Longhitano Lucia, Vicario Nunzio, Tibullo Daniele, Giallongo Cesarina, Broggi Giuseppe, Caltabiano Rosario, Barbagallo Giuseppe Maria Vincenzo, Altieri Roberto, Baghini Marta, Di Rosa Michelino, Parenti Rosalba, Giordano Antonio, Mione Maria Caterina, Li Volti Giovanni
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Catania, Italy.
Front Oncol. 2022 Apr 28;12:871798. doi: 10.3389/fonc.2022.871798. eCollection 2022.
The tumor microenvironment (TME) plays a pivotal role in establishing malignancy, and it is associated with high glycolytic metabolism and lactate release through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signaling molecule through its receptor hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), thus functioning as a paracrine and autocrine signaling molecule. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an and model. The cell proliferation, migration, and clonogenicity were tested in three different human GBM cell lines. The expressions of , , and were evaluated both and in a zebrafish GBM model. The results were further validated in patient-derived GBM biopsies. Our results showed that lactate significantly increased the cell proliferation, migration, and colony formation capacity of GBM cells, both and . We also showed that lactate increased the expressions of and . Moreover, lactate modulated the epithelial-mesenchymal transition protein markers E-cadherin and β-catenin. Interestingly, lactate induced mitochondrial mass and the gene, suggesting improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-dihydroxybenzoic acid, a known agonist of . Consistently, the GBM zebrafish model exhibited an altered metabolism and increased expressions of and , leading to high levels of extracellular lactate and, thus, supporting tumor cell proliferation. Our data from human GBM biopsies also showed that, in high proliferative GBM biopsies, Ki67-positive cells expressed significantly higher levels of compared to low proliferative GBM cells. In conclusion, our data suggest that lactate and its transporter and receptor play a major role in GBM proliferation and migration, thus representing a potential target for new therapeutic strategies to counteract tumor progression and recurrence.
肿瘤微环境（TME）在恶性肿瘤的形成过程中起着关键作用，并且与通过单羧酸转运体（MCTs）进行的高糖酵解代谢和乳酸释放有关。多项证据表明，乳酸还通过其受体羟基羧酸受体1（HCAR1/GPR81）作为信号分子发挥作用，从而作为旁分泌和自分泌信号分子发挥功能。本研究的目的是在[具体模型未提及]模型中研究乳酸在胶质母细胞瘤（GBM）进展和代谢重编程中的作用。在三种不同的人GBM细胞系中测试了细胞增殖、迁移和克隆形成能力。在[具体模型未提及]和斑马鱼GBM模型中评估了[具体基因未提及]、[具体基因未提及]和[具体基因未提及]的表达。结果在患者来源的GBM活检组织中得到进一步验证。我们的结果表明，乳酸显著增加了GBM细胞在[具体条件未提及]和[具体条件未提及]下的细胞增殖、迁移和集落形成能力。我们还表明，乳酸增加了[具体基因未提及]和[具体基因未提及]的表达。此外，乳酸调节上皮-间质转化蛋白标志物E-钙黏蛋白和β-连环蛋白。有趣的是，乳酸诱导线粒体质量和[具体基因未提及]基因，提示线粒体适应性改善。用3,5-二羟基苯甲酸（一种已知的[具体受体未提及]激动剂）处理后观察到类似效果。一致地，GBM斑马鱼模型表现出代谢改变以及[具体基因未提及]和[具体基因未提及]表达增加，导致细胞外乳酸水平升高，从而支持肿瘤细胞增殖。我们来自人GBM活检组织的数据还表明，在高增殖性GBM活检组织中，与低增殖性GBM细胞相比，Ki67阳性细胞表达的[具体基因未提及]水平显著更高。总之，我们的数据表明，乳酸及其转运体和受体在GBM增殖和迁移中起主要作用，因此代表了对抗肿瘤进展和复发的新治疗策略的潜在靶点。
