Vigorous activity is associated with lower risk of prostate cancer progression, but the biologic mechanisms are unknown. Exercise affects vascularization of tumors in animal models, and small, irregularly shaped vessels in prostate tumors are associated with fatal prostate cancer. We hypothesized that men who engaged in vigorous activity or brisk walking would have larger, more regularly shaped vessels in their prostate tumors. We prospectively examined whether physical activity was associated with prostate tumor microvessel morphology among 571 men in the Health Professionals Follow-up Study using ordinal logistic regression. Vessel size (μm2), vessel lumen regularity (perimeter2/4 · Π · area), and microvessel density (number/high-powered field) were ascertained in tumor sections stained for endothelial cell marker CD34. Vigorous activity [metabolic equivalent task (MET) ≥ 6], nonvigorous activity (MET < 6), and walking pace were assessed a median of 14 months before diagnosis. Prostate tumors from men who reported a brisk walking pace (3+ mph) had larger, more regularly shaped blood vessels compared with those of men who walked at a less than brisk pace [vessel regularity OR, 1.59; 95% confidence interval (CI), 1.11–2.27; P value, 0.01; vessel size OR, 1.48; 95% CI, 1.04–2.12; P value, 0.03]. Brisk walking was not associated with microvessel density; total vigorous and nonvigorous activities were not associated with vessel size, shape, or number. Brisk walking may be associated with larger, more regularly shaped vessels in prostate tumors. Additional research elucidating the effect of physical activity on prostate tumor biology is needed. Cancer Prev Res; 8(10); 962–7. ©2015 AACR.

Prostate cancer is the second leading cause of cancer-related death among men in the United States (1). Our group previously identified physical activity as a potential modifiable factor associated with a reduced risk of prostate cancer progression and mortality (2, 3). In animal models, exercise has been shown to suppress solid tumor growth, progression, and metastasis (4–9). However, the underlying biologic mechanisms are not well understood.

Modulation of tumor vasculature may be one potential mechanism by which exercise reduces risk of prostate cancer progression. Dysregulation of angiogenesis and the resulting abnormal vasculature have long been understood as characteristic features of malignant tumors (10, 11). Dysfunctional vasculature results in poor tumor perfusion and local hypoxia, inducing a more aggressive phenotype with increased metastatic potential and increased resistance to both the host immune system and therapeutics (12). In addition, tumor vessels have increased permeability, which may result in an increased propensity for tumor cell shedding and metastasis (12, 13). In the prostate, blood vessels in malignant tissue are smaller and more collapsed compared with normal tissue (14). Our group previously reported that markers of abnormal tumor vasculature, small vessel size and irregular shape, in prostatectomy samples were associated with 6.6- and 17.1-fold increased risks of prostate cancer mortality, respectively (15).

In animal models, tumor blood flow increases 2-fold during acute endurance exercise, and chronic physical activity modulates vasculature, increasing tumor perfusion and oxygenation and decreasing the propensity for distant metastasis (4, 5, 16, 17). We hypothesized that physical activity induces a physiologic normalization of tumor vasculature in men with prostate cancer. No prior study has investigated the association between physical activity and morphologic characteristics of prostate tumor vasculature in humans.

Thus, we examined the association between physical activity and tumor vessel size, shape, and density among 571 men with prostate cancer in the Health Professionals Follow-up Study. On the basis of our prior findings of improved clinical outcomes associated with brisk walking and 3+ hours per week of vigorous physical activity (2, 3), we expected to observe larger, more regularly shaped vessels in tumors of men reporting 3+ hours per week of vigorous physical activity or a brisk walking pace before diagnosis. Because of the lack of association between microvessel density and prostate cancer–specific mortality in our study population (15), we hypothesized that vigorous physical activity and walking pace would not be associated with the number of vessels in the prostate tumors.

Study population

The Health Professionals Follow-up Study is a prospective cohort study initiated in 1986 among 51,529 U.S. male health professionals 40 to 75 years of age. The baseline questionnaire asked men to report on medical history, medication use, body weight, physical activity, smoking behavior, and diet. Data on medical diagnoses, medications, weight, physical activity, and smoking have been updated every 2 years, and the average questionnaire response rate exceeds 90%.

This study was conducted among men in the Health Professionals Follow-up Study diagnosed with prostate cancer and treated via prostatectomy or trans-urethral resection of the prostate (TURP) between 1986 and 2000. Of the 1,593 men meeting these criteria, archival formalin-fixed paraffin-embedded specimens were obtained from 1,023 men (64%). The size, shape, and density of the tumor vasculature were assessed on a random sample of 572 men; the clinical characteristics of these men were representative of all men who donated tissue samples. These men represent the same study population as our previous report on the association between tumor vessel morphology and prostate cancer–specific mortality (15). One man was missing data on physical activity before diagnosis, leaving 571 men available for analysis.

The Institutional Review Board at the Harvard School of Public Health approved this investigation; all participants provided informed consent.

Physical activity assessment

Participants completed a validated physical activity questionnaire at baseline and every 2 years thereafter (18). The baseline questionnaire asked men to report the average time per week during the past year spent performing the following activities: Walking or hiking outdoors (including walking at golf); jogging (slower than 10 min/mile); running (10 min/mile or faster); bicycling (include stationary machine); lap swimming; tennis; squash or racket ball; and calisthenics or rowing. Responses were collected in 10 categories ranging from none to 11+ h/wk. Heavy outdoor work (e.g., digging, chopping) was added to the questionnaire in 1988 and weightlifting or Nautilus was added in 1990. Participants also reported how many flights of stairs they climbed daily in five categories ranging from two or fewer to 15 or more. Finally, participants reported their usual walking pace in four categories: easy, casual (less than 2 mph); normal, average (2 to 2.9 mph); brisk pace (3 to 3.9 mph); and very brisk, striding (4 mph or faster).

Given the short time between diagnosis and surgery for patients who undergo radical prostatectomy as their primary treatment for prostate cancer, we used physical activity reported on the questionnaire just before diagnosis as our primary exposure. If a man was missing data from the questionnaire immediately preceding diagnosis, we carried forward his physical activity information from the most recent available prediagnostic questionnaire. The median time from physical activity assessment to diagnosis was 14 months (interquartile range, 8–22 months).

On the basis of the previous studies, we considered three measures of physical activity in this analysis: duration of vigorous physical activity, duration of nonvigorous physical activity, and walking pace (2, 3). Each activity was assigned a metabolic equivalent task (MET) value, which represents the amount of energy required to perform that activity relative to the resting metabolic rate (19). Activities with MET values of six or higher were considered vigorous and activities with MET values less than six were considered nonvigorous (19). These standard cutoff points are based on data from healthy adults, and activities with lower MET values may be relatively vigorous for older men. Thus, we also considered walking pace as a measure of intensity of activity, because walking is the most common form of physical activity among men with prostate cancer (2, 3). Very few men reported walking at an easy [<2 mph; n = 30 (5%)] or very brisk [≥4 mph; n = 24 (4%)] pace; therefore, we analyzed walking pace as a dichotomous variable: less than brisk (<3 mph) versus brisk (≥3 mph).

The physical activity questionnaire was validated among 238 participants in the Health Professionals Follow-up Study (18). After completing the physical activity questionnaire in 1990, these men completed a 1-week physical activity diary every 3 months for 1 year (1991–1992), followed by the 1992 administration of the physical activity questionnaire. The deattenuated correlation between the 1992 questionnaire and the average of the diaries was 0.58 for vigorous physical activity and 0.28 for nonvigorous activity. The question on walking pace has not been validated.

Assessment of tumor vessel morphology

The methods used to assess tumor vessel morphology in the prostate tumor specimens have been previously described (15). A study pathologist identified all prostatectomy blocks that contained cancer. Immunohistochemistry was then performed on blocks containing cancer (1–9 blocks/case) to ascertain protein expression of endothelial cell marker CD34. CD34 is a myeloid progenitor cell antigen detectable in all types of endothelium. Microvascularity in the prostate, as determined by CD34 staining, is higher in malignant versus benign or hyperplastic tissue and is positively associated with risk of prostate cancer recurrence and mortality (15, 20–22). Semiautomated image analysis (Image ProPlus 4.5 software; Media Cybernetics) was conducted under the supervision of the pathologist to measure vessel size and architecture. Three measures were used to characterize tumor angiogenesis: vessel size (μm2), regularity of the vessel lumen (perimeter2/4 · Π · area), and microvessel density (number of vessels per high-powered field). For regularity of the vessel lumen, values of 1.0 indicate a perfect circle and higher values indicate less regular vessels. If a case had more than one measure available, we used the average value to characterize each case. The correlations between the tumor vasculature measures in this population have been previous reported: Microvessel density and vessel size (−0.15), microvessel density and regularity (−0.07), and vessel size and regularity (−0.31; ref. 15).

Statistical analysis

We used ordinal logistic regression to examine vigorous physical activity, nonvigorous physical activity, and walking pace in relation to vessel area, regularity of the vessel lumen, and microvessel density in the prostate tumor. We used ordinal logistic regression with the dependent variables categorized in quartiles for interpretability and consistency with our prior report examining tumor vessel morphology markers in relation to risk of lethal prostate cancer (15). The OR represents the relative odds for a 1-unit increase in the exposure of interest of being in the 4th versus 3rd–1st, 4th–3rd versus 2nd–1st, or 4th–2nd versus 1st quartile of the outcome. For interpretability, the lowest quartile (smallest vessels and lowest microvessel density) was used as the reference for vessel size and microvessel density, and the highest quartile (least regular vessels) was used as the reference for vessel regularity. Thus, OR greater than 1 are interpreted intuitively as increased odds of larger vessels, greater microvessel density, or more regularly shaped vessels.

We categorized activity levels based on our prior report and the distribution in the population as follows: vigorous activity, <1, 1 to <3, ≥3 h/wk; nonvigorous activity, <1.5, 1.5 to <3.5, 3.5 to <7, ≥7 h/wk, and walking pace, <3, ≥3 mph (2, 3). We analyzed the categories using indicator variables with the lowest level as the reference, and tested for evidence of a linear trend across categories by modeling the median value of each category as a continuous term.

Our first model was adjusted for age at diagnosis (years). Our primary multivariate model was additionally adjusted for body mass index at diagnosis (BMI; <25, 25–29.9, ≥30 kg/m2), smoking at diagnosis (current, former, and never), regular aspirin use at diagnosis (yes/no), and quartiles of intake of lycopene and vitamin E. These lifestyle factors have previously been associated with prostate cancer–related mortality, and we hypothesized that they may also be associated with markers of tumor vessel morphology (23). Vigorous activity, nonvigorous activity, and walking pace were also adjusted for one another. To examine whether the associations were independent of clinical prognostic factors, we examined our multivariate model additionally adjusted for pathologic stage (T1/T2 vs. T3/T4/N1/M1), pathologic Gleason sum (<7, 7, ≥7), and PSA level at diagnosis (ng/mL), and ran a sensitivity analysis excluding men diagnosed with advanced stage disease (T3/T4/N1/M1). Clinical stage and biopsy Gleason sum data were used for the 49 men treated via TURP. In addition, we performed a sensitivity analysis restricting to the 522 (91%) men treated via radical prostatectomy. Finally, because the etiologically relevant exposure window is unknown, we conducted an analysis examining the relation between physical activity at baseline (1986) and features of the tumor vasculature.

SAS v. 9.3 was used for all statistical analyses, and P values of <0.05 were considered statistically significant.

Clinical and sociodemographic characteristics of the 571 men by level of vigorous physical activity and walking pace approximately 1 year before diagnosis are presented in Table 1. Brisk walking was reported by 46% of the men and 18% reported engaging in ≥3 hours of vigorous activity per week. At diagnosis, men who reported engaging in more vigorous activity or walking at faster pace were younger, had a lower BMI, and were less likely to be current smokers. In addition, more active men were less likely to have Gleason sum 8 to 10 or regional/distant disease.

Table 1.

Characteristics of 571 men diagnosed with prostate cancer in the Health Professionals Follow-up Study, by level of vigorous physical activity and walking pace before diagnosis (median time from assessment to diagnosis, 14 months)

Vigorous activityWalking pace
<1 h/wk1 to <3 h/wk≥3 h/wk<3 mph≥3 mph
Participants, n 328 142 101 307 264 
Age at diagnosis (y) mean ± SD 66 ± 6 65 ± 6 64 ± 6 66 ± 6 65 ± 6 
BMI, kg/m2, mean ± SD 26 ± 3 25 ± 3 25 ± 2 26 ± 3 25 ± 3 
Smoking behavior, N (%) 
 Never 147 (45) 60 (42) 54 (53) 118 (38) 143 (54) 
 Former 138 (42) 70 (49) 37 (37) 150 (49) 95 (36) 
 Current 29 (9) 8 (6) 5 (5) 29 (9) 13 (5) 
 Missing 14 (4) 4 (3) 5 (5) 10 (3) 13 (5) 
T stage, N (%) 
 T1 N0 M0 13 (4) 3 (2) 2 (2) 12 (4) 6 (2) 
 T2 N0 M0 214 (65) 92 (65) 74 (73) 193 (63) 187 (71) 
 T3 N0 M0 79 (24) 37 (26) 20 (20) 78 (25) 58 (22) 
 T4 N0 M0 2 (1) 1 (1) 1 (1) 3 (1) 1 (0) 
 N1 M0 15 (5) 4 (3) 3 (3) 14 (5) 8 (3) 
 M1 (N0 or N1) 5 (2) 5 (4) 1 (1) 7 (2) 4 (2) 
Gleason sum, N (%) 
 2–6 83 (25) 29 (20) 23 (23) 82 (27) 53 (20) 
 7 175 (53) 87 (61) 62 (61) 160 (52) 164 (62) 
 8–10 65 (20) 23 (16) 15 (15) 61 (20) 42 (16) 
 Missing 5 (2) 3 (2) 1 (1) 4 (1) 5 (2) 
PSA at diagnosis (ng/mL), median (range) 7.3 (0.4–135.0) 6.4 (1.3–49.6) 6.4 (1.6–77.0) 7.2 (0.4–77.0) 6.9 (1.1–135.0) 
Radical prostatectomy, N (%) 297 (91) 129 (91) 96 (95) 273 (89) 249 (94) 
Regular aspirin use, N (%) 148 (45) 82 (58) 48 (48) 152 (50) 126 (48) 
Lycopene, mg/d, mean ± SD 6.8 ± 5.0 7.4 ± 4.7 7.3 ± 4.5 6.5 ± 4.2 7.6 ± 5.4 
Vitamin E, mg/d, mean ± SD 101 ± 176 117 ± 155 133 ± 207 105 ± 179 117 ± 176 
Vigorous activity, h/wk, mean ± SD 0.1 ± 0.2 1.7 ± 0.6 6.4 ± 3.6 1.5 ± 2.9 1.7 ± 2.7 
Nonvigorous activity, h/wk, mean ± SD 5.4 ± 6.4 6.9 ± 8.1 4.6 ± 4.8 5.1 ± 5.8 6.3 ± 7.5 
Vigorous activityWalking pace
<1 h/wk1 to <3 h/wk≥3 h/wk<3 mph≥3 mph
Participants, n 328 142 101 307 264 
Age at diagnosis (y) mean ± SD 66 ± 6 65 ± 6 64 ± 6 66 ± 6 65 ± 6 
BMI, kg/m2, mean ± SD 26 ± 3 25 ± 3 25 ± 2 26 ± 3 25 ± 3 
Smoking behavior, N (%) 
 Never 147 (45) 60 (42) 54 (53) 118 (38) 143 (54) 
 Former 138 (42) 70 (49) 37 (37) 150 (49) 95 (36) 
 Current 29 (9) 8 (6) 5 (5) 29 (9) 13 (5) 
 Missing 14 (4) 4 (3) 5 (5) 10 (3) 13 (5) 
T stage, N (%) 
 T1 N0 M0 13 (4) 3 (2) 2 (2) 12 (4) 6 (2) 
 T2 N0 M0 214 (65) 92 (65) 74 (73) 193 (63) 187 (71) 
 T3 N0 M0 79 (24) 37 (26) 20 (20) 78 (25) 58 (22) 
 T4 N0 M0 2 (1) 1 (1) 1 (1) 3 (1) 1 (0) 
 N1 M0 15 (5) 4 (3) 3 (3) 14 (5) 8 (3) 
 M1 (N0 or N1) 5 (2) 5 (4) 1 (1) 7 (2) 4 (2) 
Gleason sum, N (%) 
 2–6 83 (25) 29 (20) 23 (23) 82 (27) 53 (20) 
 7 175 (53) 87 (61) 62 (61) 160 (52) 164 (62) 
 8–10 65 (20) 23 (16) 15 (15) 61 (20) 42 (16) 
 Missing 5 (2) 3 (2) 1 (1) 4 (1) 5 (2) 
PSA at diagnosis (ng/mL), median (range) 7.3 (0.4–135.0) 6.4 (1.3–49.6) 6.4 (1.6–77.0) 7.2 (0.4–77.0) 6.9 (1.1–135.0) 
Radical prostatectomy, N (%) 297 (91) 129 (91) 96 (95) 273 (89) 249 (94) 
Regular aspirin use, N (%) 148 (45) 82 (58) 48 (48) 152 (50) 126 (48) 
Lycopene, mg/d, mean ± SD 6.8 ± 5.0 7.4 ± 4.7 7.3 ± 4.5 6.5 ± 4.2 7.6 ± 5.4 
Vitamin E, mg/d, mean ± SD 101 ± 176 117 ± 155 133 ± 207 105 ± 179 117 ± 176 
Vigorous activity, h/wk, mean ± SD 0.1 ± 0.2 1.7 ± 0.6 6.4 ± 3.6 1.5 ± 2.9 1.7 ± 2.7 
Nonvigorous activity, h/wk, mean ± SD 5.4 ± 6.4 6.9 ± 8.1 4.6 ± 4.8 5.1 ± 5.8 6.3 ± 7.5 

Abbreviations: h, hours; mph, miles per hour; wk, week.

Men who reported walking at a brisk walking pace had larger, more regularly shaped vessels in their prostate tumors than men who reported walking at a less than brisk pace (Table 2). Men who walked briskly had 52% greater odds of having more regular vessel lumens [OR, 1.52; 95% confidence interval (CI), 1.10–2.09; P value, 0.01]. Adjustment for pathologic stage, Gleason sum, and diagnostic PSA slightly strengthened this association (OR, 1.59; 95% CI, 1.11–2.27; P value, 0.01). There was also a positive association between walking pace and vessel size. Men who reported walking at a brisk pace had 24% higher odds of having larger vessels (OR, 1.24; 95% CI, 0.90–1.71; P value, 0.18), and this association became stronger and statistically significant after adjusting for clinical prognostic factors (OR, 1.48; 95% CI, 1.04–2.12; P value, 0.03). As hypothesized, walking pace was not associated with microvessel density.

Table 2.

Relative odds of having more regular vessel lumens, larger vessel area, or higher microvessel density in the prostate tumor by level of physical activity at diagnosis among 571 men in the Health Professionals Follow-up Study

Regularity of vessel lumen
Walking pace <3 mph ≥3 mph   Ptrenda 
Model 1b 1.0 (ref.) 1.52 (1.13–2.05)   0.006 
Model 2c 1.0 (ref.) 1.52 (1.10–2.09)   0.01 
Model 3d 1.0 (ref.) 1.59 (1.11–2.27)   0.01 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 1.32 (0.93–1.89) 0.93 (0.62–1.39)  0.87 
Model 2c 1.0 (ref.) 1.24 (0.86–1.81) 0.78 (0.51–1.20)  0.36 
Model 3d 1.0 (ref.) 1.17 (0.78–1.75) 0.89 (0.56–1.41)  0.68 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 0.90 (0.59–1.38) 1.22 (0.79–1.89) 1.00 (0.65–1.54) 0.85 
Model 2c 1.0 (ref.) 0.91 (0.59–1.41) 1.14 (0.72–1.80) 0.86 (0.55–1.35) 0.53 
Model 3d 1.0 (ref.) 0.71 (0.43–1.15) 0.86 (0.52–1.42) 0.75 (0.46–1.25) 0.55 
Vessel area 
Walking pace <3 mph ≥3 h/wk    
Model 1b 1.0 (ref.) 1.24 (0.93–1.67)   0.15 
Model 2c 1.0 (ref.) 1.24 (0.90–1.71)   0.18 
Model 3d 1.0 (ref.) 1.48 (1.04–2.12)   0.03 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 0.98 (0.69–1.40) 0.87 (0.58–1.31)  0.52 
Model 2c 1.0 (ref.) 0.92 (0.63–1.33) 0.82 (0.54–1.26)  0.36 
Model 3d 1.0 (ref.) 0.83 (0.55–1.24) 0.70 (0.44–1.11)  0.12 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 1.11 (0.72–1.70) 1.04 (0.68–1.61) 0.90 (0.58–1.39) 0.40 
Model 2c 1.0 (ref.) 1.13 (0.73–1.76) 0.95 (0.60–1.49) 0.78 (0.50–1.23) 0.12 
Model 3d 1.0 (ref.) 1.18 (0.72–1.92) 0.93 (0.57–1.54) 0.86 (0.52–1.42) 0.31 
Microvessel density 
Walking pace <3 mph ≥3 h/wk    
Model 1b 1.0 (ref.) 1.10 (0.82–1.47)   0.55 
Model 2c 1.0 (ref.) 1.02 (0.74–1.41)   0.89 
Model 3d 1.0 (ref.) 1.07 (0.75–1.53)   0.70 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 1.48 (1.04–2.12) 0.95 (0.63–1.42)  0.97 
Model 2c 1.0 (ref.) 1.53 (1.05–2.22) 0.99 (0.64–1.51)  0.87 
Model 3d 1.0 (ref.) 1.55 (1.03–2.32) 1.03 (0.65–1.64)  0.76 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 0.91 (0.59–1.39) 0.74 (0.48–1.15) 0.97 (0.63–1.50) 0.85 
Model 2c 1.0 (ref.) 0.92 (0.59–1.42) 0.73 (0.47–1.16) 0.92 (0.58–1.44) 0.89 
Model 3d 1.0 (ref.) 0.79 (0.49–1.29) 0.61 (0.37–1.01) 0.80 (0.48–1.31) 0.68 
Regularity of vessel lumen
Walking pace <3 mph ≥3 mph   Ptrenda 
Model 1b 1.0 (ref.) 1.52 (1.13–2.05)   0.006 
Model 2c 1.0 (ref.) 1.52 (1.10–2.09)   0.01 
Model 3d 1.0 (ref.) 1.59 (1.11–2.27)   0.01 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 1.32 (0.93–1.89) 0.93 (0.62–1.39)  0.87 
Model 2c 1.0 (ref.) 1.24 (0.86–1.81) 0.78 (0.51–1.20)  0.36 
Model 3d 1.0 (ref.) 1.17 (0.78–1.75) 0.89 (0.56–1.41)  0.68 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 0.90 (0.59–1.38) 1.22 (0.79–1.89) 1.00 (0.65–1.54) 0.85 
Model 2c 1.0 (ref.) 0.91 (0.59–1.41) 1.14 (0.72–1.80) 0.86 (0.55–1.35) 0.53 
Model 3d 1.0 (ref.) 0.71 (0.43–1.15) 0.86 (0.52–1.42) 0.75 (0.46–1.25) 0.55 
Vessel area 
Walking pace <3 mph ≥3 h/wk    
Model 1b 1.0 (ref.) 1.24 (0.93–1.67)   0.15 
Model 2c 1.0 (ref.) 1.24 (0.90–1.71)   0.18 
Model 3d 1.0 (ref.) 1.48 (1.04–2.12)   0.03 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 0.98 (0.69–1.40) 0.87 (0.58–1.31)  0.52 
Model 2c 1.0 (ref.) 0.92 (0.63–1.33) 0.82 (0.54–1.26)  0.36 
Model 3d 1.0 (ref.) 0.83 (0.55–1.24) 0.70 (0.44–1.11)  0.12 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 1.11 (0.72–1.70) 1.04 (0.68–1.61) 0.90 (0.58–1.39) 0.40 
Model 2c 1.0 (ref.) 1.13 (0.73–1.76) 0.95 (0.60–1.49) 0.78 (0.50–1.23) 0.12 
Model 3d 1.0 (ref.) 1.18 (0.72–1.92) 0.93 (0.57–1.54) 0.86 (0.52–1.42) 0.31 
Microvessel density 
Walking pace <3 mph ≥3 h/wk    
Model 1b 1.0 (ref.) 1.10 (0.82–1.47)   0.55 
Model 2c 1.0 (ref.) 1.02 (0.74–1.41)   0.89 
Model 3d 1.0 (ref.) 1.07 (0.75–1.53)   0.70 
Vigorous physical activity <1 h/wk 1 to <3 h/wk ≥3 h/wk   
Model 1b 1.0 (ref.) 1.48 (1.04–2.12) 0.95 (0.63–1.42)  0.97 
Model 2c 1.0 (ref.) 1.53 (1.05–2.22) 0.99 (0.64–1.51)  0.87 
Model 3d 1.0 (ref.) 1.55 (1.03–2.32) 1.03 (0.65–1.64)  0.76 
Nonvigorous physical activity <1.5 h/wk 1.5 to <3.5 h/wk 3.5 to <7 h/wk ≥7 h/wk  
Model 1b 1.0 (ref.) 0.91 (0.59–1.39) 0.74 (0.48–1.15) 0.97 (0.63–1.50) 0.85 
Model 2c 1.0 (ref.) 0.92 (0.59–1.42) 0.73 (0.47–1.16) 0.92 (0.58–1.44) 0.89 
Model 3d 1.0 (ref.) 0.79 (0.49–1.29) 0.61 (0.37–1.01) 0.80 (0.48–1.31) 0.68 

aPtrend calculated by modeling the median of the exposure categories as a continuous term.

bModel 1, ordinal logistic regression with the dependent variable categorized in quartiles and adjusted for age at diagnosis.

cModel 2, model 1 adjusted for BMI at diagnosis (<25, 25–29.9, and 30+ kg/m2), smoking status at diagnosis (never, former, and current), tissue source (radical prostatectomy and TURP), lycopene intake at diagnosis (quartiles), vitamin E intake at diagnosis (quartiles), and regular aspirin use at diagnosis (yes/no). In addition, the types of activity are adjusted for one another. Model 2 includes the 546 men who had complete data on all covariates included in the model.

dModel 3, model 2 adjusted for pathologic stage (T1/T2 vs. T3/T4), Gleason sum (2–6, 7, and 8–10), and diagnostic PSA level (ng/mL). Model 3 includes 465 men who had complete data on all covariates included in the model.

There was no association between duration of vigorous or nonvigorous physical activity and vessel size, shape, or density in prostate tumor specimens. In sensitivity analyses, the observed associations remained the same when excluding the 79 (14%) men diagnosed with stage T3b, T4, N1, or M1 disease and became stronger when restricting to the 522 (91%) men treated via radical prostatectomy (brisk walking and tumor vessel regularity OR, 1.62; 95% CI, 1.16–2.26; P value: 0.005). Finally, the relation between brisk walking pace and regularity of the vessel lumen in the tumors was slightly attenuated when examining baseline walking pace (OR, 1.32; 95% CI, 0.93–1.88), suggesting that recent brisk walking may have a greater impact on tumor vasculature than past activity levels.

In this prospective study of 571 men with prostate cancer, we observed larger more regularly shaped blood vessels in prostate tumors of men who reported a brisk walking pace approximately 1 year before diagnosis. Walking pace was not associated with the number of vessels in prostate tumors, and vigorous and nonvigorous physical activities were not associated with vessel size, shape, or density.

We previously reported that smaller vessel area and more irregular shape (markers of abnormal vasculature) at the time of prostatectomy were associated with increased risk of prostate cancer–specific mortality, independent of other clinical prognostic factors (smaller vessel area HR, 4.0; 95% CI, 1.2–13.3; irregular shape HR, 10.9; 95% CI, 1.5–81.4; Q1 vs. Q4; ref. 15). We also previously reported in a distinct study population that men who walked briskly after diagnosis had a 48% decreased risk of prostate cancer recurrence compared with men who walked at an easy pace (HR, 0.52; 95% CI, 0.29–0.91; Ptrend = 0.01; ref. 2). Here, we report that men with a walking pace ≥3 mph approximately 1 year before diagnosis had larger, more normal-shaped blood vessels in their prostate tumors. This finding adds evidence to support the hypothesis that brisk walking reduces the risk of developing lethal prostate cancer, and suggests a potential biologic mechanism by which brisk walking may inhibit prostate cancer progression.

Dysfunctional tumor vasculature results in increased permeability and local hypoxia, which may increase tumor cell shedding and activate pathways promoting metastasis, inhibition of immune-mediated tumor cell destruction, and increased therapeutic resistance (12). Animal models of breast and prostate cancer have shown that chronic exercise training increases tumor perfusion (4, 5, 24). For example, Betof and colleagues (4) recently reported that mice implanted with murine breast cancer cells that were able to exercise had significantly improved vessel function and maturity, lower hypoxia, and more uniform and centralized perfusion in their tumors compared with sedentary control mice. Here, we report for the first time that exercise may also have a beneficial effect on tumor vasculature in men with prostate cancer.

Contrary to our hypothesis, we observed no association between vigorous physical activity and characteristics of the tumor vasculature. In a prior report, we observed that men who engaged in ≥3 h/wk of vigorous physical activity after diagnosis had a 61% lower risk of prostate cancer–specific mortality compared with men engaging in <1 h/wk (HR, 0.39; 95% CI, 0.18–0.84; ref. 3). In that analysis, the inverse relation only appeared at the highest levels of vigorous physical activity; there was no difference in risk of prostate cancer–specific mortality comparing men who reported 1 to <3 h/wk of vigorous activity with men who reported <1 h/wk. In this study population, only 101 men (18%) reported engaging in ≥3 h/wk of vigorous activity. Thus, we may have lacked sufficient statistical power to detect an association between vigorous activity and markers of tumor vasculature due to low participation in vigorous activity in our study sample. In contrast, 265 (46%) of our population reported engaging in brisk walking. Brisk walking is a relatively vigorous activity for many elderly men, and data suggest that brisk walking lowers risk of prostate cancer recurrence (2). Thus, brisk walking may be sufficient for eliciting biologic changes in prostate tumors. It is also possible that men may more accurately report their usual walking pace compared with time spent in leisure-time activities, which could in part explain the lack of association between vigorous activity and tumor vessel morphology. Nevertheless, further research in larger study populations is clearly needed to improve our understanding of the complex and pleiotropic effects of physical activity, both before and after diagnosis, in the development and progression of prostate cancer.

This was an observational study, and we cannot rule out the potential for unmeasured or residual confounding. Our results were robust when controlling for clinical and lifestyle factors associated with prostate cancer progression, but predictors of tumor vessel morphology have not been well studied, and therefore it is possible that an unknown confounder was not accounted for. A randomized controlled trial is needed to definitively determine whether engaging in brisk walking changes the shape or size of vasculature in prostate tumors. In addition, we also relied on self-reported physical activity, and our measure of walking pace has not been validated. However, our assessment was collected prospectively, and therefore we expect that the error in our exposure assessment was nondifferential. Future studies using a combination of self-reported and objective measures of physical activity in relation to biologic endpoints in men with prostate cancer would be of interest. Finally, it is possible that the associations we observed between walking pace and tumor vessel size and shape are due to chance. We did not adjust for multiple testing because this was the first study to examine this question in humans, and we had a clear a priori hypothesis based on preclinical data, but replication is necessary in future studies.

In conclusion, we observed that walking pace before diagnosis was associated with having larger, more regular-shaped vessels in prostate tumors. Our data support the hypothesis that normalization of tumor vasculature is one mechanism by which brisk walking may reduce the risk of prostate cancer progression. Future work is needed to confirm our findings and further elucidate the biologic mechanisms by which physical activity may reduce risk of prostate cancer progression.

No potential conflicts of interest were disclosed.

The authors assume full responsibility for analyses and interpretation of these data.

Conception and design: E.L. Van Blarigan, S.A. Kenfield, L.W. Jones, S.K. Clinton, J.M. Chan, L.A. Mucci

Development of methodology: S.K. Clinton

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): E.L. Giovannucci, S.K. Clinton, L.A. Mucci

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): E.L. Van Blarigan, J.P. Gerstenberger, S.A. Kenfield, E.L. Giovannucci, L.W. Jones, S.K. Clinton, J.M. Chan, L.A. Mucci

Writing, review, and/or revision of the manuscript: E.L. Van Blarigan, J.P. Gerstenberger, S.A. Kenfield, E.L. Giovannucci, M.J. Stampfer, L.W. Jones, S.K. Clinton, J.M. Chan, L.A. Mucci

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S.A. Kenfield, M.J. Stampfer

Study supervision: J.M. Chan

The authors thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY.

This work was supported by grants from the National Cancer Institute [CA138624, CA142566, and CA133895 (to L.W. Jones); CA155626 (to M.J. Stampfer); CA164751 and CA179992 (to L.W. Jones); CA141298 (to M.J. Stampfer); CA112355 (to E.L. Van Blarigan), CA133891 (to E.L. Giovannucci), CA167552 and the Prostate Cancer Foundation (to S.A. Kenfield)].

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
DeSantis
CE
,
Lin
CC
,
Mariotto
AB
,
Siegel
RL
,
Stein
KD
,
Kramer
JL
, et al
Cancer treatment and survivorship statistics, 2014
.
CA Cancer J Clin
2014
;
64
:
252
71
.
2.
Richman
EL
,
Kenfield
SA
,
Stampfer
MJ
,
Paciorek
A
,
Carroll
PR
,
Chan
JM
. 
Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor
.
Cancer Res
2011
;
71
:
3889
95
.
3.
Kenfield
SA
,
Stampfer
MJ
,
Giovannucci
E
,
Chan
JM
. 
Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study
.
J Clin Oncol
2011
;
29
:
726
32
.
4.
Betof
AS
,
Lascola
CD
,
Weitzel
D
,
Landon
C
,
Scarbrough
PM
,
Devi
GR
, et al
Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise
.
J Natl Cancer Inst
2015
;
107
:
pii: djv040
.
5.
Jones
LW
,
Antonelli
J
,
Masko
EM
,
Broadwater
G
,
Lascola
CD
,
Fels
D
, et al
Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer
.
J Appl Physiol
2012
;
113
:
263
72
.
6.
Zheng
X
,
Cui
XX
,
Huang
MT
,
Liu
Y
,
Wagner
GC
,
Lin
Y
, et al
Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise
.
Nutr Cancer
2012
;
64
:
1029
37
.
7.
Zheng
X
,
Cui
XX
,
Gao
Z
,
Zhao
Y
,
Shi
Y
,
Huang
MT
, et al
Inhibitory effect of dietary atorvastatin and celecoxib together with voluntary running wheel exercise on the progression of androgen-dependent LNCaP prostate tumors to androgen independence
.
Exp Ther Med
2011
;
2
:
221
8
.
8.
Zheng
X
,
Cui
XX
,
Huang
MT
,
Liu
Y
,
Shih
WJ
,
Lin
Y
, et al
Inhibitory effect of voluntary running wheel exercise on the growth of human pancreatic Panc-1 and prostate PC-3 xenograft tumors in immunodeficient mice
.
Oncol Rep
2008
;
19
:
1583
8
.
9.
Esser
KA
,
Harpole
CE
,
Prins
GS
,
Diamond
AM
. 
Physical activity reduces prostate carcinogenesis in a transgenic model
.
Prostate
2009
;
69
:
1372
7
.
10.
Hanahan
D
,
Weinberg
RA
. 
The hallmarks of cancer
.
Cell
2000
;
100
:
57
70
.
11.
Vaupel
P
,
Kallinowski
F
,
Okunieff
P
. 
Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review
.
Cancer Res
1989
;
49
:
6449
65
.
12.
Goel
S
,
Duda
DG
,
Xu
L
,
Munn
LL
,
Boucher
Y
,
Fukumura
D
, et al
Normalization of the vasculature for treatment of cancer and other diseases
.
Physiol Rev
2011
;
91
:
1071
121
.
13.
Mazzone
M
,
Dettori
D
,
Leite de Oliveira
R
,
Loges
S
,
Schmidt
T
,
Jonckx
B
, et al
Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization
.
Cell
2009
;
136
:
839
51
.
14.
Tretiakova
M
,
Antic
T
,
Binder
D
,
Kocherginsky
M
,
Liao
C
,
Taxy
JB
, et al
Microvessel density is not increased in prostate cancer: digital imaging of routine sections and tissue microarrays
.
Hum Pathol
2013
;
44
:
495
502
.
15.
Mucci
LA
,
Powolny
A
,
Giovannucci
E
,
Liao
Z
,
Kenfield
SA
,
Shen
R
, et al
Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study
.
J Clin Oncol
2009
;
27
:
5627
33
.
16.
McCullough
DJ
,
Nguyen
LM
,
Siemann
DW
,
Behnke
BJ
. 
Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model
.
J Appl Physiol
2013
;
115
:
1846
54
.
17.
McCullough
DJ
,
Stabley
JN
,
Siemann
DW
,
Behnke
BJ
. 
Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise
.
J Natl Cancer Inst
2014
;
106
:
dju036
.
18.
Chasan-Taber
S
,
Rimm
EB
,
Stampfer
MJ
,
Spiegelman
D
,
Colditz
GA
,
Giovannucci
E
, et al
Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals
.
Epidemiology
1996
;
7
:
81
6
.
19.
Ainsworth
BE
,
Haskell
WL
,
Herrmann
SD
,
Meckes
N
,
Bassett
DR
 Jr
,
Tudor-Locke
C
, et al
2011 compendium of physical activities: a second update of codes and MET values
.
Med Sci Sports Exerc
2011
;
43
:
1575
81
.
20.
Bettencourt
MC
,
Bauer
JJ
,
Sesterhenn
IA
,
Connelly
RR
,
Moul
JW
. 
CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy
.
J Urol
1998
;
160
:
459
65
.
21.
de la Taille
A
,
Katz
AE
,
Bagiella
E
,
Buttyan
R
,
Sharir
S
,
Olsson
CA
, et al
Microvessel density as a predictor of PSA recurrence after radical prostatectomy. A comparison of CD34 and CD31
.
Am J Clin Pathol
2000
;
113
:
555
62
.
22.
Lekas
A
,
Lazaris
AC
,
Deliveliotis
C
,
Chrisofos
M
,
Zoubouli
C
,
Lapas
D
, et al
The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and angiogenesis markers in hyperplastic and malignant prostate tissue
.
Anticancer Res
2006
;
26
:
2989
93
.
23.
Zu
K
,
Mucci
L
,
Rosner
BA
,
Clinton
SK
,
Loda
M
,
Stampfer
MJ
, et al
Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era
.
J Natl Cancer Inst
2014
;
106
:
djt430
.
24.
Jones
LW
,
Viglianti
BL
,
Tashjian
JA
,
Kothadia
SM
,
Keir
ST
,
Freedland
SJ
, et al
Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer
.
J Appl Physiol
2010
;
108
:
343
8
.