Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth

Fibroblasts are the most abundant “non-cancerous” cells in tumors. However, it remains largelyunknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, drivingchemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAFsignaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although itis well established that altered cancer metabolism enhances tumor growth, little is known about the roleof fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs betweencatabolic 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 secondaryto a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFKBsignaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. Thesecatabolic 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) andMCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinicaloutcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts canalso help us to understand the effects of cancer cells at an organismal level, explaining para-neoplasticphenomena, 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, acrossa whole-body “ecosystem”