Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production
Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production
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DOI：
10.4161/cc.20718
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发表时间：
2012-06-15
期刊：
影响因子：
4.3
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
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作者：
Capparelli, Claudia;Guido, Carmela;Lisanti, Michael P.
已知衰老的成纤维细胞促进肿瘤生长。然而，确切的机制在很大程度上仍然未知。一个重要的线索来自最近的研究，将自噬与衰老的发生联系起来。因此，自噬和衰老可能是同一生理过程的一部分，称为自噬-衰老转变（AST）。为了验证这一假设，用端粒酶永生化的人成纤维细胞（hTERT-BJ 1）用自噬基因（BNIP 3、CTSB或ATG 16 L1）稳定转染。它们的过度表达足以诱导组成性自噬表型，具有线粒体自噬、线粒体功能障碍和向有氧糖酵解转变的特征，导致L-乳酸和酮体产生。自噬性成纤维细胞也表现出衰老的特征，具有增加的p21（WAF 1/CIP 1）（CDK抑制剂）、细胞肥大和增加的β-半乳糖苷酶活性。因此，我们从遗传学上证实了自噬-衰老过渡的存在。重要的是，当与人乳腺癌细胞共注射时，自噬衰老成纤维细胞促进肿瘤生长和转移，而不依赖于血管生成。当两种细胞类型共培养时，自噬衰老成纤维细胞刺激相邻癌细胞中的线粒体代谢，如通过MitoTracker染色所观察到的。特别是，产生大量酮体（3-羟基丁酸酯）的自噬性ATG 16 L1成纤维细胞具有最强的作用，并促进高达11倍的转移。相反，上皮癌细胞中ATG 16 L1的表达抑制了肿瘤生长，这表明自噬的作用具有区室特异性。因此，自噬衰老成纤维细胞通过旁分泌产生高能线粒体燃料代谢促进肿瘤生长和转移。我们目前的研究提供了遗传学支持的重要性，“二室肿瘤代谢”在驱动肿瘤的生长和转移，通过一个简单的能量转移机制。最后，β-半乳糖苷酶，一种已知的溶酶体酶和衰老的生物标志物，定位于人乳腺癌组织中的肿瘤间质，为我们的假设提供了体内支持。对从人类乳腺癌中分离的肿瘤间质的全基因组转录谱的生物信息学分析也证实了自噬-衰老转变的开始。总之，这些研究建立了宿主衰老，自噬，肿瘤微环境和癌症代谢之间的新功能联系。
Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIP1), a CDK inhibitor, cellular hypertrophy and increased beta-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of "two-compartment tumor metabolism" in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, beta-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.