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1Departments of Kinesiology and 2Veterinary Pathobiology, University of Illinois, Urbana-Champaign, Illinois 61801; and 3Canberra University, Canberra, Australia
Submitted 12 November 2003 ; accepted in final form 2 February 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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angiogenesis; cancer; transplant; mice
Relatively few studies have examined the role of exercise as an adjunct therapy in cancer treatment. The limited evidence does, however, suggest a beneficial role of exercise in cancer patients (8, 23, 28). Although many mechanisms have been offered to explain why exercise and physical activity are protective against certain cancers (e.g., decreased lifetime exposure to estrogen or other hormones, reduced body fat, enhanced gut motility, improved antioxidant defenses, and stimulation of anti-tumor immune defenses), none have been definitively tested (49).
Animal models have the potential to provide important mechanistic information about the influence of exercise on cancer incidence and progression (for review, see Ref. 49). Animal studies have examined the relationship between forced or voluntary exercise and the growth of transplantable, chemically induced, and/or spontaneous tumors in rodents. Many (15, 33, 39, 45), but not all (12, 47, 50), of these studies have reported some beneficial effect of exercise on tumor incidence or progression. Unfortunately, many of these studies have been descriptive in nature and have failed to examine plausible biological mechanisms as to how exercise might influence tumor growth. Moreover, few have examined the influence of exercise on the structure or composition of the tumor itself.
Neoplastic progression and regression is a complex process regulated by multiple factors such as inflammatory reactions, angiogenic growth factors, cytokines, and hormones (7). Use of the well-established EL-4 allogeneic tumor model (3–5) in this study allowed us to examine the influence of exercise on both progression and, importantly, regression of an experimental tumor. Unlike a syngeneic cancer model, the use of this tumor allowed us to examine tumor regression. In keeping with the theory that prolonged, intense exercise results in immunosuppression (26), we hypothesized that the stressful exercise applied in these experiments would lead to a more rapid progression and a slower (or no) regression of the subcutaneously implanted tumor. This hypothesis was based on the observations that stress, perhaps mediated through immunosuppression, inhibits the rejection of allogeneic tumors (20, 22, 31). Past animal studies that examined the effects of exercise on tumor progression have, in general, not examined the microenvironment of the tumor. Examination of the effects of exercise on the tumor-host interface may shed light on how exercise affects tumor growth and regression. Therefore, the purposes of this study were to 1) determine the effects of daily intense, prolonged exercise on EL-4 tumor progression and regression and 2) to examine whether this exercise paradigm influenced the composition of cells and blood vessels over the course of tumor development.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Exercise protocol. Treadmill running was the exercise mode used. This mode was selected because exercise intensity and duration could be experimentally manipulated and quantified. Mice were randomly assigned to a sedentary control group (Con) or a daily intense, prolonged exercised group (EXH). EXH exercised for 3 h or until volitional fatigue (e.g., failure to maintain pace with the treadmill) at gradually increasing speeds from 20 to 40 m/min at a 5% grade. The mean time run to exhaustion across all days was 135 ± 25 min. Mice ran without electric shock or prodding. Con were subjected to the noise of the treadmill, housed near the treadmill without food and water (during the time of the exercise bouts), and did not exercise.
EL-4 tumor cells. EL-4 cells are neoplastic lymphoid cells originally induced by 9,10-dimethyl-1,2-benzanthracene in C57/Bl6 mice (14). An allogeneic model was selected to demonstrate a complete cycle of progression and regression of a tumor. EL-4 cells (American Type Culture Collection, Manassas, VA) were cultured in 90% RPMI 1640 medium containing 9% horse serum and 1% penicillin/streptomycin/glutamine (Sigma Chemical, St. Louis, MO). The cultures were initiated at 2 x 105 cells/ml and maintained at 
1 x 105 cells/ml by passage every day. Each mouse was subcutaneously injected (in the back behind the neck) with 0.25 ml of viable 20 x 106 EL-4 cells in sterile phosphate-buffered saline immediately after the first exercise session with a sterile 25-gauge needle and 1-ml syringe.
Experiment 1. Our first experiment was designed to examine the effects of exercise on tumor growth and rejection by measuring tumor volume in Con (n = 7) and EXH (n = 8) mice. Measurement of tumor volume is a common technique used to repeatedly measure growing tumors in rodents. Tumor volume was evaluated beginning the first day the tumor was measurable (approximately day 4) and then daily before each exercise session for both EXH and Con. The tumors were measured in a blinded fashion with Vernier calipers and recorded in millimeters. Duplicate measures were taken and then averaged. Many different formulas of area and volume have been used in studies; however, the formula 
/6 x length x width x height has the highest correlation to tumor mass (40). This is the formula of an ellipsoid, which was the shape of the subcutaneous EL-4 tumors in our experiments.
Experiments 2–4. Three follow-up experiments were performed to examine the kinetic effects of exercise on tumor histology. In experiment 2, we euthanized mice on days 6–10 (n = 4 in each treatment each day). In experiment 3, we euthanized mice on days 5, 6, 8, and 10 (n = 6 in each treatment each day; except for day 7, where n = 7 for EXH). In experiment 4, we euthanized mice on days 10, 12, and 14 (n = 6 in each treatment each day). This gave us a total subject number of 6 in each group (e.g., Con and EXH) at days 5, 12, and 14; 4 in each group at days 7 and 9; 10 in each group on days 8 and 10 in Con and 11 in EXH at day 6; and 16 in each group at day 10. In these experiments, mice were euthanized by rapid CO2 asphyxiation 24 h after their last exercise bout on days 5–10, 12, and 14 after injection of EL-4 tumor cells. The animals were weighed, and tumors were removed and weighed. Tumors were divided in half for fluidcontent analysis or for histological analysis. Because differences in tumor volume can be influenced by the fluid content of the tumor and because prolonged exercise can affect hydration status, it was important to measure whether exercise affected tumor fluid volume and thus overall tumor volumes. This was done by weighing harvested wet tumors on days 5, 6, 8, 10, 12, and 14 immediately after exercise (or control) and then heating the tumors for 72 h at 40°C and measuring dry weight. The difference in weight was calculated as the tumor fluid content. For histological analysis, the tumors were fixed in 10% neutral buffered formalin for 12 h under constant gentle agitation. The fixed tissues were then stored in 80% ethyl alcohol. Tissues were dehydrated in graded alcohol, embedded in paraffin blocks, and then cut in 3-µm sections with a microtome.
Histological analysis. After staining with hematoxylin and eosin, all slides were analyzed under a light microscope in a blinded fashion by a trained observer. Verification of the results was performed by an independent blinded observer on approximately one-half of the slides for each variable assessed. There were no significant differences between the results obtained from the two different observers, and interrater reliability coefficients were high (>0.85) for all variables measured. For tumor sections from each mouse, histological parameters were measured in six predetermined areas (4 peripheral and 2 central) at x400 magnification (0.196-mm2 field of view). Cells and structures were counted in each viewing area, and the average was taken from the six viewing sites and adjusted to number per square millimeter. All hematoxylin and eosin slide results were analyzed in three separate experiments on days 5–10, 12, and 14.
Hematoxylin and eosin-stained slides were used to evaluate the number of EL-4 cells, neutrophils, macrophages, blood vessels, apoptotic bodies, mitotic figures, and necrotic area. Figure 1 shows an example of a hematoxylin and eosin-stained slide identifying many of the components assessed in this study. Briefly, any endothelial cell cluster that was clearly separate from surrounding blood vessels was considered a single blood vessel and counted. Neutrophils were counted as cells of 10–12 µm in diameter with a multilobed nucleus and containing lightly stippled, purplish azurophilic primary granules. Macrophages were counted as cells of 15–80 µm in diameter with an oval or reniform nucleus, gray-blue cytoplasm, and/or small vacuoles and occasional granules. Apoptotic bodies were counted if there was a rounding up and fragmentation of an individual cell with nuclear chromatin in a crescent formation along one edge of the intact nuclear membrane. Necrotic tissue was classified when the cytoplasm became hypereosinophilic and hyalinized, the cytoplasm became fragmented, or chromatin clumps were found in an irregular fashion with the integrity of the nuclear membrane being lost. These necrotic areas were counted by the percentage of each viewing area that was necrotic on a 1–5 scale corresponding to 1 = 0–19%, 2 = 20–39%, 3 = 40–59%, 4 = 60–79%, and 5 = 80–100%. EL-4 tumor cells were counted as large (20–80 µm in diameter) cells with irregular growth. Any cell undergoing mitosis and corresponding to a metaphase, anaphase, or early telophase figure was counted as a mitotic figure. For each mouse, tumor-infiltrating lymphocytes were assessed in six surrounding areas (not a central region) of the section of each tumor where lymphocytes are most prevalent. Any cell that was of the size 6–9 µm in diameter with a round, densely stained nucleus and a relatively small amount of pale basophilic, nongranular cytoplasm was counted as a lymphocyte.
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Immunohistochemical staining of factor VIII-associated antigen. Deparaffinized tissue sections of 3-µm thickness were stained with antibody against von Willebrand factor VIII-associated antigen (Dako, Carpinteria, CA) and counterstained with hematoxylin. Factor VIII-associated antigen-stained slides were analyzed on days 5 and 10 to verify the results of the visual determination of blood-vessel density in tumors from six mice per group at each time point.
Statistical analysis. All data are reported as means ± SE. A repeated-measures two-way (time x treatment) ANOVA was used to determine significant differences between groups for time and treatment and their interactions for tumor volume data (experiment 1; Fig. 1). The SPSS general linear model multivariate procedure was used to analyze tumor histology data from experiments 2–4 (Figs. 3, 4, 5, 6, 7 and 9, 10, 11). Significant overall multivariate effects were followed up by a series of 2 (group) by 8 (days since death) ANOVAs with Bonferroni adjust for number of tests conducted (P < 0.006 was considered statistically significant). Pearson's correlation was used to determine the relationship between the blood-vessel data obtained with visual analysis and that of immunohistochemically determined factor VIII-related antigen staining. Significance level was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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10 days to reject the tumor graft, whereas rejection occurred in 7 days in EXH (Fig. 2). Unlike other exercise studies (30, 42, 44), we found no significant differences in peak tumor volume (390 ± 96 and 409 ± 140 mm3 for Con and EXH, respectively) between groups in this study using the EL-4 tumor.
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Effects of exhaustive exercise body weight and tumor fluid volume. There were no significant differences between preexperiment (day 0) and terminal body weights for either treatment group (18.2 ± 1.5 vs. 18.6 ± 1.3 g for EXH pre- and postexperiment, respectively, and 18.1 ± 1.2 vs. 18.4 ± 1.3 g for Con pre- and postexperiment, respectively). This indicates that the EXH animals were not in an energy-deficient state relative to Con. This was important to demonstrate because nutritional energy deficits have been shown to reduce the growth of tumors in mice (19).
Exercise affects hydration status, which could have an impact on the volume of fluid within a tumor and contribute to exercise-induced changes in tumor volume. We assessed tumor fluid content by measuring the difference between wet and dry tumor weights on days 5, 6, 8, 10, 12, and 14. Although the fluid content of the tumors decreased in both groups as a function of time, there were no significant differences in the amount of fluid lost between Con and EXH. For example, on day 8, the percentage of tumor weight that was fluid was 21 ± 2.5 and 24 ± 6% for Con and EXH, respectively. This suggests that there were no exercise-induced differences in hydration (e.g., edema) in the tumors from EXH compared with Con.
Exercise-induced changes in intratumoral cellular composition. Solid tumors contain many cell types, including tumor cells and host leukocytes like inflammatory cells (macrophages and neutrophils) and tumor-infiltrating lymphocytes (usually CD8+ T lymphocytes) (2). The host cellular infiltrate influences the growth and regression of the tumor (2, 6). Therefore, we examined the density of EL-4 tumor cells, macrophages, neutrophils, and lymphocytes in tumor sections obtained from EXH and Con on days 5–10, 12, and 14 after implantation.
EL-4 cells are large lymphocytes with a distinct nuclear-to-cytoplasmic ratio easily identifiable at x400 magnification (see Fig. 1). EL-4 cells made up a large amount of the tumor volume and area in each cross section. Results of the multivariate ANOVA revealed that there was a significant time main effect, no treatment main effect, and a significant time x treatment interaction (Fig. 3). As can be see in Fig. 3, the density of EL-4 cells decreased as a function of time after implant. With regards to the interaction effect, on day 7, there was a lower EL-4 density in Con compared with EXH; however, on day 10, the pattern was reversed. There were no differences between groups on days 5–9, 12, and 14. It is important to remember that the number of EL-4 cells can be influenced by other cell types present in the cross sections and not just by the size or compactness of the EL-4 cells. In this regard, it is interesting to note that there were a significantly higher number of host lymphocytes in the tumors from the exercised mice at day 10 (Fig. 6). Their presence and the fact that these host lymphocytes kill EL-4 cells (see Refs. 4 and 5) could be the reason the number of EL-4 cells counted in the exercised group was lower than Con.
The microenvironment of a tumor is characterized by the presence of host leukocytes both in the supporting stroma and in the tumor area (25). Based on their unique morphology (see Fig. 1), we were able to distinguish and count intratumoral neutrophils and macrophages, which are two cells of the innate immune system involved in inflammation. There were significant time and treatment main effects but no interaction for both cell types. In both groups, macrophage density decreased as a function of time (Fig. 4), whereas neutrophil density increased (Fig. 5). We found consistently higher densities of macrophages (Fig. 4) and neutrophils (Fig. 5) in tumor cross sections of Con compared with EXH, especially at early time points. Post hoc analysis indicated significant differences between groups on days 5, 6, and 10 for macrophages (Fig. 4) and days 6 and 10 for neutrophils (Fig. 5).
Host lymphocytes can also be found in tumors. These cells are typically CD8+ T lymphocytes that express a memory phenotype (2). In the EL-4 model, these killer T cells are responsible for rapid tumor regression (3). We visualized T lymphocytes based on their small size and low nuclear-to-cytoplasmic ratio. Two-way multivariate ANOVA revealed a significant time main effect and a significant time x treatment interaction. Lymphocyte density increased as a function of time up to day 8–10 (peaking at the same time of largest tumor volume) and then decreased as the tumors regressed (Fig. 6). Regarding the significant interaction effect, post hoc analysis revealed lower lymphocyte densities early in tumor growth (days 5 and 7) in EXH compared with Con. This pattern reversed itself on day 10, when significantly higher lymphocyte densities were found in EXH compared with Con (Fig. 6).
Exercise reduces blood-vessel density within tumors. We evaluated blood-vessel density in tumor sections from Con and EXH mice both visually (on days 5–10, 12, and 14) and via immunohistochemistry with an antibody directed against factor VIII-associated antigen (days 5 and 10). There were significant time and treatment main effects and a significant time x treatment interaction. Blood-vessel density decreased as a function of time in both groups (Figs. 7 and 8). Post hoc analysis revealed significant differences between groups on days 6, 8, 10, and 14 (Fig. 7). Tumors from EXH consistently exhibited a 25–50% reduction in blood-vessel density compared with Con. Moreover, there was a high correlation (r = 0.969, P < 0.0001) between the visual technique for determining blood-vessel number and immunohistochemical staining for factor VIII-associated antigen.
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Effects of exercise on markers of cell proliferation and death. Mitotic figures in hematoxylin and eosin-stained slides are easily identifiable by the tangled chromosomes and dark-staining chromatin threads. Mitotic figures are used histologically to predict how extensively cells are undergoing division (36). The multivariate ANOVA revealed significant main effects for time, treatment, and an interaction. As expected, the density of mitotic figures decreased as a function of time in both groups, and levels were very low during tumor regression (Fig. 9). The treatment main effect arose as a consequence of the higher density of mitotic figures in the control group on day 5. This higher density of mitotic figures on day 5 in Con suggests a higher level of cell division in Con compared with EXH early in tumor development.
Apoptosis is generally defined as a type of genetically programmed cell death. It is one of the major mechanisms by which tissue growth is regulated and a way in which tissues are rejected. An apoptotic cell has marked nuclear and cytoplasmic condensation and fragments into multiple apoptotic bodies bound by an intact and functional plasma membrane. There were significant main effects for time, treatment, and an interaction effect. The density of apoptotic bodies decreased as a function of time in both groups (Fig. 10). However, significant group differences existed on days 6 and 10, when the density of apoptotic bodies was higher in Con compared with EXH. In contrast to apoptosis, necrosis is a pathological response to irreversible injury. There was a significant time main effect but no treatment effect or interaction. As seen in Fig. 11, necrotic area in the tumors increased as a function of time with no consistent differences observed between groups.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Many studies have found that prolonged, intense exercise or overtraining can suppress many aspects of immune function, including the development of T helper 1 responses (37, 38). This is of relevance to the present findings in that the generation of CD8+ T cells (e.g., the cells responsible for rejection of the EL-4 tumors) is dependent on proper signals (e.g., T helper 1 cytokines IL-2, IL-12, IFN-
) produced by T helper 1 cells (41). Based on our findings, it appeared that prolonged exercise in this instance had no negative effect on the ability of mice to generate an anti-EL-4 CD8+ T cell-mediated immune response and may have had a positive one. The delay in peak tumor volume was not associated with any exercise-induced changes in fluid content of the tumor or body weight loss. Consistent with the delay in tumor growth, on day 5, we found a lower number of mitotic figures (an indication of proliferation) in tumors from the exercised mice. Although not statistically significant, the apparent slower mitotic rate in the exercised group early in tumor progression may have contributed to the delay in peak tumor volume, suggesting that exercise may have slowed the progression of the tumor through some mitotic cell cycle checkpoint, such as p53 or pRB (16).
Early animal studies have reported an exercise-induced inhibition of tumor growth in transplantable tumor systems (15, 33) or tumor occurrence in chemically induced or spontaneous tumor models (13, 24, 32). Unfortunately, interpretation of these early studies is confounded by the fact that the animals were subjected to very large (e.g., 16 h/day in Ref. 33) amounts of exercise. A primary concern in the interpretation of these early data was whether exercise exerted an effect on caloric energy status; the thinking here was that tumor cells were less likely to develop or continue to grow if there was little or no excess food energy available. In the present study, we documented no exercise-induced changes in body weight relative to Con and concluded that the exercise employed in this study did not drastically affect energy status and, therefore, contribute to the delay in tumor growth.
In more recent animal studies (30, 39, 42, 44–46), more realistic exercise protocols have been utilized, and results have tended to be less dramatic in terms of reducing tumor growth compared with the earlier studies. In some instances, exercise had no effect on tumor growth (12, 47). For example, in a previous study (50), our laboratory demonstrated that moderate or exhaustive treadmill exercise, when performed during (but not before) tumor implantation, did not significantly alter the incidence or growth of a syngeneic mammary adenocarcinoma in mice. Unlike most of the studies that found significant exercise effects, in the present study, we document a delay in growth but not a significant reduction in tumor size. One reason for the differences in tumor growth between the present study and others was that, in this study, we used an allogeneic tumor.
A major finding in our study was that exercise significantly reduced (33%) the density of macrophages and neutrophils within the tumors, especially during the early stages of tumor development (days 5–7). The presence of inflammatory cells within tumors constitutes a double-edged sword. On the one hand, these cells have the capacity to kill tumor cells, inhibit their growth, and clean up debris from dying cells (2, 7). On the other hand, macrophages and neutrophils secrete growth and angiogenic factors that promote tumor growth and proliferation (2, 7). Indeed, recent evidence suggests that a high content of macrophages within breast tumors dictates a poor prognosis (21). To our knowledge, only one other study has examined the effect of exercise on macrophage content within a tumor (50). In that study, our laboratory found that moderate exercise (30 min/day) increased, whereas prolonged, exhaustive exercise (2–3 h/day) slightly decreased the content of phagocytic cells (85% macrophages and 15% neutrophils) within a transplanted syngeneic tumor. Our previous study supports the findings of the present study, despite the fact that two different tumor cell lines were used.
A tumor cannot grow beyond 2–3 mm3 without blood-vessel formation (angiogenesis), which provides oxygen and nutrients to the rapidly dividing cells. Moreover, high-blood vessel density in tumors is correlated with poorer prognosis and an enhanced potential for metastasis (17). Indeed, recent studies in cancer treatment have targeted the process of angiogenesis as a means of combating tumors. It was interesting to note that, in addition to reducing intratumoral macrophage and neutrophil content, exercise also significantly reduced tumor blood-vessel density by 25–50%. This effect was seen with both visual blood-vessel identification and immunohistochemistry against factor VIII-associated antigen (von Willebrand Factor). Based on our data, a scenario can be offered where exercise reduced the content of inflammatory cells in the tumor, which in turn reduced angiogenic growth factor levels leading to a reduction in blood-vessel density within the tumor and a delay in its growth. In agreement with other studies (43), we found a significant positive correlation of 0.59 (P < 0.001) between blood-vessel and macrophage numbers when both groups were analyzed throughout the experiment. Prolonged exercise is known to result in elevated glucocorticoid levels (51) that may act as anti-inflammatory signals to cells like macrophages inhibiting their migration into sites of inflammation (29). Future experiments are planned to dissect the relationships described above and whether intratumoral expression of angiogenic growth factors like vascular endothelial growth factor is affected by exercise. In support of this latter contention, Radak et al. (30) found vascular endothelial growth factor expression in solid leukemia tumors to be slightly (but not statistically significantly) lower in mice exposed to 1 h of swimming per day.
It was interesting to note that, even though the exercise employed in this experiment was intense and prolonged, there was no difference in the ability of the mice to reject the tumors. In fact, the tumors were rejected slightly faster in the exercised mice. This was contrary to our hypothesis that the tumors would be rejected slower or not at all. There are several factors that could be responsible for this more rapid rejection in EXH vs. Con, including lack of oxygen due to a reduction in blood-vessel density and/or a higher density of lymphocytes in the tumors at peak tumor volume. The differences in apoptosis and necrosis within the tumors suggest that alterations in tumor regression may have occurred through different mechanisms in the two groups. It is known that rejection of this EL-4 tumor corresponds to the generation of anti-EL-4 specific cytotoxic CD8+ T lymphocytes (4, 5, 18), although lymphokine-activated killer cells may also play a role (35). To our knowledge, no studies have examined the effect of exercise on the generation of antigen-specific cytotoxic T lymphocytes. In this study, we clearly show that the content of intratumoral lymphocytes increases as a function of time, peaking at time when the tumors are largest. What we do not know is whether these lymphocytes were CD8+ cytolytic T cells or lymphokine-activated killer cells. We speculate that they were cytolytic T cells and not lymphokine-activated killer cells based on their small size and lack of granules.
In conclusion, our results are the first to demonstrate that prolonged, intense exercise has an effect on the microenvironment of a subcutaneously transplanted allogeneic tumor. We found that daily intense, prolonged exercise caused a delay in tumor growth, a decrease in the number of inflammatory cells (macrophages and neutrophils), and a decrease in the number of blood vessels within the tumors. Contrary to our hypothesis, the tumors were rejected faster in EXH compared with Con. It is the decreased angiogenesis observed in EXH that may be the most significant finding in this study, perhaps accounting for the slower growth of the tumor and its rapid regression. Future experiments will examine whether angiogenic growth factors are differentially expressed in tumors from strenuously exercised mice. Moreover, we will also determine whether shorter duration, moderate exercise also impacts allogeneic tumor growth and composition.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work supported by National Institute on Aging Grant AG-13928 (to J. A. Woods).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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