Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise
Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise
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DOI：
10.1093/jnci/dju036
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发表时间：
2014-04-01
影响因子：
10.3
通讯作者：
Behnke, Bradley J.
中科院分区：
文献类型：
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作者：
McCullough, Danielle J.;Stabley, John N.;Behnke, Bradley J.
背景以前的研究假设在运动过程中肿瘤血流量可能增加或减少，这可能会影响肿瘤微环境。然而，到目前为止，技术上的限制排除了在运动期间测量肿瘤血流量的可能性。利用前列腺癌的原位临床前模型，我们检验了在运动过程中肿瘤将经历1)血管阻力减少，2)血流量增加，3)灌流血管数量增加，4)组织缺氧减少，以及前列腺肿瘤小动脉血管收缩减少的假说。方法将Dunning R-3327MatLyLu肿瘤细胞注射到4~6月龄雄性哥本哈根大鼠的前列腺腹侧，随机分为荷瘤组(n=42)和赋形剂对照组(n=14)。结果与安静时相比，运动时肿瘤血流量增加约200%，开放血管数显著增加(静息平均+/-标准差=12.7+/-1.3；运动平均+/-SD=14.3+/-0.6个/视野；学生t双侧P=0.02)，缺氧明显减少。在肿瘤小动脉中，去甲肾上腺素引起的最大收缩与对照组相比减弱了约95%。结论在运动中，肿瘤血流增强，肿瘤缺氧减少，部分原因是血管收缩减弱。这些发现的临床相关性是，运动可能会增加肿瘤靶向药物的输送，并减弱肿瘤内的低氧微环境，导致侵袭性较弱的表型。
Background Previous studies have hypothesized that tumor blood flow may be elevated or reduced during exercise, which could impact the tumor microenvironment. However, to date technical limitations have precluded the measurement of tumor blood flow during exercise. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that during exercise tumors would experience 1) diminished vascular resistance, 2) augmented blood flow, 3) increased numbers of perfused vessels, and 4) decreased tissue hypoxia and, furthermore, that the increased perfusion would be associated with diminished vasoconstriction in prostate tumor arterioles.Methods Dunning R-3327 MatLyLu tumor cells were injected into the ventral prostate of male Copenhagen rats aged 4 to 6 months randomly assigned to tumor-bearing (n = 42) or vehicle control (n = 14) groups. Prostate tumor blood flow, vascular resistance, patent vessel number, and hypoxia were measured in vivo in conscious rats at rest and during treadmill exercise, and vasoconstrictor responsiveness of resistance arterioles was investigated in vitro.Results During exercise there was a statistically significant increase in tumor blood flow (approximately 200%) and number of patent vessels (rest mean +/- standard deviation [SD] = 12.7 +/- 1.3; exercise mean +/- SD = 14.3 +/- 0.6 vessels/field; Student t test two-sided P = .02) and decreased hypoxia compared with measurements made at rest. In tumor arterioles, the maximal constriction elicited by norepinephrine was blunted by approximately 95% vs control prostate vessels.Conclusions During exercise there is enhanced tumor perfusion and diminished tumor hypoxia due, in part, to a diminished vasoconstriction. The clinical relevance of these findings are that exercise may enhance the delivery of tumor-targeting drugs as well as attenuate the hypoxic microenvironment within a tumor and lead to a less aggressive phenotype.