Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid
Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid
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DOI：
10.1073/pnas.1610954113
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发表时间：
2016-09-06
影响因子：
11.1
通讯作者：
Swietach, Pawel
中科院分区：
文献类型：
--
作者：
Hulikova, Alzbeta;Black, Nicholas;Swietach, Pawel
癌细胞的增殖和侵袭需要有利的pH值，但代谢过程中会产生大量潜在的有毒酸。膜结合转运体从癌细胞中挤出酸，但是当酸被释放到灌注不良的细胞外空间时，其处理机制却知之甚少。在这里，我们研究了肌成纤维细胞（结肠癌来源的Hs675）对酸的处理。T，肠InMyoFib，胚胎结肠来源的CCD-112-CoN)，皮肤成纤维细胞（NHDF-Ad）和结直肠癌（CRC）细胞（HCT116, HT29）在单培养或共培养中生长。在肌成纤维细胞和成纤维细胞中检测到载酸转运体阴离子交换器2 (AE2) （SLC4A2产物）的表达，但在结直肠癌细胞中未检测到。与结直肠癌细胞相比，Hs675。T和InMyoFib肌成纤维细胞具有非常高的吸收细胞外酸的能力。与CRC细胞相比，CCD-112-CoN和NHDF-Ad细胞的酸摄取速度较慢，但在转化生长因子β 1 （TGF β 1）的刺激下，酸摄取随SLC4A2表达的增加而增加，TGF β 1是一种参与癌症间质相互作用的细胞因子。肌成纤维细胞和成纤维细胞通过连接蛋白43等蛋白质形成的间隙连接连接在一起，这种连接蛋白允许吸收的酸负荷通过间质合胞体传递。为了匹配对酸摄取的刺激作用，TGF β 1增强了NHDF-Ad和CCD-112-CoN细胞的细胞间偶联。相比之下，在CRC细胞之间不存在酸传递，即使在TGF β 1治疗后也是如此。因此，间质细胞具有必要的分子装置来组装酸排放途径，可以改善代谢酸通过肿瘤的流动。重要的是，基质AE2和连接蛋白43的活动不会给癌细胞带来能量负担，从而允许资源被转移到其他活动上。
Proliferation and invasion of cancer cells require favorable pH, yet potentially toxic quantities of acid are produced metabolically. Membrane-bound transporters extrude acid from cancer cells, but little is known about the mechanisms that handle acid once it is released into the poorly perfused extracellular space. Here, we studied acid handling bymyofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDF-Ad), and colorectal cancer (CRC) cells (HCT116, HT29) grown in monoculture or coculture. Expression of the acid-loading transporter anion exchanger 2 (AE2) (SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared with CRC cells, Hs675. T and InMyoFib myofibroblasts had very high capacity to absorb extracellular acid. Acid uptake into CCD-112-CoN and NHDF-Ad cells was slower and comparable to levels in CRC cells, but increased alongside SLC4A2 expression under stimulation with transforming growth factor beta 1 (TGF beta 1), a cytokine involved in cancer-stroma interplay. Myofibroblasts and fibroblasts are connected by gap junctions formed by proteins such as connexin-43, which allows the absorbed acid load to be transmitted across the stromal syncytium. To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGF beta 1. In contrast, acid transmission was absent between CRC cells, even after treatment with TGF beta 1. Thus, stromal cells have the necessary molecular apparatus for assembling an acid-venting route that can improve the flow of metabolic acid through tumors. Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities.