Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells.

Cancer-associated fibroblasts (CAFs) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAFs isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Here, we analyzed the mechanisms underlying this support of tumor-cell survival by CAFs. As direct contact between lymphoma cells and CAFs was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAFs. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was cancelled by the inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in co-culture with CAFs demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination with not only anaerobic glycolysis, but also aerobic metabolism termed the reverse-Warburg effect, involving the secretion of pyruvate from CAFs resulting in increased use of the citric acid cycle in lymphoma cells. This article is protected by copyright. All rights reserved.