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.