Figure 2.

The autophagic tumor stroma model of cancer metabolism: Role of oxidative stress, recycled nutrients and random mutagenesis. (A) Oxidative Stress, Recycled Nutrients and Resistance to Apoptosis. We have shown that human breast cancer cells induce ROS (reactive oxygen species) production in adjacent cancer-associated fibroblasts (CAFs), leading to the onset of stromal oxidative stress. Oxidative stress in CAFs, in turn, drives autophagy via HIF1 induction and NFκB activation, resulting in the autophagic destruction of mitochondria (mitophagy) and caveolin-1 (Cav-1). Stromal autophagy and mitophagy provides recycled nutrients via catabolism and aerobic glycolsysis to feed the appetite of adjacent cancer cells. These recycled chemical building blocks (derived from autophagy and aerobic glycolysis) “fuel” oxidative mitochondrial metabolism in cancer cells and provide resistance against apoptosis. Mechanistically, fibroblasts induce the expression of TIGAR in adjacent cancer cells, which shuts down autophagy and apoptosis in these cancer cells. (B) Random mutagenesis and tumor-stroma co-evolution. Oxidative stress in cancer-associated fibroblasts (CAFs) also produces a local DNA damage response, with increased ROS production. ROS amplification in the tumor stroma then leads to an antioxidant defense in adjacent cancer cells. In addition, stromal ROS production also leads to DNA damage in adjacent cancer cells via a “Bystander Effect”. As a consequence, stromal ROS promotes aneuploidy and genomic instability in cancer cells, driving tumor-stroma co-evolution. CAFs, cancer-associated fibroblasts; ROS, reactive oxygen species.