the cell to grow uncontrollable and ignore the usual signals that tell them to stop growing
- The more mutations a cell acquires, the more likely it is to acquire more mutations and so on… their progeny cells have those mutations, and then their progeny cells will acquire even more mutations…
- Most of the mutations are in tumour suppressor genes or oncogenes – these drive/ govern the control of that cell cycle growth and division
The immune system and cancer:
- Research from Dundee Uni: rise in cancer incidence is correlated to the rise in decreased immune system with age
- Specific immune cells – T cells released by thymus (sits behind sternum)- stops growing at 2years old
- The thymus shrinks as you age – this is why elderly have a poorer immune system – less T cells produced by thymus
- Rate of thymus shrinkage is faster in men than women
- HIV and aids – more susceptible to a specific type of cancer as they had low immune function: no T cells to kill off the cancer
Cancer metastasis and cancer stem cells:
- Over 2/3rds of cancer related deaths caused by secondary metastases, NOT the primary tumour – when cancer comes back it is more aggressive and difficult to treat
- Tumours are made up of many different cell types (tumour cells, stromal cells, stem cells)
- Cancer stem cells are very plastic in their nature – differentiate into different cell types
- Study: separated cells from a tumour and just took the normal cancer cells and put up to 10,000 of these cells a mouse – new tumours didn’t develop. However, when they separated a subtype of these cells- cancer stem cells ( which have specific proteins on the surface of the cel: CD44+/CD24)-, when they put as few as 100 of these stem cells into the mice- new tumours did grow.
- Tumour initiating cells/ cancer stem cells: Genomic instability – more likely to develop more mutations – more resistant to chemotherapy
How does our immune system protect us against cancer?
- NK cells – roam around the bloodstream to find rogue cancer cells and kill them
- Every nucleated cell in the body expressed MHC+1 molecules. If NK cells encounter these MHC+ molecules, it will leave it alone. However, Tumours often lose these MHC+1molecules. NK cell will bind to these activatory receptors and the NK cell will receive a signal to kill these cells
- NK cells kill directly by expressing receptors on the surface - Perforin molecules bind together and land on the surface of a cell to create a pore. Granzimes get in through this pore and cause the cell the liaise.
- NK cells kill indirectly by releasing cytokines – to recruit cells of the specific immune response e.g., TNF-a
Tumours lose MHC class 1:
1) Cytolytic activity – secrete granzymes
2) Cytokine release – recruits’ specific immunity e.g., IFN-g, TNF-a, GM-CSF, CCL1, 2, 3, 4, 5 & CXCL8
Immune cells and specific anti-tumour immunity:
- Dendritic cells – antigen presenting cells e.g., macrophages that phagocytose (to engulf tumour antigens)
- B cells – produce antibodies that are specific to the antibodies they’ve just met (tumour fragments)
- T cells. Naïve killer T cells: CD8+ T cells/ - Naïve CD4 T cells = helper T cells (produce cytokines to help boost the response of NK cells
The 3 Es of immunosurveillance:
How cancer evades the immune system:
- Elimination: immune system destroys the weakest cancer cells and the strongest will survive in the system
*Darwinian survival of the fittest: - “In the struggle for survival, the fittest win out at the expense of their rivals because they succeed in adapting themselves best to their environment”
- Equilibrium: small subpopulation survive and lie dormant – they will eventually grow and divide to repopulate (they are more resilient, resistant to the immune response/ chemotherapy)
- Escape: Clonal outgrowth of surviving cancer cells. Every cell in this population will have the original mutation
Risk factors for cancer:
- Nearly 50% of all cancers and roughly a third of all cancer – related deaths may actually be preventable
- Obesity is the biggest risk factor for cancer
- Genetics can contribute to a small proportion of risk- Brac1 and Brac2 account for 10% of breast cancers
- Refined sugars and high processed foods
- Cancer is a multifactorial disease
- Pesticides on fruit on veg
- Certain pathogen scan cause cancer – imbalance of the gut flora/ bacteria
Most important behaviours for reducing cancer risk:
- Limiting exposures to UV radiation
- Not using tobacco
- Avoiding infectious agents
- Exercising
- Eating well
- Maintaining a healthy body weight
Leisure-time PA reduces the risk of SOME cancers:
1) Oesophageal adenocarcinoma
2) Liver
3) Lung
4) Kidney
5) Gastric cardia
6) Endometrial
7) Myeloid leukaemia (blood)
8) Myeloma (blood)
9) Colon
10) Head and neck
11) Rectal
12) Bladder
13) Breast
14) Prostate cancer (recently added)
How can exercise help prevent cancer?
1) Sex hormones:
- Exercise reduced oestrogen in breast cancer survivors – oestrogen produced by fat cells and drives the growth of tumours. Less fat cells = less oestrogen
- Indirect – via reduction in adiposity
2) Metabolic hormones:
- Exercise stabilises metabolic hormones
- Improved insulin sensitivity and reduced IGF-1
3) Inflammation and adiposity:
- Chronic inflammation promotes cancer
- Exercise can reduce chronic inflammation
- Regulates cytokines: IL-6, CRP, and TNFa
4) Immune function:
- Immunodeficiency – increased cancer risk
- Moderate intensity exercise (50% vo2 max)– increased T cells, NK cells and neutrophils
What happens to existing cancers with exercise?
- Effects of tumour growth and spread:
- Voluntary wheel running in mice reduces cancer cell growth by 67%
- But doesn’t reduce size of existing tumours in mice or humans
- However, cancer cells incubated with exercised serum form fewer tumours when inoculated into mice
Various exercise interventions significantly reduced breast cancer cell viability, proliferation and tumorigenic potential in vitro:
- Exercise causes a reduction in migration, viability and proliferation (in vitro breast cancer cells)
Effects on tumour metabolism:
- Warburg effect and glycolysis – normal cells metabolise glucose through mitochondria via oxygen – energy efficient. If there’s not enough oxygen present they will get energy via the lactate producing pathway (energy poor)
- Cancer cells always metabolise by the lactate producing pathway – to get around this energy poor pathway they overexpress a protein called GLUT1 transporter, so they can mop up as much of the free CHOs and free glucose in the system
- Cancer cells more susceptible to exercise-induced energy stress
Should cancer patients cut out sugar?
If you starve the body of all CHOs, you will preferentially starve your healthy tissue (greedy cancer cells will take up whatever they can).
Better idea = reduce CHO load but not cut it out entirely e.g., intermittent fasting/ keto
