Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cell Cycle. 2013 Mar 1;12(5):818-25. doi: 10.4161/cc.23722. Epub 2013 Feb 6.
Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora of different human cancer subtypes, including breast cancers. The prevailing view is that cigarette smoke acts as a mutagen and DNA damaging agent in normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on the normal stromal microenvironment have been largely ignored. Here, we propose a new mechanism by which carcinogen-rich cigarette smoke may promote cancer growth, by metabolically "fertilizing" the host microenvironment. More specifically, we show that cigarette smoke exposure is indeed sufficient to drive the onset of the cancer-associated fibroblast phenotype via the induction of DNA damage, autophagy and mitophagy in the tumor stroma. In turn, cigarette smoke exposure induces premature aging and mitochondrial dysfunction in stromal fibroblasts, leading to the secretion of high-energy mitochondrial fuels, such as L-lactate and ketone bodies. Hence, cigarette smoke induces catabolism in the local microenvironment, directly fueling oxidative mitochondrial metabolism (OXPHOS) in neighboring epithelial cancer cells, actively promoting anabolic tumor growth. Remarkably, these autophagic-senescent fibroblasts increased breast cancer tumor growth in vivo by up to 4-fold. Importantly, we show that cigarette smoke-induced metabolic reprogramming of the fibroblastic stroma occurs independently of tumor neo-angiogenesis. We discuss the possible implications of our current findings for the prevention of aging-associated human diseases and, especially, common epithelial cancers, as we show that cigarette smoke can systemically accelerate aging in the host microenvironment. Finally, our current findings are consistent with the idea that cigarette smoke induces the "reverse Warburg effect," thereby fueling "two-compartment tumor metabolism" and oxidative mitochondrial metabolism in epithelial cancer cells.
香烟烟雾已被直接牵连到多种不同人类癌症亚型的疾病发病机制中，包括乳腺癌。目前的观点认为，香烟烟雾在正常上皮细胞中充当诱变剂和 DNA 损伤剂，从而驱动肿瘤起始。然而，其对正常基质微环境的潜在负面代谢影响在很大程度上被忽视了。在这里，我们提出了一个新的机制，即富含致癌物的香烟烟雾可能通过代谢“施肥”宿主微环境来促进癌症生长。更具体地说，我们表明，香烟烟雾暴露确实足以通过诱导肿瘤基质中的 DNA 损伤、自噬和线粒体自噬来驱动癌症相关成纤维细胞表型的出现。反过来，香烟烟雾暴露诱导基质成纤维细胞过早衰老和线粒体功能障碍，导致高能线粒体燃料（如 L-乳酸和酮体）的分泌。因此，香烟烟雾在局部微环境中诱导分解代谢，直接为邻近的上皮癌细胞的氧化线粒体代谢（OXPHOS）提供燃料，积极促进合成代谢肿瘤生长。值得注意的是，这些自噬衰老的成纤维细胞使体内乳腺癌肿瘤生长增加了高达 4 倍。重要的是，我们表明香烟烟雾对成纤维细胞基质的代谢重编程发生在肿瘤新生血管形成之外。我们讨论了我们目前发现对预防与衰老相关的人类疾病的可能影响，特别是常见的上皮癌，因为我们表明香烟烟雾可以系统性地加速宿主微环境中的衰老。最后，我们目前的发现与香烟烟雾诱导“反向瓦堡效应”的观点一致，从而为上皮癌细胞中的“双室肿瘤代谢”和氧化线粒体代谢提供燃料。
