Pole of Pharmacology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium.
PLoS One. 2012;7(3):e33418. doi: 10.1371/journal.pone.0033418. Epub 2012 Mar 13.
Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.
向糖酵解代谢的转变是肿瘤细胞对缺氧的快速适应。尽管这种代谢转换主要可能代表一种挽救途径，以满足增殖肿瘤细胞的生物能量和生物合成需求，但它也会产生与肿瘤中氧气梯度相匹配的乳酸盐梯度。除了代谢废物之外，已知乳酸盐阴离子通过激活肿瘤细胞中的缺氧诱导因子-1（HIF-1）途径参与癌症侵袭性，部分原因在于。然而，乳酸盐是否也可以直接有利于内皮细胞（ECs）中的 HIF-1 激活，从而为阻断血管生成提供新的可药物选择，这是一个尚未解决的问题。在这项研究中，我们因此专注于我们之前确定为癌细胞中乳酸摄取的主要促进剂的单羧酸转运蛋白 1（MCT1）在 ECs 中的作用。我们发现，阻断乳酸盐流入 ECs 会导致 HIF-1 依赖性血管生成受到抑制。我们的证明基于在常氧 ECs 中乳酸诱导的 HIF-1 激活的前所未有的表征，以及随后血管内皮生长因子受体 2（VEGFR2）和碱性成纤维细胞生长因子（bFGF）表达的增加。此外，使用包括内皮细胞迁移和管状形成在内的各种功能测定，以及通过活体显微镜和免疫组织化学对肿瘤血管生成进行体内成像，我们记录了 MCT1 阻断剂可以作为真正的 HIF-1 抑制剂，从而产生抗血管生成作用。结合先前证明 MCT1 是肿瘤细胞之间乳酸盐交换的关键调节剂，目前的研究确定 MCT1 抑制作为一种联合代谢和抗血管生成活性的治疗方式。
