Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia.
Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia.
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DOI：
10.1038/sj.bjc.6690273
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发表时间：
1999-04
影响因子：
8.8
通讯作者：
Wilson, D
中科院分区：
文献类型：
--
作者：
Dewhirst, MW;Ong, ET;Braun, RD;Smith, B;Klitzman, B;Evans, SM;Wilson, D
我们之前报道过窗腔肿瘤的小动脉输入数量有限，并且被限制从一个表面进入肿瘤，并且肿瘤小动脉的pO2低于正常组织的类似小动脉。平均而言，这些肿瘤上表面血管的pO2低于筋膜侧血管的pO2，提示可能存在陡峭的血管纵向梯度（定义为血管pO2沿血流传入路径下降），导致肿瘤上表面血管缺氧。然而，我们以前没有在同一肿瘤中测量这些腔室两个表面的组织pO2。在本报告中，我们研究了一种假设，即肿瘤一侧小动脉供应的解剖学约束导致pO2的纵向梯度足以在背侧皮瓣窗室中生长的肿瘤中产生血管缺氧。fisher -344大鼠在皮肤褶处植入背侧皮瓣窗室，同时移植R3230AC肿瘤。在移植后9-11天研究肿瘤，直径为3-4 mm；组织厚度为200 μm。为了磁共振显微镜成像，静脉注射钆DTPA牛血清白蛋白（BSA-DTPA-Gd）复合物，然后在10%福尔马林中固定并从动物身上取出。样品在9.4 T下成像，体素尺寸为40 μm。使用活体显微镜观察进入窗腔肿瘤制剂的小动脉的位置和数量。磷光寿命成像（PLI）测量血管pO2。对窗腔上下表面进行蓝光和绿光激发（光穿透深度分别为~50 vs >200 μm）。窗腔肿瘤的小动脉输入仅限于1或2条血管，并且似乎局限于肿瘤生长的筋膜表面。肿瘤表面的PLI显示与绿光激发相比，蓝光激发下缺氧程度更高（第10和25百分位数以及百分比像素< 10 mmHg时P < 0.03）。相比之下，蓝光照射筋膜表面与肿瘤表面相比，缺氧程度更低（第10和25百分位数，以及百分比像素< 10 mmHg, P < 0.05）。蓝光和绿光激发下筋膜表面pO2分布无显著差异，绿光激发下也无显著差异。PLI数据表明，肿瘤的上表面更缺氧，因为蓝光激发产生的pO2值比绿光激发低。与肿瘤表面相比，筋膜表面的蓝光激发显示更高的pO2分布，这在腔室子集中得到进一步验证。这些结果表明，在该肿瘤模型中，血管pO2存在陡峭的纵向梯度，这是由小动脉数量和方向有限造成的。这导致肿瘤缺氧。动脉供应在其他肿瘤中也经常受到限制，提示这可能是肿瘤缺氧的另一个原因。这是第一个直接证明纵向氧梯度实际上导致肿瘤缺氧的报告。©1999癌症研究运动
We previously reported that the arteriolar input in window chamber tumours is limited in number and is constrained to enter the tumour from one surface, and that the pO2 of tumour arterioles is lower than in comparable arterioles of normal tissues. On average, the vascular pO2 in vessels of the upper surface of these tumours is lower than the pO2 of vessels on the fascial side, suggesting that there may be steep vascular longitudinal gradients (defined as the decline in vascular pO2 along the afferent path of blood flow) that contribute to vascular hypoxia on the upper surface of the tumours. However, we have not previously measured tissue pO2 on both surfaces of these chambers in the same tumour. In this report, we investigated the hypothesis that the anatomical constraint of arteriolar supply from one side of the tumour results in longitudinal gradients in pO2 sufficient in magnitude to create vascular hypoxia in tumours grown in dorsal flap window chambers. Fischer-344 rats had dorsal flap window chambers implanted in the skin fold with simultaneous transplantation of the R3230AC tumour. Tumours were studied at 9–11 days after transplantation, at a diameter of 3–4 mm; the tissue thickness was 200 μm. For magnetic resonance microscopic imaging, gadolinium DTPA bovine serum albumin (BSA-DTPA-Gd) complex was injected i.v., followed by fixation in 10% formalin and removal from the animal. The sample was imaged at 9.4 T, yielding voxel sizes of 40 μm. Intravital microscopy was used to visualize the position and number of arterioles entering window chamber tumour preparations. Phosphorescence life time imaging (PLI) was used to measure vascular pO2. Blue and green light excitations of the upper and lower surfaces of window chambers were made (penetration depth of light ~50 vs >200 μm respectively). Arteriolar input into window chamber tumours was limited to 1 or 2 vessels, and appeared to be constrained to the fascial surface upon which the tumour grows. PLI of the tumour surface indicated greater hypoxia with blue compared with green light excitation (P < 0.03 for 10th and 25th percentiles and for per cent pixels < 10 mmHg). In contrast, illumination of the fascial surface with blue light indicated less hypoxia compared with illumination of the tumour surface (P < 0.05 for 10th and 25th percentiles and for per cent pixels < 10 mmHg). There was no significant difference in pO2 distributions for blue and green light excitation from the fascial surface nor for green light excitation when viewed from either surface. The PLI data demonstrates that the upper surface of the tumour is more hypoxic because blue light excitation yields lower pO2 values than green light excitation. This is further verified in the subset of chambers in which blue light excitation of the fascial surface showed higher pO2 distributions compared with the tumour surface. These results suggest that there are steep longitudinal gradients in vascular pO2 in this tumour model that are created by the limited number and orientation of the arterioles. This contributes to tumour hypoxia. Arteriolar supply is often limited in other tumours as well, suggesting that this may represent another cause for tumour hypoxia. This report is the first direct demonstration that longitudinal oxygen gradients actually lead to hypoxia in tumours. © 1999 Cancer Research Campaign
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影响因子：
3.4
作者：
DEWHIRST, MW;ONG, ET;GROSS, JF
通讯作者：
GROSS, JF
影响因子：
8.4
作者：
FALK, P
通讯作者：
FALK, P
DOI：
10.1016/0360-3016(93)90070-c
发表时间：
1993-02-15
影响因子：
7
作者：
SECOMB, TW;HSU, R;GROSS, JF
通讯作者：
GROSS, JF
某些人类肺癌的组织学结构以及对放射疗法的可能影响。
影响因子：
8.8
作者：
THOMLINSON, R H;GRAY, L H
通讯作者：
GRAY, L H
自发犬肿瘤中缺氧标记的免疫组织化学检测。
影响因子：
8.8
作者：
Cline, J M;Thrall, D E;Page, R L;Franko, A J;Raleigh, J A
通讯作者：
Raleigh, J A