Figure 2. Metabolic crosstalk between epithelial cancer cells and surrounding stroma.

Proposed existence of a two-compartment tumor metabolism whereby epithelial cancer cells, via reactive oxygen species (ROS) and ammonia, released as by-product of preferential glutamine use, stimulate stromal cell autophagy, mitophagy (a form of autophagy targeting selectively the mitochondria) and subsequent glycolysis. Autophagy can lead to a senescent phenotype in stromal fibroblasts, with senescence-dependent or -independent production of various SASP components. In addition, changes in metabolism of stromal cells result in release of high-energy catabolites (e.g. lactate) that fuel-back to the cancer cells (reverse Warburg effect) [6]. As discussed in the text, autosecretion, an autophagy-based unconventional secretion enabling leaderless cytokines to exit the cell without entering the secretory pathway, might contribute to modifying this stromal environment.