Acidity generated by the tumor microenvironment drives local invasion.
Acidity generated by the tumor microenvironment drives local invasion.
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肿瘤微环境产生的酸度驱动局部侵袭。
DOI：
10.1158/0008-5472.can-12-2796
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发表时间：
2013-03-01
期刊：
影响因子：
11.2
通讯作者：
Gillies RJ
中科院分区：
文献类型：
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作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
由于发酵代谢增加和灌注不良，实体瘤的pH呈酸性。据推测，酸性pH促进局部浸润性生长和转移。酸介导侵袭的假设提出H+从近端肿瘤微环境扩散到邻近的正常组织中，在那里它引起允许局部侵袭的组织重塑。在目前的工作中，随着时间的推移，使用活体显微镜监测肿瘤浸润和瘤周pH值。在每一种情况下，肿瘤周围的pH值是酸性和异质性和最高的肿瘤浸润的区域对应的最低pH值的区域。肿瘤浸润没有发生到正常或接近正常的pH值的区域。免疫组织化学分析显示，在侵袭边缘的细胞表达葡萄糖转运蛋白GLUT-1和钠氢交换NHE-1，这两者都与肿瘤周围酸中毒。为了支持我们的发现的功能重要性，在临床前模型中，口服碳酸氢钠足以增加肿瘤周围pH值并抑制肿瘤生长和局部侵袭，支持酸介导的侵袭假说。
The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H+ diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal pHe. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter GLUT-1 and the sodium-hydrogen exchanger NHE-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis.