Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay

Abstract

Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox-and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability. Cancer Res; 72(19); 5130-40. Ó2012 AACR.

15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma

“…Consistent with the findings from Fiaschi et al (2012), we also demonstrated that microenvironment, represented by fibroblasts, strongly affects tumor metabolism and growth capacity. In particular, we demonstrated that primary fibroblasts and tumor cells establish reciprocal metabolic changes.…”

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…38 Then, it was demonstrated that stromal cells may perform aerobic glycolysis under the influence of tumor cells and donate lactate to feed OxPhos metabolism of tumor cells, the so-called "Reverse Warburg Effect." [39][40][41] Metformin, a drug that is found to be effective in tumors, [42][43][44][45] when it was added in acidic medium, which will be used for MSC conditioning, blocks TGFb expression and reverts inhibition of GLUT 1 and 3 elicited by acidic medium in MSC. Moreover, melanoma cells conditioned by LpH-metformin-treated MSC medium exhibited a reconstituted epithelial-like profile and a reduced invasion, that were associated with a reduction of GLUT 1, 3.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…FDG-PET cannot be used to detect primary tumors; reviewed in [124,125]) suggest that other substrates are fueling cancer growth. Specifically, a lactate-shuttle between cancer-associated fibroblasts and tumor-tissue was proposed [126], since cancer-associated fibroblasts express the monocarboxylate transporter 4 and tumors overexpress the monocarboxylate transporter 1 (reverse Warburg effect) [127][128][129][130]. This relationship allows the tumor to take up lactate and to convert it to pyruvate, which is processed in the tricarboxylic acid cycle.…”

“…This suggests that a substantial portion of the glucose taken up is channeled through the pentose phosphate pathway for reduction of NADP + and consequently glutathione disulfide, as well as for de novo nucleotide biosynthesis [168,169]. Besides, prostate cancer still relies on oxidative phosphorylation, which is enforced by the interaction with cancer-associated fibroblasts as shown for PC-3 cells [127]. Consistently metformin, an inhibitor of mitochondrial complex I, provokes a decrease of proliferation with a subsequent activation of reductive glutamine metabolism in vitro and in a TRAMP mouse model [159,170].…”