Fibroblasts are the most abundant "non-cancerous" cells in
tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote
tumor growth and
metastasis, driving
chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote
tumor growth. Although it is well established that altered
cancer metabolism enhances
tumor growth, little is known about the role of fibroblast metabolism in
tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic
cancer cells, in many types of human
tumors, including breast, prostate, and head &
neck cancers, as well as
lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFκB signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support
tumor growth, via the local stromal generation of mitochondrial fuels (
lactate,
ketone bodies,
fatty acids,
glutamine, and other
amino acids). New
biomarkers of this catabolic CAF phenotype (such as
caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with
anti-oxidants, are strong predictors of poor clinical outcome in various types of human
cancers. How
cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of
cancer cells at an organismal level, explaining para-neoplastic phenomena, such as
cancer cachexia. In conclusion,
cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body "ecosystem".