Exercise - cancer and MS - L5

Question 1

What is evidence based medicine?

Answer 1

The integration of the best research evidence with clinical expertise and patient values. It is the physician’s duty to find the best and most current information and apply it judicously for the benefit of the patient.

Question 2

Explain the following terms:
* therapeutic effect
* toxic effect
* ED50
* TD50

Answer 2

• therapeutic effect: the desired effect of drug administration
• toxic effect: an adverse effect of a drug administered
• ED50: the dose of a medication that produces a beneficial/desired effect in 50% of the population
• TD50: the dose of a medication that produces an adverse effect in 50% of the population

Question 3

What is the problem with treatment of cancer regarding exercise?

Answer 3

Less than 20% of cancer patient meet WHO recommendations regarding exercise, while evidence is strong that for a variety of cancers, exercise reduces the relative risk for cancer for up to 36%.

Question 4

What is cancer?

Answer 4

Mutations that are induced by physical, chemical or biological stimuli that may alter protein function preventing cells from apoptosis and increasing the risk for further mutations. It is characterized by: unregulated growth, lack of differentiation, and lack of function.

Question 5

What is the tumor microenvironment?

Answer 5

The ecosystem that surrounds a tumor inside the body. A tumor and its microenvironment can interact with each other and influence each other either positively or negatively. Usually, tumors alter their microevironment in a way that it is beneficial for tumor growth such as inhibiting tumorcompetitive lymphocytes and promoting vascular changes to provide oxygen and nutrients for the tumor.

Question 6

Name tumor characteristics that influence treatment options.

Answer 6

• Cancer type (side, mutations, immune sensitivity, etc.)
• Stage of disease (size, location, metastasis, etc.)
• Patient related conditions (age, comorbidities, etc.)

Question 7

What is meant with hot and cold tumors?

Answer 7

• Hot tumor: tumors that show signs of inflammation, meaning that the tumor has been infiltrated by T cells rushing to fight the cancerous cells. Therefore, in hot tumors, the immune system is activated.
• Cold tumor: tumors that have not yet been infiltrated with T cells. Therefore, in cold tumors, the immune system is not (yet) activated.

Question 8

Which immune cells are known to reside in the tumor microenvironment of cold tumors?

Answer 8

Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs), known to dampen the immune response and inhibit T cells.

Question 9

What effect was found for prostate cancer patients who underwent a 12 week HIIT program compared to the control group?

Answer 9

HITT increased cardiorespiratory fitness levels and decreased prostate specific antigens (PSA) levels, PSA velocity and prostate cancer cell growth in men with localized prostate cancer.

Note: not statistically significant, but major differences were found.

Question 10

What effect was found for breast cancer patients undergoing radiotherapy who did resistance exercise compared to the healthy subjects?

Answer 10

That resistance training reduced kynurenine pathway metabolites

Also found for pancreatic cancer patients

Question 11

What was found in pre-clinical animal studies on the effect of exercise on tumor growth?

Answer 11

That exercise reduces tumor growth and that the earlier animals started exercise, the better the outcome was.

Question 12

Can changes in immune cell activity/count be observed post intensive running? If yes, which cells decrease/increase after running?

Answer 12

Yes. Post intensive running is associated with an increase in granulocytes and a decrease in T cells.

Question 13

(Endurance) training is also known to increase CD8+/Treg ratio in tumor tissues. What is the effect of this CD8+/Treg ratio increase?

Answer 13

The increase in this ratio, means that more Treg cells are supressed and more CD8+ T cells are activated, resulting in increased tumor microenvironment infiltration and a more efficient immune response to the tumor.

Question 14

Acute exercise is also known to be associated with the recruitment and activation of NK cells. Describe how acute exercise can lead to NK cell recruitment and activation.

Answer 14

Acute exercise causes the release of epinephrine and IL-6. Epinephrine can mobilize NK cells to the blood stream. IL-6 enhances this process. NK cells can therefore enter the tumor tissue and aid in reduced tumor growth.

Question 15

NK cell activation as a result of exercise may be driven by altered receptor expression. Explain this statement.

Answer 15

Exercise causes epigenetic modifications (specifically acetylation) in the DNA of NK cells. This results in the translation of additional NK cell receptors that ar needed to activate the NK cell. NK cells of a patient who exercises, is thus associated with enhanced NK cell activation.

Question 16

Name other processes that are known to change with exercise (except changes in immune cell activity).

Answer 16

• Exercise may alter drug delivery
• Exercise may alter the vascular architecture in tumors
• Exercise alters systemic and local inflammation

Question 17

Name characteristics of MS.

Answer 17

• Auto-immune disase
• Most common chronic inflammatory disease of the CNS
• Demyelination of axons which can occur everywhere in the CNS
• Different disease courses
• Risk factors: jevenile adipositas, smoking, viral infections.

Question 18

What is the outside in hypothesis in MS?

Answer 18

• Chronic systemic inflammation
• Lack of BBB integrity
• Infilitration of immune cells
• Auto reactivity with CNS structures

Question 19

How does EBV infection result in MS?

Answer 19

EBV shares protein structures with components of the central nervous system. Upon infection and immune activation, the immune system is mislead to also attack its own nervous system (such as myelin). Besides this, EBV can modulate the immune system, affecting its regulation and potentially contributing to the development of MS.

Question 20

What evidence is there that exercise is beneficial for MS patients?

Answer 20

• RCTs in humans: evidence low
• Animal models: substanial evidence

Question 21

Name the indirect and direct effects of exercise on systemic inflammation and describe for the direct effects the acute and chronic effects of exercise.

Answer 21

• Indirect effects of exercise: sedentary lifestyle or obesity is associated with a Th1 response, leading to the production of IFN-y and TNF-a (Th1 cytokines) that promote the mobilization of M1 macrophages, ultimately resulting in a pro-inflammatory environment. Excess glucose in obese people enhances the mobilization of M1 macrophages.
• Direct acute effects of exercise: IL-6, TNF-R, IL-1Ra, IL-10 increase after exercise, which are cytokines known to have an anti-inflammatory effect (most also normalize over time).
• Direct chronic effects of exercise: intensity-dependent effect of chronic exercise on Treg-cell number.

Question 22

What is associated with disease progression and prognosis in MS patients and does exercise modify this?

Answer 22

The neutrophil-lymphocyte ratio (NLR) is associated with disease progression and prognosis in MS patients. Exercise, specifically HIIT, was found to reduce NLR in MS patients.

Question 22

What DNA modifying process occurs in an age-dependent manner that can be slowed down with exercise?

Answer 22

When aging, a process of demethylation of pro-inflammatory genes occurs, meaning that genes that were inactive, are activated. Exercise counteracts this age-dependent demethylation of pro-inflammatory genes.

Question 23

Does the intensity of exercise matter in neuroinflammation?

Answer 23

Yes, a study investigated the difference between moderate exercise (swimming) and high intensity exercise (swimming). Their results strongly suggest that high intensity exercise has beneficial effects in MS patients.

Question 23

Describe the kynurenine pathway in short.

Answer 23

Inflammation can trigger this pathway. Here, tryptophan is converted to kynurenine by enzymes IDO/TDO. Upon inflammation, kynurenine can be converted to quinolinic acid, which is converted to NAD+. Quinolinic acid and NAD+ are neurotoxic.
Without inflammation, kynurenine is converted to kynurenic acid with the help of KAT enzyme, which is neuroprotective and immunemodulatory.

Question 23

Does the type of exercise matter in neuroinflammation?

Answer 23

Yes. Although both strength training and endurance training are known to decrease clinical score of MS, there are profound differences in the effects of the different types of training. Here, endurance training seems to be to most efficient tool to decrease neuroinflammation.

Question 24

Explain how regular exercise increases the body’s anti-inflammatory potential.

Answer 24

• In one of the previous flashcards, it was already shown that chronic exercise is associated in an intensity-dependent manner with an increase in Treg cells. Treg cells can suppress the immune system and can thus also prevent the activation of pro-inflammatory cells.
• In the same previous flashcards, it was also shown that acute exercise stimulates the secretion of anti-inflammatory cytokines.
• The activation of the kynurenine pathway is also known to increase development of chronic diseases such as cancer or MS. Exercise is known to indirectly diminish activation of this pathway.

Question 25

Why can the kynurenine pathway be linked to exercise?

Answer 25

Because key drivers of the kynurenine pathway are inflammatory triggers such as IL-6 and IFN-y. These same inflammatory triggers for this pathway are also known to be secreted as a result of exercise. Especially endurance exercise is known to increase IL-6 and cortisol.

Question 26

Besides the fact that exercise results in the release of inflammatory triggers that activate the kynurenine pathway, describe another way how exercise aids in the prevention of the formation of toxic metabolites from the kynurenine pathway.

Answer 26

Exercise increases the transcription and translation of KATs enzyme genes in skeletal muscles. KAT enzymes enter the periphery, where kynurenine is converted into the neuroprotective kynurenic acid rather than the neurotoxic quinolinic acid.

Question 27

Explain how kynurenine can act as an immunemodulator and how kynurenic acid can act as a neuroprotector and/or an immunemodulator.

Answer 27

• Kynurenine can act as a ligand for the aryl hydrocarbon receptor (AhR). When kynurenine interacts with AhR, it translocates to the nucleus where it activates transcription and translation of AhR signature genes. Among others, these AhR signature genes have a role in stimulating CD4+ T cells to differentiate into Treg cells (rather than Th17 cells).
• Kynurenic acid can interact with the transmembrane G-protein coupled receptor 35 (GPR35), where in a signaling cascade, the nucleus is stimulated to transcribe and translate genes important for lipid metabolism, thermogenesis, and anti-inflammation. It has an important role in the regulation of adipose tissue.

Question 28

Complete the sentence.

Acute exercise activates … and promotes … differentiation by activation of the kynurenine pathway.

Answer 28

Acute exercise activates AhR and promotes Treg differentiation by activation of the kynurenine pathway.

Question 29

How does quinolinic acid act as a potent endoneurotoxin?

Answer 29

• It acts as a NMDA-R ligand, which causes overstimulation of NMDA-R. Overstimulation of NMDA-R results in pathological increases in glutamate levels.
• It is associated with decreased antioxidant enzyme activity.
• It inhibits mitochondrial complexes.
• It activates caspases.

Question 30

How does acute exercise promote neuroprotection and how does this associate to the kynurenine pathway?

Answer 30

Acute exercise decreases the availability of central kynurenine, due to the enhanced transcription and translation of KATs enzyme genes in skeletal muscles. KAT enzymes convert kynurenine to kynurenic acid, resulting in less availability of central kynurenine. Therefore, less kynurenine is available to be converted into quinolinic acid.