Exercise and Cancer Flashcards
What is cancer?
- In a nutshell, 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
- Tumour derived from Latin = meaning swelling
Which hormone is associated with the greatest influence on preventing cancer growth by exercise?
- adrenaline, released from adrenal gland is a key molecule in the exercise associated improved tumor control by cells of the immune system.
- because elicits fight-or-flight response
Which interleukin is increased during exercise?
why?
How might this impact tumour growth?
- IL-6, in an intensity dependent manner
- anti-infammatory by inhibiting TNF-α and IL-1, and activation of immune suppressive IL-10
- this increases NK cell release from thymus as they have the IL-6 receptor
Which is the main cell that kills tumour growths in non-specific immunity?
- NK cells
- high level of cytotoxic activity among peripheral blood lymphocytes was associated with a lower risk of cancer
- suggests NK cells as active in early tumor surveillance.
- NK cells cause cytotoxic T cell infiltration
Name 2 cancer stem cells:
- CD44+
- CD24-
What is the role of tumour suppressor genes?
- Tumour suppressors genes - prevent inappropriate growth of cells, need for them to be switched back on to stunt growth
- Suppressor genes stops scar skin from getting too big
- P53 prevents tumours from sunburn
- Switched on and off
What percent can exercise reduce tumour growth rate?
The control of tumor growth by exercise
training in established tumors may be as high as a 67% reduction in growth rate
Explain the role of the Akt/mTOR pathway during exercise in relation to cancer?
- Akt/mTOR pathway has been shown to
be deactivated with endurance exercise in several tumour models - Plays a central for control of growth and protein synthesis and plays a pivotal role in the muscular response to resistance training
- However, no causation effects have been found
Describe Oncogenes:
DNA mutations can cause cancer:
* Oncogenes – ”mitogenic” signals - growth promoting, drive cell growth & division without repair
* Tend to be always switched on
* Mutations –> inappropriate activation of cell growth/division, preventing DNA repair
Describe
- germline
- somatic
mutations
- germline e.g.: braca 1 & 2 is inherited & occur in the DNA of an organism’s reproductive cells(Cystic fibrosis)
- Every cell in tumour mass carries the same mutation
- Somatic are acquired throughout life
- only cells daughter cells of the cell will carry the mutation = polyclonal mass created
e.g.: damage from UV rays, P53 is the guardian of the genome, facilitates the repair of damaged DNA, can trigger apoptosis if not= pealing after sunburn & increases sensitivity to breast cancer
What immunological issue can lead to cancer?
- Termed Thymic involution
Thymus is in middle of the sternum, which produces T-cells, shrinking by about half every 16 yrs. - Faster in men than women
- Aging decreases immune function
- Immune system keeps it in check
How does the non-specific immune system protect us against cancer?
- Innate immunity contributes to inflammation, creating an environment hostile to tumor development.
- natural killer (NK) cells look for virus infected/cancer cells.
- NK cells have inhibitory receptors & activating receptors
- inhibitory receptors bind to MHC class 1 on cancer cells
- activatory receptors activated as MHC class 1 is down regulated on cancer cells = detection that it is a bad cell
- causes NK cell to kill off tumour cell by 2 mechanisms
1. secreting of granzymes - an enzyme triggering cell death in target cell
2. secreting cytokines e.g.: TNF-α, CCL 1,2,3,4,5 = recruitment of specific immunity
What is the only cell in the body that does not present MHC class 1?
- red blood cells
How does our specific immune system protect us against cancer?
involves dendritic cells(APC’s), T cells & B cells
- dendritic cells have antigens that are from dying tumour cells presented on its surface. Presented on MHC class 1/2 molecules
- Activates T effectors: Cytotoxic T(CD8+), T helper(CD4+) & Tregs
- Cytotoxic T cells (CD8+ T cells) recognize MHC class I and directly kill cancer cells by inducing apoptosis. They release perforin and granzymes to induce apoptosis in target cells.
- MHC class II cells are recognised by CD4+ OR B cells, producing antibodies that can recognize other cancer cells & facilitate their destruction
- all of these responses store memory cells
Describe
- cancer metastasis
- cancer stem cells
- process when cancer cells spread from the primary site of origin to other parts of the body, forming secondary tumors.
- 90% of cancer-related deaths caused by secondary metastasis NOT primary tumour
- tumour made up of tumour cells, stromal cells, stem cells
Cancer stem cells give rise to a new tumour - Different expression patterns
What is the effect of exercising on cancer?
- If exercise after diagnosis can still improve chemo response etc
- Hard to control for in humans
- Catecholamines including epinephrine (adrenaline), and norepinephrine (noradrenaline) are significantly elevated during exercise through increased release from the adrenal glands.
- These hormones are part of the fight-or-fight response associated with increases in heart rate, blood pressure, blood glucose levels—and; immune function
Describe what happened in the Lewis lung transplant:
- exercise had a significant impact on tumour size in the transplanted Lewis lung cancer and B16 melanoma models
- NK cells were repeatedly increased in both subcutaneous and lung metastases of B16 tumours,
What are some cancers which leisure-time PA can reduce the risk of?
However, what cancer can exercise induce?
liver, kidney, lung, rectal, breast, blood myeloma, bladder, endometrial
- malignant melanoma: Increase exposure of sunlight causes increase of malignant melanoma
What are 4 ways exercise can prevent cancer in the first place?
- Sex hormones
* Reduced oestrogen in breast cancer survivors
* Indirect – via reduction in adiposity
- Counteracts progesterone effects, more balanced - Metabolic hormones
* Insulin and insulin growth factor-1 (IGF-1)
* Improved insulin sensitivity - Inflammation and adiposity
* Chronic inflammation promotes cancer - enough to drive the growth of cancer slowly
* IL-6, CRP and TNFa - Immune function
* Immunodeficiency –> increased cancer risk
* Moderate intensity exercise –> increased T cells, NK cells and neutrophils
What happens to existing cancer when we exercise?
- Effects on 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
What are exercise’s effects on tumour growth and spread?
exercised serum secreted into the blood form fewer tumours
What are exercise’s effects on chemotherapy?
- Effects on chemotherapy in patients:
- Increased vasculature – augmented treatment efficacy
More chemo into the centre of vasculature to kill off most of the cells - Enhanced drug tolerance – can withstand higher doses
Outside cells will be killed, but inside cells will survive
What are exercise’s effects on tumour metabolism - Warburg effect?
- Warburg effect during glycolysis
- Glycolysis generates energy quickly, supporting the high energy demands of rapidly dividing cancer cells.
- lactic acid through glycolysis helps maintain an acidic microenvironment, which can promote tumor invasion and metastasis. –> try to increase GLU uptake via increase GLUT 1 transporters on membrane
- Because of this cancer cells more susceptible to exercise-induced energy stress, by disrupting cancer cell metabolism
- Exercise can induce stress on cancer cells which can kill them off
What is exercise’s effect on immune response to cancer?
- Exercise mobilises cells involved in the anti-tumour immune response
- NK cells sensitive to exercise
- First immune cell type to be mobilised following acute exercise
- NK cells express more b-adrenergic receptors (receptor for catecholamines) than other immune cell types, adrenaline and nor-adrenaline bind to. More likely to pick up cells as they roam around the body, exercise associated mobilization of NK cells can be mimicked by administration of epinephrine
- epinephrine is a key molecule in the exercise associated improved tumour control by cells of the immune system.
What is the anti-tumour response to cancer when exercising?
- Patients with more NK cells and cytotoxic T cells typically have better prognosis
- Exercise mobilises NK cells and cytotoxic T cells
- Increased blood flow = shear stress on blood vessel walls –> “SOS” signals – b adrenergic signalling –> recruits immune cells and primes them to attack and destroy the cancer cells
What is the impact of exercise on immune function in cancer patients?
- Cancer patients who participated in moderate intensity exercise showed:
- Increased NK cell cytotoxic activity
- Increased lymphocyte proliferation - more T, B cells
- Increased numbers of granulocytes
- Exercise appears to be most beneficial for patients with compromised immune function, starting at lower level of immune function allows for the most benefits to be seen
Does exercise have an effect on secondary metastases?
- Yes, improves chemoresponse and recovery for survival
- Stem cells are more chemo resistant as they have adapted through mutations.
- Exercise effects on stem cell populations has no research/no relevant findings
