Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo.
Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo.
复制标题
DOI：
10.1038/s41416-018-0216-5
复制
发表时间：
2018-08
影响因子：
8.8
通讯作者：
Griffiths JR
中科院分区：
文献类型：
--
作者：
Lee SH;McIntyre D;Honess D;Hulikova A;Pacheco-Torres J;Cerdán S;Swietach P;Harris AL;Griffiths JR
肿瘤碳酸酐酶IX（CAIX）是一种缺氧诱导的肿瘤相关细胞表面酶，被认为通过水合CO2形成质子和碳酸氢盐来酸化肿瘤微环境，但在体内实体瘤中没有明确的证据。我们使用细胞外pH探针咪唑基琥珀酸（ISUCA）的1H磁共振光谱成像（MRSI）来测量和空间映射在SCID小鼠中转染表达CAIX和空载体对照的HCT 116肿瘤中的细胞外pH。我们还测量了细胞内的pH值原位与31 P MRS和测定乳酸在冷冻夹肿瘤。表达CAIX的肿瘤具有比对照肿瘤低0.15个pH单位的中值细胞外pH（pH 6.71肿瘤vs pH 6.86对照，P = 0.01）。重要的是，CAIX表达将肿瘤细胞外pH的上限设定为6.93。尽管CAIX表达肿瘤中乳酸浓度增加，但31P MRS显示细胞内pH值无差异，表明CAIX仅酸化肿瘤细胞外间隙。CAIX酸化肿瘤微环境，还提供细胞外pH控制机制。我们提出，CAIX因此充当细胞外pH恒定剂，维持癌细胞耐受的酸性肿瘤细胞外pH，并有利于侵袭和转移。
Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. We used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours. CAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space. CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.
登录
查看更多内容
影响因子：
11.2
作者：
Gallagher, Ferdia A.;Sladen, Helen;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.
影响因子：
29
作者：
Marin-Valencia I;Yang C;Mashimo T;Cho S;Baek H;Yang XL;Rajagopalan KN;Maddie M;Vemireddy V;Zhao Z;Cai L;Good L;Tu BP;Hatanpaa KJ;Mickey BE;Matés JM;Pascual JM;Maher EA;Malloy CR;Deberardinis RJ;Bachoo RM
通讯作者：
Bachoo RM
影响因子：
--
作者：
GILLIES, RJ;LIU, Z;BHUJWALLA, Z
通讯作者：
BHUJWALLA, Z
影响因子：
11.2
作者：
Panagiotaki, Eletheria;Walker-Samuel, Simon;Alexander, Daniel C.
通讯作者：
Alexander, Daniel C.
影响因子：
4.8
作者：
Li, Ying;Tu, Chingkuang;Frost, Susan C.
通讯作者：
Frost, Susan C.