The goal of this study was to identify differential changes in biological marker profiles for insulin and cytokines in subjects who were randomized to a integrative medicine TCC intervention compared to a PST control, and to identify novel correlative relationships between insulin and insulin-related molecules, cytokines, and fat and fat-free mass. Of the insulin and insulin-related proteins and cytokines assessed for group differences at post-intervention (), only insulin showed a change that was significant. Levels were stable and within normal range in the TCC group but almost doubled in the PST group over the 12-week intervention period to a level that would be considered high. The increase in insulin in the non-exercising (PST) group and the stabilized levels of insulin observed in the TCC group in our study are consistent with reports from others who prospectively measured insulin levels in breast cancer survivors undergoing an exercise intervention (21
). We hypothesize that the increases in insulin in the PST group may be related to increases in weight and BMI observed in that group but not in the TCC group; however, further study would be needed to assess this.
Because the TCC intervention led to stable levels of insulin over the 12-week period, this mind-body intervention with a physical activity component may represent an effective intervention to maintain stable insulin levels in breast cancer survivors, much like conventional exercise programs. Maintenance of stable insulin levels appears to be very important in view of recent research showing that increased insulin levels are associated with increased recurrence risk and reduced survival in breast cancer survivors (8
This study revealed novel patterns in the relationships between changes in IL-6, IL-2, fat mass and fat-free mass, particularly those observed in the TCC group. We believe the positive correlation of changes in IL-6 and fat-free mass and inverse correlation of changes in IL-6 with fat mass, associations that are observed most strongly in the TCC group, might be indicative of physical activity-mediated changes in cytokines that are beneficial for maintenance of a healthy body weight in breast cancer survivors.
IL-6 is a pleiotropic molecule that has both pro- and anti-inflammatory effects that may be related to the cellular source of production. In clinical studies, higher circulating levels of IL-6 have been identified in those diagnosed with breast cancer than in healthy individuals (38
). IL-6 secreted from adipose tissue has been implicated in promoting invasion of breast cancer cells (39
), and in a chronic inflammatory setting, IL-6 may be secreted by T-cells leading to growth factor expression that may promote survival of tumor cells (40
In the presence of physical activity, paradoxically, circulating IL-6 is markedly increased (41
) and, at these levels, IL-6 can elicit anti-inflammatory effects due to its secretion from muscle (42
). In our study, we believe that the elevated IL-6 levels are a marker of the positive effects of TCC on fat-free mass. At this point, we are unsure whether TCC-induced IL-6 is a mediator that contributes or a responder that reflects fat reduction, and whether it may have direct anti-inflammatory effects on risk of recurrence. However, it is biologically plausible that TCC, which has both physical activity and meditative properties and can elicit similar positive effects on physical function as more traditional exercise programs, can dampen the pro-inflammatory state associated with cancer progression by increasing fat-free mass and reducing fat mass. Ultimately, we are interested in whether the association of IL-6 with lean body mass in breast cancer survivors produced by TCC could be a link between a healthy body weight and reduced risk of disease recurrence, a focus of future studies. We are also interested in whether the changes elicited by TCC are due to physical activity components, meditative components, or both.
Similar patterns of associations for IL-2, fat-free mass, and fat mass were observed herein as were observed for IL-6, which may indicate another mechanism of physical activity-mediated changes that are beneficial for maintenance of a healthy body weight. IL-2 is produced by T cells as a necessary proliferative factor; these cells accumulate in adipose tissue (43
) and likely play a role in the inflammatory response within this tissue (44
) and may ultimately promote tumor progression. Physical activity, therefore, by increasing fat-free mass and reducing fat mass may lead to reduced adiposity, leading to reduced accumulation of T cells within adipose tissue and lower levels of IL-2, which may ultimately lower the likelihood of tumor progression.
We found a positive correlation between changes in insulin and IFN-γ levels in the PST group; both insulin and IFN-γ increased in this group but remained relatively stable in the TCC group. Another study that assessed the effects of TCC on immune function found that TCC can enhance production of CD4+CD25+ regulatory T cells (45
) which could mitigate IFN-γ production from inflammatory T cells in adipose tissue, thus providing another possible explanation for the difference in IFN-γ expression between groups. In a recent animal study of diet-induced obesity, IFN-γ promoted inflammation in adipose tissue and promoted insulin resistance (46
), which provides a rationale for the positive correlation of IFN-γ and insulin observed in our non-exercising group. Further studies are needed to determine whether the correlation of IFN-γ and insulin is causal.
Based upon these preliminary data and the pertinent literature, we propose a model () whereby physically inactive breast cancer survivors will have a higher inflammatory status mediated by factors such as IL-2, IFN-γ, and TNF-α that are produced by T-cells, macrophages, and adipocytes. This inflammatory environment may directly enhance abnormal cellular proliferation which may increase weight gain and the risk of recurrence. Additionally, inflammation might promote insulin resistance and increased levels of insulin and IGFs in the blood that drive abnormal cellular proliferation and ultimately affect recurrence. We hypothesize, further, that the physical activity component of the TCC intervention could reduce the inflammatory state in breast cancer survivors through muscle release of IL-6, thus promoting anti-inflammatory processes and lowering insulin and IGF levels, which would maintain normal cellular proliferative processes, maintenance of a healthy body weight, and a reduced the rate of cancer recurrence.
The major limitation of this study is small sample size; all conclusions from these data are preliminary. Even though we had a small sample size in this pilot study, we were able to detect a significant main effect of TCC on insulin levels. Higher powered confirmatory studies will allow for more precise determination of TCC-mediated effects on insulin and other biomarkers assessed in this study. Such studies should also assess the influence of menopausal status, pre-morbid weight (e.g. obesity), other co-morbid conditions and medication usage on these markers. Also, we did not follow the study subjects for long enough to obtain adequate recurrence information for correlation with biological markers assessed. We did not use a criterion gold standard for body composition such as hydrostatic weighing or dual-energy x-ray absorptiometry; given the positive findings of this study, future studies should incorporate a gold standard. Additional studies should also include a measure of overall muscle strength. We were concerned about exercise contamination in this study; however, we previously reported that only 20% of the PST group reported increasing their level of exercise, whereas 100% of the TCC group reported exercise due only to the intervention (34
). Future studies should include daily exercise diaries to more accurately reflect dose and intensity of any exercise. Lastly, our results pertain only to breast cancer survivors; studies of the effects of TCC in other cancer populations are needed.
A major strength of this study is our preliminary identification of a significant difference in post-intervention levels of insulin between TCC and PST groups; this difference suggests that the unique mind-body intervention, TCC, has a similar effect on insulin in breast cancer survivors as do traditional exercise regimens, making TCC a possible attractive alternative intervention. Furthermore, we identified novel relationships between cytokines, insulin, insulin-related molecules, and body composition that may explain the biological effects of our yang-style TCC intervention in breast cancer survivors. Future studies should investigate the relationships between these biological markers and recurrence rates in breast cancer survivors in a larger randomized controlled trial with a TCC intervention.