title: Cigarette smoke metabolically promotes cancer, via autophagy and premature aging in the host stromal microenvironment.
abstract: 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.
authors: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. salem_ahmed82@yahoo.com
authors: Ahmed F
authors: AF
authors: Salem
authors: Mazhar Salim
authors: MS
authors: Al-Zoubi
authors: Diana
authors: D
authors: Whitaker-Menezes
authors: Ubaldo E
authors: UE
authors: Martinez-Outschoorn
authors: Rebecca
authors: R
authors: Lamb
authors: James
authors: J
authors: Hulit
authors: Anthony
authors: A
authors: Howell
authors: Ricardo
authors: R
authors: Gandara
authors: Marina
authors: M
authors: Sartini
authors: Ferruccio
authors: F
authors: Galbiati
authors: Generoso
authors: G
authors: Bevilacqua
authors: Federica
authors: F
authors: Sotgia
authors: Michael P
authors: MP
authors: Lisanti
mesh_terms: D001343:Autophagy; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006019:Glycolysis; D006801:Humans; D007657:Ketone Bodies / Q000096:biosynthesis; D019344:Lactic Acid / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D007657:Ketone Bodies; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid
keywords: autophagy; breast cancer; cancer prevention; carcinogens; cigarette smoke; ketone bodies; lactate; microenvironment; mitochondrial dysfunction; premature aging; senescence; tumor growth
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