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癌相关细胞释放柠檬酸以支持肿瘤转移进展。

Cancer-associated cells release citrate to support tumour metastatic progression.

机构信息

Department of Dermatology, University Medical Centre, Regensburg, Germany.

Department of Surgery, University Medical Center, Regensburg, Germany.

出版信息

Life Sci Alliance. 2021 Mar 23;4(6). doi: 10.26508/lsa.202000903. Print 2021 Jun.

DOI:10.26508/lsa.202000903
PMID:33758075
原文链接:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7994318/
Abstract

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter's major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression.

摘要

除了产生 ATP 外，柠檬酸盐对于脂质合成和表观遗传调控也很重要。我们之前曾报道过，癌细胞通过 pmCiC 转运蛋白摄取细胞外的柠檬酸盐，以支持其代谢。在这里，我们首次表明，肿瘤相关基质 (cancer-associated stroma，CAS) 为肿瘤提供了柠檬酸盐，并且柠檬酸盐的合成和释放是后者的主要代谢任务之一。癌细胞通过细胞间通讯控制来自 CAS 的柠檬酸盐的释放。来自 CAS 的柠檬酸盐的可用性通过调节细胞因子谱、代谢和细胞侵袭特征来调节肿瘤的进展。此外，CAS 释放的柠檬酸盐参与诱导癌症进展，特别是增强侵袭性和器官定植。与体外观察结果一致，我们表明，使用 pmCiC 的特异性抑制剂葡萄糖酸盐剥夺癌细胞中的柠檬酸盐，可显著减少体内人胰腺癌细胞的生长和转移扩散，并减弱基质激活和血管生成。我们的结论是，CAS 向肿瘤细胞提供柠檬酸盐，而柠檬酸盐摄取在癌症转移进展中起着重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/e8a352482302/LSA-2020-00903_FigS12.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/c8612e5f7b28/LSA-2020-00903_FigS8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/8a587a7a6b0d/LSA-2020-00903_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/6ef7cbac77c7/LSA-2020-00903_FigS10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/e211640a9433/LSA-2020-00903_FigS11.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d433/7994318/e8a352482302/LSA-2020-00903_FigS12.jpg

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