Catalan Institute of Oncology, Girona.
Cell Cycle. 2010 Nov 15;9(22):4461-8. doi: 10.4161/cc.9.22.14048.
Transforming Growth Factor-b (TGFb) is a major driving force of the Epithelial-to-Mesenchymal (EMT) genetic program, which becomes overactive in the pathophysiology of many age-related human diseases. TGFb-driven EMT is sufficient to generate migrating cancer stem cells by directly linking the acquisition of cellular motility with the maintenance of tumor-initiating (stemness) capacity. Chronic diseases exhibiting excessive fibrosis can be caused by repeated and sustained infliction of TGFb-driven EMT, which increases collagen and extracellular matrix synthesis. Pharmacological prevention and/or reversal of TGFb-induced EMT may therefore have important clinical applications in the management of cancer metastasis as well as in the prevention and/or treatment of end-state organ failures. Earlier studies from our group have revealed that clinically-relevant concentrations of the biguanide derivative metformin, the most widely used oral agent to lower blood glucose concentration in patients with type 2 diabetes and metabolic syndrome, notably decreased both the self-renewal and the proliferation of trastuzumab-refractory breast cancer stem cell populations. Given that: a.) tumor-initiating cancer stem cells display a significant enrichment in the expression of basal/mesenchymal or myoepithelial markers, including an increased secretion of TGFb; b.) metformin treatment impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing key drivers of the EMT genetic program (e.g. ZEB1, TWIST1, SNAIL2 [Slug], TGFbs), we recently hypothesized that prevention of TGFb-induced EMT might represent a common molecular mechanism underlying the anti-cancer stem cells and anti-fibrotic actions of metformin. Remarkably, metformin exposure not only impedes TGFb-promoted loss of the epithelial marker E-cadherin in MCF-7 breast cancer cells but it prevents further TGF-induced cell scattering and accumulation of the mesenchymal marker vimentin in Madin-Darby canine kidney (MDCK) cells. We now propose that metformin, by weakening the ability of TGFb signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis (e.g. chronic renal disease, non-alcoholic steatohepatitis, heart failure or sclerosis) and malignant progression (and likely by reducing TGFb-regulated inflammation and immune responses -inflamm-aging-), molecularly behaves as a bona fide anti-aging modality.
转化生长因子-β（TGF-β）是上皮间质转化（EMT）遗传程序的主要驱动力，该程序在许多与年龄相关的人类疾病的病理生理学中过度活跃。TGF-β 驱动的 EMT 通过将细胞迁移与肿瘤起始（干性）能力的维持直接联系起来，足以产生迁移性癌症干细胞。表现出过度纤维化的慢性疾病可由 TGF-β 驱动的 EMT 的反复和持续发作引起，这会增加胶原蛋白和细胞外基质的合成。因此，TGF-β 诱导的 EMT 的药理学预防和/或逆转可能在癌症转移的管理以及终末期器官衰竭的预防和/或治疗中具有重要的临床应用。我们小组的早期研究表明，二甲双胍这种双胍衍生物的临床相关浓度，即最广泛用于降低 2 型糖尿病和代谢综合征患者血糖浓度的口服药物，可显著降低曲妥珠单抗耐药性乳腺癌干细胞群体的自我更新和增殖。鉴于：a）肿瘤起始的癌症干细胞在表达基底/间质或肌上皮标志物方面表现出明显富集，包括 TGF-β的分泌增加；b）二甲双胍治疗通过转录抑制 EMT 遗传程序的关键驱动因素（例如 ZEB1、TWIST1、SNAIL2[Slug]、TGFbs）来阻止产生干细胞表型的发生，我们最近假设 TGF-β 诱导的 EMT 的预防可能代表二甲双胍抗癌症干细胞和抗纤维化作用的共同分子机制。值得注意的是，二甲双胍暴露不仅阻止了 MCF-7 乳腺癌细胞中 TGF-β 促进的上皮标志物 E-钙粘蛋白的丢失，而且阻止了进一步的 TGF 诱导的细胞分散和间充质标志物波形蛋白在 Madin-Darby 犬肾（MDCK）细胞中的积累。我们现在提出，二甲双胍通过削弱 TGFβ 信号在各种病理过程（包括纤维化（例如慢性肾病、非酒精性脂肪性肝炎、心力衰竭或硬化）和恶性进展（并可能通过减少 TGFβ 调节的炎症和免疫反应）中充分诱导间充质细胞状态的能力，在分子水平上表现为一种真正的抗衰老方式。
