Martinelli Serena, Amore Francesca, Mello Tommaso, Mannelli Massimo, Maggi Mario, Rapizzi Elena
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy.
Centro di Ricerca e Innovazione Sulle Patologie Surrenaliche, AOU Careggi, 50134 Florence, Italy.
Cancers (Basel). 2022 Jul 17;14(14):3471. doi: 10.3390/cancers14143471.
Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.
嗜铬细胞瘤/副神经节瘤（PPGLs）是神经内分泌肿瘤，通常为非转移性肿瘤，但对于其转移性形式尚无有效的治疗方法。最近的研究表明，二甲双胍在包括PPGLs在内的许多人类癌症中具有抗增殖活性。然而，关于二甲双胍对PPGL细胞（二维，2D）和球体（三维，3D）迁移/侵袭作用的数据尚不可得。在本研究中，我们观察到二甲双胍对嗜铬细胞瘤小鼠肿瘤组织（MTT）的二维和三维培养物具有抗增殖作用，无论其SDHB亚基是否沉默。然而，二甲双胍并不影响MTT的迁移。另一方面，二甲双胍对小鼠原代成纤维细胞的增殖没有短期影响，但显著降低了它们的迁移能力。尽管二甲双胍诱导的代谢变化在MTT和成纤维细胞之间相似（即ATP产生总体减少，细胞内乳酸浓度增加），但激活的信号通路不同。事实上，给予二甲双胍后，MTT显示Akt和Erk1/2的磷酸化减少，而成纤维细胞则表现为N-钙黏蛋白下调和E-钙黏蛋白上调。在此，我们证明二甲双胍对细胞生长和扩散的影响因细胞类型而异，强调了肿瘤微环境在决定药物反应中的重要性。
