衰老 → MMA → 肿瘤

 ॐ  

左上方蓝字“HACS”！ॐ

导读：

关于衰老与癌症的因果关系，最近的一篇nature文章给出了答案。

---

文章截图

Abstract：

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifcally, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.

原文摘要：

从65岁起，人类患癌症的风险和癌症相关死亡率大幅增加。然而，我们对年龄和癌症之间复杂关系的理解仍处于初级阶段。几十年来，这种联系很大程度上归因于老年人接触诱变剂的时间增加。这种观点并不能解释饮食、运动和小分子在代谢衰老中的作用。本研究表明，随着年龄增长发生的代谢变化可以产生一个有利于肿瘤发展和侵袭性的系统环境。具体地说，甲基丙二酸(MMA)——丙酸代谢的副产品——在老年人的血清中被上调，并作为肿瘤发展的调节子。我们就此现象继续研究，发现MMA可以诱导SOX4表达，从而引起转录重编程，进而赋予癌细胞侵略性特性。因此，MMA 的积累构建了衰老和癌症发展之间的桥梁，这提示MMA是一个有希望的晚期癌症治疗靶点。

正文：    

在这篇文章之前，就已经有很多证据表明癌细胞的外部因素是调节肿瘤增殖的关键因素。作者就猜想衰老可能会产生一个易于肿瘤增殖和侵袭的系统微环境。（而不是肿瘤细胞通过基因突变来适应衰老本身创造的环境）

     为了验证这个猜想，他们分别用30名年轻(≤30岁)和30名老年(≥60岁)健康捐赠者的10%人血清(Human serum，HS)培养了人类癌症细胞（A549、HCC1806）。

实验结果：

	细胞形状	EMT相关标志物（癌变）	侵袭性相关标志物
年轻血清培养的细胞	上皮的形态	上皮细胞标志物E-cadherin	--
老年血清培养的细胞	间充质细胞（失去了极性并且显示一个纺锤状形态）	间充质标志物纤连蛋白（fibronectin）和波形蛋白（vimentin）	侵袭性表型相关的serpine1和MMP2蛋白

作者在小鼠上也得到了同样的结果。以上结果表明，全身性衰老和年龄诱导的循环因子（也就是血液中的因子）有助于促进癌症获得侵袭性。

An age-induced circulatory factor promotes cancer aggression

年龄诱导的循环因子促进癌症侵袭性

a, Diagram showing experimental design (see Methods). b, Immunoblots of A549 cells cultured for 4 days in HS from young or old donors; see Extended Data Fig. 4a (total of n = 30 biologically independent samples per HS donor group). c, Resistance to carboplatin in A549 cells cultured for 4 days in HS (n = 15 biologically independent samples per HS donor group, two-sided ANOVA). d, e, Metastatic properties of MDA-MB-231-luciferase cells cultured for 5 days in HS evaluated by immunoblots (d; n = 6 biologically independent samples per HS donor group) and lung colonization assay (e; n = 11 biologically independent samples, each the average of three mice used as technical replicates, per HS donor group, two-sided t-test); examples shown to the right. c, e, Data presented as mean ± s.e.m. For gel source data, see Supplementary

     确定不同血清产生的效果过后，需要分析两种血清的不同之处才能确定具体是那种因素导致的结果。作者检测了两种血清的代谢物组成，发现只有三种代谢物——磷酸烯醇丙酮酸、喹啉酸和甲基丙二酸(MMA)——在老年血清中持续增加，这说明很可能是三种代谢物的增加促进的癌细胞的发展。然而，用这三种代谢物处理癌细胞后只有MMA（主要是丙酸代谢的副产物）会引起完全的促进侵袭的EMT表型和促进侵袭蛋白的表达。这样的话研究对象就更加具体了。

MMA induces aggressive traits of cancer cells

甲基丙二酸诱导肿瘤细胞具有侵袭性

a, Concentrations of MMA in all HS samples (n = 30 biologically independent samples per HS donor group). b, Immunoblots of A549 cells treated with MMA for 10 days; representative images (n = 4 independent experiments). c, Transwell migration and invasion assays of MCF-10A cells treated with MMA for 10 days (n = 4 independent experiments). d, Lung colonization assay of MDA-MB-231-luciferase cells treated with MMA for 5 days (n = 10 mice per group; example mice shown to right). e–g, End-point serum MMA concentrations (e; n = 8 mice per group), bioluminescence intensity of the primary tumours (f, n = 9 mice per group), and metastases (g; n = 9 mice per group) in mice that were xenografted with MDA-MB-231-luciferase cells and subcutaneously injected with MMA daily. h, Kaplan–Meier curve of mice xenografted with MDA-MB-231-luciferase cells and treated with MMA either subcutaneously or through drinking water (n = 19 mice per experimental group). a, c–g, Mean ± s.e.m., two-sided t-test; h, Mantel–Cox test. For gel source data, see Supplementary Fig. 2.

      为了进一步研究MMA是怎样诱发癌细胞的这种表型，作者利用Gene set enrichment analysis (GSEA)实验发现MMA可以诱导SOX4（一种不良预后标志物，有助于肿瘤增值和转移形成，在多种侵袭性肿瘤中异常高表达，并被认为是EMT的主要调控因子）的表达，通过验证发现是MMA激活TGFβ信号从而诱导SOX4表达，进而引发侵袭性相关的转录重编程，赋予癌细胞侵袭性。 

MMA triggers pro-aggressive transcriptional reprogramming by activation of TGFβ signalling and consequent induction of SOX4

MMA 通过激活TGFβ信号产生SOX4诱导促进侵袭性转录重编程

a, b, Immunoblots of A549 cells treated with MMA for 10 days (a; n = 4 independent experiments) or HS for 4 days (b; n = 6 biologically independent samples, each the average of three mice used as technical replicates, per HS donor group). c, d, Lung colonization assay of MDA-MB-231-luciferase cells with SOX4 knockdown (shSOX4 no. 1 or no. 2) and treated with 5 mM MMA (c; n = 8 mice per group) or HS from old donors (d; n = 6 mice per group) for 5 days. shNT, non-specific shRNA. e, Levels of TGFβ-2 ligand in conditioned medium from A549 cells treated with 5 mM MMA (n = 4 independent experiments). f, g, TGFB2mRNA levels determined by qPCR (f; vehicle n = 5, MMA n = 8 mice) and immunoblots (g; representative images, n = 8 mice per group) in tumour samples from mice subcutaneously injected with the lower dose of MMA daily. h, Immunoblots of A549 cells treated with 5 mM MMA in the presence of TGFβ-neutralizing antibody; representative images (n = 4 independent experiments). c–f, Mean ± s.e.m., two-sided t-test. For gel source data, see Supplementary Fig. 2. ppSMAD3 S423/S425: SMAD3 phosphorylated on serine 423 and serine 425.

总之，MMA代谢物的积累架起了衰老和癌症增殖之间的桥梁，提示MMA是晚期癌的一个有前途的治疗靶点。

------------------------------------------------------------------------

嫌太长不爱看的看这：

由于衰老引起的甲基丙二酸（MMA）代谢物的积累会促进肿瘤的增殖。下图是它的结构式。

甲基丙二酸(MMA)

-------------------------------------------------------------------------