Cancer, defined by the National Cancer Institute (n.d), is “a disease in which abnormal cells divide without control and can invade nearby tissues”. It is estimated that in the United States of America in 2018, about 1.7 million new cases of cancer will be diagnosed and around 600,000 people will pass away because of the disease (National Cancer Institute n.d). This source also predicts that roughly 38.4% of people will be diagnosed with cancer at some point throughout their lives (NCI n.d). With these startling statistics, it is conceivable to see how much of an impact cancer has on individual lives, families, and society overall. An article written by the National Cancer Institute, states that emotions felt by cancer patients include: denial, anger, worry, anxiety, and guilt. In addition to the emotional and mental aspects of this disease, cancer also severely decreases the quality of life physically. When cancer is left untreated, patients experience serious anemia, fatigue, nausea, pain, and a weakened immune system. These effects have become less severe in patients who regularly exercise, according to observational studies; however, these studies do not have explicit evidence that directly relates
Cancer begins due to mutations in the DNA of a cell that allows for uncontrolled growth; this grows into a tumor and in order to spread and survive the tumor releases chemicals near host cells. This release of chemicals triggers tumor angiogenesis, which is the growth of new blood cells around a tumor. Tumor angiogenesis nourishes the tumor, allowing it to grow and replicate; leading to metastasis, which is the spread of cancer cells from the part of the body where they originated to other areas in the body through blood vessels or the lymph system. When cancer spreads to other areas of the body, it leads to the symptoms mentioned above; the severity of these symptoms depends on the growth and size of the metastatic tumor and the primary tumor, which is a tumor located where the cancer progression began. For example, when cancer metastasizes to the lung shortness of breath may occur; when it spreads to the brain, headaches, nausea, and dizziness may occur (NCI n.d.).
Cancer begins due to mutations in the DNA of a cell that allows for uncontrolled growth; this grows into a tumor and in order to spread and survive the tumor releases chemicals near host cells. This release of chemicals triggers tumor angiogenesis, which is the growth of new blood cells around a tumor. Tumor angiogenesis nourishes the tumor, allowing it to grow and replicate; leading to metastasis, which is the spread of cancer cells from the part of the body where they originated to other areas in the body through blood vessels or the lymph system. When cancer spreads to other areas of the body, it leads to the symptoms mentioned above; the severity of these symptoms depends on the growth and size of the metastatic tumor and the primary tumor, which is a tumor located where the cancer progression began. For example, when cancer metastasizes to the lung shortness of breath may occur; when it spreads to the brain, headaches, nausea, and dizziness may occur (NCI n.d.).
LITERATURE REVIEW
In healthy bodies, the bone marrow produces all white blood cells or lymphocytes and generates mature myeloid cells including granulocytes, which fight off pathogens including bacteria and fungus, macrophages, which detect foreign pathogens, and dendritic cells, which act as messengers for the immune system. Myeloid cells are hematopoietic stem cells found in the bone marrow. The lack of these cells in the cancer patient, due to them being unable to develop, further weakens the immune system and body. The release of pro-inflammatory chemical signals, primarily IL-6 and GM-CSF, by the tumor mentioned above contributes to the development of harmful myeloid-derived suppressor cells, known as MDSCs. MDSCs are cells of myeloid origin that are heterogeneous and comprised of myeloid progenitor cells (progenitor cells differentiate into other cells), immature macrophages, immature granulocytes, and immature dendritic cells (Talmadge and Gabrilovich n.d.). Combined, these MDSCs become very strong suppressors of T cells and their functions. T cells also are known as T lymphocytes and play a significant role in protecting the body from infection and maintaining immunity. One of the two types of T cells, known as a killer T cell or natural killer cell, is able to scan the intracellular environment for viruses and bacterium and then immediately kill these infected cells. The killer T cell also naturally eliminates cancer cells. Both jobs of the killer T lymphocyte play major roles in preventing the growth and spread of cancer, as well as maintaining the body’s immune system and preventing infection and disease. MDSCs suppress the functions of T cells by direct cell contact through the use of either cell-surface receptors or through the release of short-lived soluble mediators. MDSC are able to suppress T cells through the metabolism of L-arginine. L-arginine is a substrate for two enzymes: iNOS and arginase. MDSCs contain high levels of both arginase and iNOS which provides direct evidence of their inhibition of T cell function. iNOS uses L-arginine to produce nitric oxide. L-arginine is a protein that T cells use to proliferate, therefore when the MDSCs use up all the L-arginine, they leave less available for T cells, which in return inhibits their function. Increased production of the signaling molecule ROS, which is highly toxic, also plays a role in the suppression of T cells, as this molecule is produced in abundance after interaction between MDSCs and T cells (Ostrand-Rosenberg and Fenselau 2018).
MDSCs accumulate in patients with cancer due to chemical signals sent out by cancer cells as mentioned above. Components that lead to the development of MDSCs include cyclooxygenase-2 (COX 2), prostaglandins, stem-cell factor (SCF), macrophage colony-stimulating factor (M-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF)41, and vascular endothelial growth factor (VEGF) (Bronte et al., 2016). Pathways which induce signaling in MDSCs are triggered by most of these factors which converge on Janus kinase (JAK) protein family members and signal transducers and activators of transcription 3 (STAT3). These signaling molecules, especially STAT3, are responsible and crucial for cell survival, proliferation, differentiation, and apoptosis, which is controlled and regular cell death. Continuous activation of STAT3 in myeloid progenitors prevents their differentiation into mature myeloid cells, such as macrophages or neutrophils, and therefore increases MDSC expansion. Recently in mice expression of S100A8 and S100A9 by myeloid progenitor cells has been shown to prevent differentiation and also result in the expansion and growth of MDSCs (Ostrand-Rosenberg and Fenselau 2018).
As mentioned above, many observational studies have been conducted on the effects of exercise on patients with cancer. These studies state that exercise does, in fact, decrease symptoms of cancer including a weakened immune system in cancer patients (Pedersen et al., 2016). According to an article about the correlation between exercise and breast cancer, evidence for a risk reduction associated with increased physical activity was found in 47 out of 62 patients with an average decrease in risk of 25–30%. Also, serious decreases in risk were seen in recreational activity, lifetime or later life activity, and vigorous activity among various groups of women. (Shephard 2009). Exercise also has beneficial effects on natural killer cells and T cells. Overall, acute exercise mobilizes NK cells and T cells to the bloodstream and ultimately to the tumor, where the NK cells can diminish the spread of cancer. Also, regular exercise improves immune function by promoting apoptosis in older T cells, allowing for the generation of younger and more efficient T cells to replace them and in turn improve immune function (Pederson 2016).
The predicted outcomes for the T cell suppression assay are that the cancerous and sedentary T cells should have the least proliferation out of all the cells. The cancerous and exercised cells should have less proliferation than the control but more than the sedentary cells. And the control group without MDSC the T Cells should have the highest proliferation index. The aim of this research, as hypothesized, is to increase T cell proliferation and decrease the effectiveness of MDSCs T cell suppression through voluntary exercise in tumor-bearing mice and additionally to find direct biological evidence which proves that exercise provides physical benefits for the patient with cancer instead of relying on observational evidence.
MDSCs accumulate in patients with cancer due to chemical signals sent out by cancer cells as mentioned above. Components that lead to the development of MDSCs include cyclooxygenase-2 (COX 2), prostaglandins, stem-cell factor (SCF), macrophage colony-stimulating factor (M-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF)41, and vascular endothelial growth factor (VEGF) (Bronte et al., 2016). Pathways which induce signaling in MDSCs are triggered by most of these factors which converge on Janus kinase (JAK) protein family members and signal transducers and activators of transcription 3 (STAT3). These signaling molecules, especially STAT3, are responsible and crucial for cell survival, proliferation, differentiation, and apoptosis, which is controlled and regular cell death. Continuous activation of STAT3 in myeloid progenitors prevents their differentiation into mature myeloid cells, such as macrophages or neutrophils, and therefore increases MDSC expansion. Recently in mice expression of S100A8 and S100A9 by myeloid progenitor cells has been shown to prevent differentiation and also result in the expansion and growth of MDSCs (Ostrand-Rosenberg and Fenselau 2018).
As mentioned above, many observational studies have been conducted on the effects of exercise on patients with cancer. These studies state that exercise does, in fact, decrease symptoms of cancer including a weakened immune system in cancer patients (Pedersen et al., 2016). According to an article about the correlation between exercise and breast cancer, evidence for a risk reduction associated with increased physical activity was found in 47 out of 62 patients with an average decrease in risk of 25–30%. Also, serious decreases in risk were seen in recreational activity, lifetime or later life activity, and vigorous activity among various groups of women. (Shephard 2009). Exercise also has beneficial effects on natural killer cells and T cells. Overall, acute exercise mobilizes NK cells and T cells to the bloodstream and ultimately to the tumor, where the NK cells can diminish the spread of cancer. Also, regular exercise improves immune function by promoting apoptosis in older T cells, allowing for the generation of younger and more efficient T cells to replace them and in turn improve immune function (Pederson 2016).
The predicted outcomes for the T cell suppression assay are that the cancerous and sedentary T cells should have the least proliferation out of all the cells. The cancerous and exercised cells should have less proliferation than the control but more than the sedentary cells. And the control group without MDSC the T Cells should have the highest proliferation index. The aim of this research, as hypothesized, is to increase T cell proliferation and decrease the effectiveness of MDSCs T cell suppression through voluntary exercise in tumor-bearing mice and additionally to find direct biological evidence which proves that exercise provides physical benefits for the patient with cancer instead of relying on observational evidence.