Giant cell tumour of bone (GCTB) is a histologically benign, locally aggressive skeletal lesion with an unpredictable propensity to relapse after surgery and a rare metastatic potential. The microscopic picture of GCTB shows different cell types, including multinucleated giant cells, mononuclear cells of the macrophage-monocyte lineage, and spindle cells. The histogenesis of GCTB is still debated, and morphologic, radiographic or molecular features are not predictive of the clinical course. Characterization of the unexplored cell metabolism of GCTB offers significant clues for the understanding of this elusive pathologic entity. In this study we aimed to characterize GCTB energetic metabolism, with a particular focus on lactate release and the expression of monocarboxylate transporters, to lie down a novel path for understanding the pathophysiology of this tumour. We measured the expression of glycolytic markers (GAPDH, PKM2, MCT4, GLUT1, HK1, LDHA, lactate release) in 25 tissue samples of GCTB by immunostaining and by mRNA and ELISA analyses. We also evaluated MCT1 and MCT4 expression and oxidative markers (JC1 staining and Bec index) in tumour-derived spindle cell cultures and CD14+ monocytic cells. Finally, we quantified the intratumoural and circulating levels of lactate in a series of 17 subjects with GCTB. In sharp contrast to the benign histological features of GCTB, we found a high expression of glycolytic markers, with particular reference to MCT4. Unexpectedly, this was mainly confined to the giant cell, not proliferating cell component. Accordingly, GCTB patients showed higher levels of blood lactate as compared to healthy subjects. In conclusion, taken together, our data indicate that GCTB is characterized by a highly glycolytic metabolism of its giant cell component, opening new perspectives on the pathogenesis, the natural history, and the treatment of this lesion.

中文翻译：

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良性糖酵解：骨巨细胞瘤中的 MCT4 表达和乳酸释放

骨巨细胞瘤 (GCTB) 是一种组织学上良性的局部侵袭性骨骼病变，具有不可预测的术后复发倾向和罕见的转移潜能。GCTB 的显微图片显示了不同的细胞类型，包括多核巨细胞、巨噬细胞-单核细胞谱系的单核细胞和梭形细胞。GCTB 的组织发生仍存在争议，形态学、放射学或分子特征不能预测临床病程。GCTB 未探索的细胞代谢特征为理解这种难以捉摸的病理实体提供了重要线索。在这项研究中，我们旨在表征 GCTB 能量代谢，特别关注乳酸释放和单羧酸转运蛋白的表达，为了解这种肿瘤的病理生理学开辟一条新途径。我们通过免疫染色以及 mRNA 和 ELISA 分析测量了 25 份 GCTB 组织样本中糖酵解标志物（GAPDH、PKM2、MCT4、GLUT1、HK1、LDHA、乳酸释放）的表达。我们还评估了肿瘤衍生的梭形细胞培养物和 CD14+ 单核细胞中的 MCT1 和 MCT4 表达和氧化标志物（JC1 染色和 Bec 指数）。最后，我们量化了一系列 17 名 GCTB 受试者的瘤内和循环乳酸水平。与 GCTB 的良性组织学特征形成鲜明对比的是，我们发现糖酵解标志物的高表达，特别是 MCT4。出乎意料的是，这主要局限于巨细胞，而不是增殖细胞成分。因此，与健康受试者相比，GCTB 患者的血乳酸水平更高。总之，我们的数据表明，GCTB 的特征在于其巨细胞成分的高度糖酵解代谢，为该病灶的发病机制、自然病程和治疗开辟了新的视角。