Affiliations of authors: M. E. Martínez, D. Roe, J. R. Marshall, Arizona Cancer Center and Arizona Prevention Center, University of Arizona, Tucson; D. Heddens, C. L. Bogert, J. Einspahr, Arizona Cancer Center, University of Arizona; D. L. Earnest, D. S. Alberts, Arizona Cancer Center and Department of Medicine, University of Arizona.
Correspondence to:María Elena Martínez, Ph.D., Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724 (e-mail: emartinez{at}azcc.arizona.edu).
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ABSTRACT |
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INTRODUCTION |
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Several biologic mechanisms have been proposed for the inverse association between physical activity and colon cancer (8); these include a decrease in bowel transit time, alteration of immune function, decreased bile acid metabolism, and, more recently, insulin resistance (9,10). An additional mechanism by which physical activity may protect against colon cancer is through an effect on prostaglandin levels, which are thought to be related to the development of colon cancer and adenomas. Increased prostaglandin production, particularly of the E series, has been reported in human colonic tumor cells in both humans and experimental models (11-14). It has also been shown that individuals with colorectal polyps or cancer have higher levels of colonic mucosal prostaglandin E2 (PGE2) than control individuals (15). Moreover, increased prostaglandin production by tumors has been associated with aggressive tumor progression (16). Support for this mechanism is also derived from human studies in which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of prostaglandin synthesis, reduce risk of colorectal cancer and adenomas (17-19), presumably through the inhibition of cyclooxygenase (COX-1 and COX-2), key enzymes involved in the synthesis of prostaglandins from arachadonic acid (20).
Given the biologic plausibility and the need to understand mechanisms by which physical activity and obesity might alter risk of colon cancer, we investigated whether higher levels of leisure-time physical activity or a lower BMI was associated with lower concentrations of PGE2 in rectal mucosa.
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SUBJECTS AND METHODS |
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The analysis was conducted among participants in a randomized clinical trial testing the effects of piroxicam on rectal mucosal PGE2. Eligible for the study were male and female individuals, aged 40-80 years, living in the Tucson metropolitan area, with removal of one or more adenomatous colorectal polyp(s) within the previous 6 months, no history of invasive cancer within 5 years, no severe metabolic disorders or other life-threatening acute or chronic diseases, and no additional radiation therapy or chemotherapy anticipated. Individuals were ineligible if they used aspirin or other NSAIDs or had adverse effects to these agents, had a history of a gastric or duodenal ulcer within 12 months prior to entry in the trial, or had a colon resection of greater than 40 cm or of the ileocecal valve. Height and weight were obtained from baseline measurements. Weight in kilograms was divided by the square of height in meters to calculate BMI. Only participants who provided rectal biopsy specimens at visits 1 and 2 prior to randomization were included in the analyses. The study was approved by the University of Arizona Human Subjects Committee. Written informed consent was obtained from all participants.
Physical Activity Questionnaire
Physical activity was assessed through a self-administered questionnaire collected at baseline that targeted the previous month. The questionnaire was a modified version of the Minnesota Leisure Time Physical Activity Questionnaire (21), which has been previously evaluated for reliability and validity (22,23). Although total daily activity was surveyed, a priori-only leisure-time activities, yardwork, and housework were considered for the present analyses. Participants reported the frequency and average time spent for leisure-time, yardwork, and housework activities. The overall missing data for leisure-time activities were less than 1%, and they applied to questions relevant to frequency and time spent in each activity. However, for housework and yardwork activities, the missing rate was higher (11%). Therefore, these activities were dropped from subsequent analyses. Given the high degree of completeness for leisure-time activities, we decided to focus only on these activities. The reported time spent at each activity per week was multiplied by its typical energy expenditure requirements expressed in metabolic equivalents (METs) (24) and added together to yield a MET-hours per week score. One MET, the energy expended sitting quietly, is equivalent to 3.5 mL of oxygen uptake per kilogram of body weight per minute for a 70-kg adult. We used the following MET values for each of the activities: walking, 3; walk/jog combination, 6; jogging, 7; climbing stairs, 8; bicycling, 4; dancing, 4.5; aerobic exercise, 6; home calisthenics, 4.5; health club exercise, 5.5; swimming, 8; water aerobics, 6; bowling, 3; golf (riding cart), 3.5; golf (walking, clubs on cart), 4.5; golf (walking and carrying clubs), 5.5; tennis singles, 8; and tennis doubles, 6.
PGE2 Analyses
Methodology for PGE2 analysis for this study was performed as previously described (25). Briefly, after the sigmoidoscope was inserted into the rectum, four biopsy specimens were taken perpendicular to the mucosal surface from the upper half of the rectum. Samples were placed in cryovials containing aqueous indomethacin and snap-frozen in liquid nitrogen. Tissue was later thawed and homogenized in an indomethacin buffer. Protein determination aliquots were taken, and extraction of sample was performed. The [125I]PGE2 radioimmunoassay kit (Du Pont NEN, Boston, MA) was used to determine the PGE2 content in the extracted tissue, made up of one or two biopsy samples. Two sets of rectal biopsy samples, taken 8 weeks apart at visits 1 and 2 prior to randomization, were used in the analyses.
Statistical Analysis
Summary statistics were computed for the explanatory variables of age, BMI (kg/m2), total time spent on activities (hours per week), and MET-hours per week, and the dependent variables of PGE2 concentrations in rectal mucosa measured at visit 1 and visit 2 before randomization into the clinical trial. All variable distributions, except for age, were skewed and, therefore, were log (natural) transformed before analyses. Shapiro-Wilk statistics were computed to test for the normality of the untransformed and transformed variables (26). Associations among the variables were measured by use of the Pearson correlation coefficient. PGE2 concentration was modeled as a function of age, sex, BMI, and MET-hours per week by use of a maximum likelihood repeated measures model, with visits one and two as the repeated factor (26).
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RESULTS |
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DISCUSSION |
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The positive correlation of PGE2 with BMI and the negative correlation with physical activity are intriguing. The mechanism by which BMI and activity levels might affect PGE2 levels in the rectal mucosa is uncertain. One factor that is correlated in the same direction with these variables is insulin resistance (9). It has been shown that physical activity lowers insulin levels by increasing insulin sensitivity (30,31) and abdominal obesity is directly related to insulin resistance and hyperinsulinemia (32,33). Insulin is an important growth factor for colonic mucosal cells and colonic carcinoma cells in vitro (34-36). Prostaglandins of the E series are also capable of stimulating insulin secretion (37,38), and this effect is thought to be mediated through cyclic-adenosine monophosphate (cAMP) (37). In addition, in various cell cultures, it has been shown that insulin-like growth factor-I (IGF-I) synthesis is regulated by PGE2 as well as other agents that stimulate cAMP (39-41). It is unclear whether BMI or physical activity could directly influence rectal mucosa PGE2 concentrations. It is possible that the risk-enhancing effect of BMI and activity levels on PGE2 is mediated through insulin or IGF-I synthesis or that PGE2 serves as a marker of insulin levels.
One limitation of the present study is that assessment of physical activity was based on a self-reported questionnaire that has not yet been validated in this population. However, the leisure-time activities used in our study are nearly identical to those in an existing, validated questionnaire that has been used to document a significant inverse association between leisure-time physical activity and colon cancer and adenoma in the Health Professionals Follow-up Study (2) and the Nurses' Health Study (1). Although the results of the validation studies in these two populations indicate that this activity questionnaire is valid and reliable, when compared with the average of four, 7-day activity diaries recorded over a 1-year period (42,43), its substantial imprecision suggests that it could underestimate the impact of physical activity on PGE2 levels. Our activity questionnaire assessed only the previous month. Although we conclude that there was no significant variation in activity levels by month of the year, we cannot be certain that this is representative of longer term activity patterns. An additional consideration deals with the select nature of the study population. Although we presume that the observed activity levels in our study population have similar effects among different groups of individuals, this is yet to be determined. Furthermore, given the relatively small study sample, particularly of females, we were not able to test the effects separately for males and females.
Although the PGE2 levels we obtained were within the range of those in our previous study (25), their overall significance to colorectal cancer risk is unknown. The significance of the change in PGE2 as linked to the variation in physical activity or BMI in colorectal carcinogenesis is uncertain. Although it is likely that PGE2 in the upper rectum is reflective of PGE2 levels in the colon, this requires further study. Nonetheless, given the current knowledge of increased prostaglandin production in human colonic tumor cells, these data are supportive of the potential for PGE2 playing a role in the protective mechanism of physical activity or BMI on risk of colon cancer.
In conclusion, the results of our study show a significant reduction in rectal mucosal PGE2 levels associated with a higher level of leisure-time physical activity and a lower BMI. It is worth noting that the study population comprised nonusers of aspirin or other NSAIDs; it is not known whether similar effects would be observed among users of these agents. It is possible that higher levels of physical activity are only protective among nonusers of NSAIDs if the mechanism for both NSAIDs and physical activity underlie similar activities (i.e., COX-1 and COX-2 inhibition). The findings of this study should stimulate much needed work in the area of mechanisms of action for the effect of a well-established protective factor (i.e., physical activity) for colon cancer as well as other chronic diseases.
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NOTES |
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We thank Dr. Edward Giovannucci for his expert advice.
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Manuscript received November 20, 1998; revised March 25, 1999; accepted April 5, 1999.
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