Figure 16.

Autophagy in cancer associated fibroblasts (CAFs) fuels tumor cell survival. Here, we present a new model in which cancer cells trigger oxidative stress and activate two pro-autophagic drivers, namely HIF-1α and NFκB, in adjacent fibroblasts. Thus, CAFs undergo autophagy and mitophagy, leading to a loss of Cav-1 and metabolic re-programming. A loss of stromal Cav-1 aggravates oxidative stress and further promotes autophagy and mitophagy. Stromal autophagy generates building blocks (such as recycled free amino acids, fatty acids and nucleotides) that can be directly utilized by cancer cells to sustain growth and maintain cell viability. HIF-1α activation and consequent mitophagy in CAFs induces mitochondrial dys-function and enhances aerobic glycolysis, leading to the secretion of high-energy nutrients (such as lactate and pyruvate) that can directly feed mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Loss of Cav-1 in stromal cells protects cancer cells from apoptosis, at least in part via TIGAR upregulation. In this model, TIGAR protects epithelial cancer cells from oxidative stress by simultaneously inhibiting three inter-related cellular processes, namely (1) aerobic glycolysis, (2) apoptosis and (3) autophagy. Thus, epithelial cancer cells exploit CAFs to satisfy their increased energy demand by forcing these stromal cells to undergo a unilateral and vectorial energy transfer (via compartment-specific autophagy) to sustain epithelial cancer cell growth. Transfer of nutrients from autophagy-prone catabolic stromal cells to autophagy-resistant anabolic cancer cells promotes epithelial cancer cell survival, thereby enhancing tumor growth.