Characterized by abnormal, uncontrollable cell growth resulting from critical mutations in DNA, cancer becomes malignant when the primary tumor metastasizes, spreading to form new tumors and further disrupting the body’s natural processes and functions (3). These cancerous cells are able to thrive while endangering the life of the tumor-bearing individual by working with the individual’s own body. Ignoring signals that command apoptosis, cancer cells influence their microenvironment to foster the growth of the tumor by inducing nearby normal cells to form blood vessels and supply the tumor with excess oxygen and nutrients (3). Through their interactions with specific lymphocytes, cancer cells can also manipulate the immune system into defending the growth of a tumor and prevent the immune system from attacking these cells (3).
The immune system comprises various lymphocytes responsible for identifying and eliminating antigens. B and T cells circulate between blood and lymphoid tissues to monitor protein markers present on the surface of each cell. The recognition of an abnormal antigen releases signaling molecules such as interleukins and cytokines that activate B cells or stimulate specific subtypes of T cells. B lymphocytes produce antibodies intended to interlock with the antigen and thereby mark the antigen for destruction. T lymphocytes can destroy targeted cells on direct contact, as well as signal other cells to direct and regulate immune responses (15).
T cells can be primarily classified into cytotoxic T cells, helper T cells, and regulatory T cells. Cytotoxic T cells kill cells that are foreign, infected, or cancerous. Helper T cells direct the immune response of B cells and other T cells. Regulatory T (Treg) cells suppress the immune system to modulate self-reactive lymphocytes (3). Newly formed, immature lymphocytes in the central lymphoid organs are induced to either alter their receptors in the presence of self-antigens or undergo apoptosis. However, mature lymphocytes that have migrated to peripheral lymphoid organs, if not inactivated or terminated, must be suppressed by Tregs in order to prevent autoimmune disease (15).
Treg cells work to maintain immune homeostasis so that other lymphocytes do not damage healthy tissue, yet this very process can aid the progression of cancer in a tumor-bearing individual. Though the primary function of Foxp3-expressing Treg cells is to inhibit immune response against self-antigens, in tumor-bearing individuals, they have been found to subdue the anti-tumor immune response and induce tumor-specific local immune tolerance (5). Moreover, the tumor cells specifically recruit and direct Tregs to impede antitumor immunity in the tumor microenvironment.
Recent studies have found increased counts of CD4+CD25+ Treg cells relative to the total T cell population in the tumor tissues of several cancers including lung, breast, ovarian, liver, pancreatic, and gastrointestinal (9,16). Furthermore, elevated levels of Treg cells among tumor-infiltrating lymphocytes in tumor tissues have been linked with poor prognosis in cancer patients (9,17). Due to the role played by Treg cells in contributing to tumor growth, greater quantities of Treg cells at the site of the tumor inhibit the body’s anti-tumor immune response to a greater extent. Therefore, depletion of Treg cells should augment anti-tumor immune responses (17).
Removal of Tregs has improved endogenous antitumor immunity and the efficacy of active immunotherapy in numerous models (17). In a syngeneic intracranial glioblastoma mouse model, systemic depletion of Treg cells 15 days after tumor implantation resulted in improved long-term survival. In a highly metastatic breast cancer model, lung metastasis was prevented through the depletion of Treg cells (18). Extending this research to humans has shown the depletion of Tregs to be an effective treatment strategy for various cancers (10).
Exercise has been shown to have a considerable impact on the immune competence, lymphocyte populations, and lymphocyte proliferative response. In addition to mitigating the adverse effects of invasive treatment such as chemotherapy, exercise regulates and deters tumor growth and reduces the risk of primary cancer development, cancer recurrence, and cancer mortality (11). With regard to the effects of cancer treatment, exercise was reported to improve mobility, functional capacity, muscular strength, body weight and composition, and flexibility, as well as help manage symptoms such as fatigue, nausea, diarrhea, pain, anxiety, rigor, anger, mood, self-esteem, and depression, causing a decrease in side effects and symptoms (11).
In a study of Wistar rats, the tumor growth of intensely exercised rats was compared with that of extremely confined rats. The weights of tumors of the restricted group were considerably larger than those of the active rats, and it was noted that some of the exercised animals experienced complete tumor regression (14). Another study found a 60% reduction in tumor incidence and growth among voluntary-exercised rats (19).
A collection of studies, a positive correlation between the level of exercise and the reduction of risk was present in 80% of the studies concerned with the relationship between breast cancer risk and physical activity. With an average reduction of risk by 25%, the association between physical activity and risk of breast cancer was categorized as convincing by the International Agency for Research on Cancer. Results also linked higher physical activity with lower rate of breast and colon cancer recurrences (12).
The effect of exercise on the prognosis of cancer has been consistent throughout various studies. Evidence from 27 observational studies associated physical activity with reduced all-cause, breast cancer-specific, and colon cancer-specific mortality (13). In another meta-analysis, 75% of the studies demonstrated a significant inverse relationship between exercise and prognosis with a range of risk reduction between 15% to 67% and 18% to 67% for cancer-specific mortality and all-cause mortality, respectively (13). These studies suggest that physical activity has a substantial influence over the risk of cancer incidence, recurrence, and mortality, and contributes to regulating tumor growth and inhibiting cancer progression.
The immune system comprises various lymphocytes responsible for identifying and eliminating antigens. B and T cells circulate between blood and lymphoid tissues to monitor protein markers present on the surface of each cell. The recognition of an abnormal antigen releases signaling molecules such as interleukins and cytokines that activate B cells or stimulate specific subtypes of T cells. B lymphocytes produce antibodies intended to interlock with the antigen and thereby mark the antigen for destruction. T lymphocytes can destroy targeted cells on direct contact, as well as signal other cells to direct and regulate immune responses (15).
T cells can be primarily classified into cytotoxic T cells, helper T cells, and regulatory T cells. Cytotoxic T cells kill cells that are foreign, infected, or cancerous. Helper T cells direct the immune response of B cells and other T cells. Regulatory T (Treg) cells suppress the immune system to modulate self-reactive lymphocytes (3). Newly formed, immature lymphocytes in the central lymphoid organs are induced to either alter their receptors in the presence of self-antigens or undergo apoptosis. However, mature lymphocytes that have migrated to peripheral lymphoid organs, if not inactivated or terminated, must be suppressed by Tregs in order to prevent autoimmune disease (15).
Treg cells work to maintain immune homeostasis so that other lymphocytes do not damage healthy tissue, yet this very process can aid the progression of cancer in a tumor-bearing individual. Though the primary function of Foxp3-expressing Treg cells is to inhibit immune response against self-antigens, in tumor-bearing individuals, they have been found to subdue the anti-tumor immune response and induce tumor-specific local immune tolerance (5). Moreover, the tumor cells specifically recruit and direct Tregs to impede antitumor immunity in the tumor microenvironment.
Recent studies have found increased counts of CD4+CD25+ Treg cells relative to the total T cell population in the tumor tissues of several cancers including lung, breast, ovarian, liver, pancreatic, and gastrointestinal (9,16). Furthermore, elevated levels of Treg cells among tumor-infiltrating lymphocytes in tumor tissues have been linked with poor prognosis in cancer patients (9,17). Due to the role played by Treg cells in contributing to tumor growth, greater quantities of Treg cells at the site of the tumor inhibit the body’s anti-tumor immune response to a greater extent. Therefore, depletion of Treg cells should augment anti-tumor immune responses (17).
Removal of Tregs has improved endogenous antitumor immunity and the efficacy of active immunotherapy in numerous models (17). In a syngeneic intracranial glioblastoma mouse model, systemic depletion of Treg cells 15 days after tumor implantation resulted in improved long-term survival. In a highly metastatic breast cancer model, lung metastasis was prevented through the depletion of Treg cells (18). Extending this research to humans has shown the depletion of Tregs to be an effective treatment strategy for various cancers (10).
Exercise has been shown to have a considerable impact on the immune competence, lymphocyte populations, and lymphocyte proliferative response. In addition to mitigating the adverse effects of invasive treatment such as chemotherapy, exercise regulates and deters tumor growth and reduces the risk of primary cancer development, cancer recurrence, and cancer mortality (11). With regard to the effects of cancer treatment, exercise was reported to improve mobility, functional capacity, muscular strength, body weight and composition, and flexibility, as well as help manage symptoms such as fatigue, nausea, diarrhea, pain, anxiety, rigor, anger, mood, self-esteem, and depression, causing a decrease in side effects and symptoms (11).
In a study of Wistar rats, the tumor growth of intensely exercised rats was compared with that of extremely confined rats. The weights of tumors of the restricted group were considerably larger than those of the active rats, and it was noted that some of the exercised animals experienced complete tumor regression (14). Another study found a 60% reduction in tumor incidence and growth among voluntary-exercised rats (19).
A collection of studies, a positive correlation between the level of exercise and the reduction of risk was present in 80% of the studies concerned with the relationship between breast cancer risk and physical activity. With an average reduction of risk by 25%, the association between physical activity and risk of breast cancer was categorized as convincing by the International Agency for Research on Cancer. Results also linked higher physical activity with lower rate of breast and colon cancer recurrences (12).
The effect of exercise on the prognosis of cancer has been consistent throughout various studies. Evidence from 27 observational studies associated physical activity with reduced all-cause, breast cancer-specific, and colon cancer-specific mortality (13). In another meta-analysis, 75% of the studies demonstrated a significant inverse relationship between exercise and prognosis with a range of risk reduction between 15% to 67% and 18% to 67% for cancer-specific mortality and all-cause mortality, respectively (13). These studies suggest that physical activity has a substantial influence over the risk of cancer incidence, recurrence, and mortality, and contributes to regulating tumor growth and inhibiting cancer progression.