# Exercise as it relates to Disease/Effects of Exercise on Colon Cancer Metastasis

Colon cancer, also known as Colorectal cancer, is the second-leading cause of cancer related mortality in the USA. Due to the poor prognosis of metastatic colorectal cancers it is important to look into prevention of angiogenesis and metastasis of tumours. Exercise is known to reduce the risk factors involved in developing colorectal cancers, and now new studies in metastatic triggers and the systemic effects of exercise have shown that exercise has beneficial effects on lowering the risk of cancer progression.

## Background
### Colon Cancer

Colon cancer is the 4th highest cause of cancer-related morbidity world wide, and is most prevalent in developed countries. Modifiable risk factors of the disease include smoking, physical inactivity and obesity, excess red meat consumption, and excessive alcohol consumption. Genetics has a key role in a person's predisposition to colon cancers and the nature of the cancer's progression. Research into the genetic link of colorectal cancers has become a leading source of information in the understanding of genetics and cancer.

### Colon Cancer Prognosis

| Grade | Description | 5 year Survival Rate |
| l | Mucosa Infiltrated. No lymph node involvement or Metastasis | 74% |
| llA | Outermost Layers of Colon/Rectum infiltrated. No lymph node involvement or Metastasis | 67% |
| llB | Colon/Rectum infiltrated. No lymph node involvement or Metastasis | 59% |
| llC | Colon/Rectum infiltrated as wel as local attachment to tissue/organ. No lymph node involvement or Metastasis | 37% |
| lllA | Mucosa Infiltrated. Lymph Node involved. No Metastasis | 73% |
| lllB | Outer Most Layer Colon/Rectum Infiltrated. Lymph Node and Lymph node adipose involvment. No Metastasis | 46% |
| lllC | Outer Most Layer Colon/Rectum Infiltrated, local tissue/organ attachment. Lymph Node and Lymph node adipose involvment. No Metastasis | 28% |
| lV | Cancer Metastasis to 1 or more distant organs/lymph nodes or to to distant parts of the peritoneum | 6% |
Results taken from SEER, premier source for cancer statistics in the US, 1998-2000 data.

### Colorectal Cancer and Physical Activity

The risk of developing colorectal cancer has been found to be inversely associated with levels of leisure-time and housework related physical activity. It has also been found that the population attributable risk, which is the proportion of positive diagnoses that would be avoided if those considered high risk (less than 30 minutes of physical activity per day) changed their lifestyle to be considered low risk (more than 30 minutes of physical activity per day), is just under 10%.
Body mass index, as well as relative body weight, both of which are closely linked to levels of physical activity, have been shown to be associated with greater risk of developing colorectal cancer. Physical activity levels maintain an inverse relationship with risk of colorectal cancer over a range of BMI values.

### Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a known angiogenic factor that induces migration and proliferation of vascular endothelial cells. VEGF levels have shown to have roles to both normal blood cell development and pathogenic blood cell development, aiding in the angiogenesis of tumours. Exercise induces increased VEGF production due to muscle hypoxia. In some resistance exercises, VEGF mRNA is upregulated by about 3.5 fold for at least 6 hours after exercise, with circulating VEGF returning to baseline levels between 6–24 hours post activity. Research has found plasma VEGF levels do not increase due to chronic exercised-induced muscle hypoxia. Disease-related angiogenesis caused by VEGF allows the metastasis of tumors, which significantly decreases survival rates in colorectal cancer sufferers in a 5 year prognosis. The pathogenic role of VEGF is recognised in breast cancer, rheumatoid arthritis and diabetic retinopathy, and VEGF plasma and serum levels are also seen to be highly elevated in colorectal cancer patients. VEGF is found in both serum and plasma, with levels of both associated with platelet numbers, due to platelets being carriers for VEGF. Consequently, elevated platelet numbers can be markers for disease and the risk of adenomas progressing to carcinomas.

## Theory of Exercise Reducing the Risk of Colon Cancer Metastasis

Exercise (with proper nutrition) helps manage adipose tissue levels. Adipose tissue is an active endocrine organ and produces inflammatory mediators, one of which is VEGF. VEGF levels have shown to be increased in obese populations, with higher adipose tissue expression of VEGF during fat cell hypertrophy, due to its effect of vascular bed expansion (within adipose cell tissue). Platelet aggregation and concentration correlate with plasma VEGF levels and are markers for disease. Physical activity is significantly inversely associated with several hemostatic and inflammatory variables, including blood platelet concentration. Evidence also shows that sedentary individuals have higher platelet adhesion and aggregation, increasing their risk of disease. Fibrinogen, a blood plasma protein, is also found to increase with inactivity, and decrease in concentration with exercise. Fibrinogen causes the aggregation of VEGF, and VEGF binds to Fibrinogen and stimulates endothelial cell proliferation. Aggregation of VEGF is found in pathologic vascular growth, and Fibrinogen's role in allowing adenoma to progress to carcinomas is already recognised in colorectal disease.

### Supporting Studies

A 2010 study from Washington University School of Medicine collected data from national registries regarding Physical Activity and Colon Cancer Incidence and Mortality. The ten year analysis included 1,863 incident and 826 fatal cases, showing that consistently high physical activity levels over 10 years was associated with a decreased risk of colon cancer mortality. A 2012 study by the University of Waterloo examined the effects of chronic exercise on inflammatory mediators expressed in the intestine of older, (15–16 months) healthy mice. Animals underwent 4 months of freewheel running, or were in the sedentary control group. The active mice had lower expressions of inflammatory cytokines and apoptopic proteins compared to sedentary controls within the intestine.

## Recommendations

* Further research should be conducted into the significance of exercise in lowering circulating levels of VEGF.
* Research into exercise prescription for those at higher risk of developing colorectal cancer (such as genetically predisposed, obese, and sedentary individuals).
* Research into exercise as an intervention strategy for low grade colorectal patients to help combat the progression of the cancer into its higher stages.

## Further reading

* Vascular endothelial growth factor
* Bowel & Cancer Research
* Genentech USA (Roche Group) VEGF Research

## References

* ↑ Wang, D and DuBois, R. 2007. Inflammatory Mediators and Nuclear Receptor Signaling in Colorectal Cancer. Cell Cycle. 6 (6): 682-685
* ↑ Jemal, A. Bray, F. Center, M. Ferlay, J. Ward, E. Forman, D. 2011. Global Cancer Statistics. Cancer Journal for Clinics, 61(69); 96-90
* ↑ Chapelle, A. 2004. Genetic Predisposition to Colorectal Cancer. Nature Reviews: Cancer, 4:769-780
* ↑ American Cancer Society: Colorectal Cancer. 2012. [Online] Available at <www.cancer.org/Cancer/ColonandRectumCancer. [Accessed 17 September 2012]
* ↑ Slattery, M. L., Edwards, S. L., Ma, K., Friedman, G. D., Potter, J. D. 1997, 'Physical Activity and Colon Cancer: A Public Health Perspective', Annals of Epidemiology, vol. 7(2), pp.137-145
* ↑ Larsson, S. C., Rutegard, J., Bergkvist, L., Wolk, A 2006, 'Physical Activity, Obesity, and Risk of Colon and Rectal Cancer in a Cohort of Swedish Men', European journal of Cancer, vol. 42, pp. 2590-2597
* 1 2 Fantuzzi, G. Mazone, T. eds., 2007. Adipose Tissue and Adipokine in Health and Disease. Human Press Inc, Totowa, USA, pp76-90
* ↑ Stefanini, M. Wu, F. Mac Gabhann, F. Popel, A. 2008. A Compartment Model of VEGF distribution in blood, healthy and diseased tissue. BMC systems and Biology, 2:77
* ↑ Morici, G.Bonanno,A. Licciardo, A. Vali, G. Passino, C. Bonardo, D. Fasano, V. Agnesi, M. Bernardi, L. Chimenti, L. Benigno, A. Cogo, A. Bonsignore, M. 2010. Plasma Leptin and VEGF Levels After Maximal Exercise at High Altitude. Acta Physiologica, 200:123
* ↑ Peterson,j. Zurakowski,D. Italiano, J. Michel, L. Coners, S. Oenick, M. D'Amato, R. Klemet, G. Folkman, J. 2012. VEGF, PF4 and PDGF are elevated in Platelets of Colorectal Cancer Patients. Angiogenesis, 15(2): 265-273
* ↑ Vireira, V. Valentine, R. 2009. Mitochondiral Biogenesis in Adipose Tissue. Journal of Physiology, 587(14):3427-3428
* ↑ Wannamethee, S. Lowe, G. Whincup, P. Rumley, A. Walker,M. Lennon, L. 2002. Physical Inactivity and Haemostatic and Inflammatory Variables in Elderly Men. Clinical Investigation and Reports, 105:1780-1790
* ↑ Booth, F. Chakravarthy, M. Gordon, S. Spangenburgm E. 2002. Waging War on Physical Inactivity: Using Modern Molecular Ammunition Againt an Ancient Foe. Journal of Applied Physiology, 93:1-28
* ↑ Ernst, E. 1993. Regular Exercise Reduces Fibrinogen levels: a Review Longitudinal Studies. Britain Journal of Sports Medicine, 97:175-176
* ↑ Sahni, A. Francis, C. VEGF Binds to Fribrinogen and Fribrin stimulates endothelial cell proliferation. Journal of American Society of haematology, 96(12): 3772-3778
* ↑ Ropponen, K. Tammi, M. Parkkinen,J. 1998. Tumor Cell Asccociated Hyaluronan as an Unfavourable Prognastic Factor in Colorectal Cancer. Cancer Research, 58:342-347
* ↑ K. Y. Wolin, A. V. Patel, P. T. Campbell, E. J. Jacobs, M. L. McCullough, G. A. Colditz, S. M. Gapstur. Change in Physical Activity and Colon Cancer Incidence and Mortality. Cancer Epidemiology Biomarkers & Prevention, 2010; 19 (12): 3000
* ↑ Packer, N. Hoffman-Goetz, L. 2012.Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice. Canada Journal of Ageing, 31(2):161-71