Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer

Abstract

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD + /NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

“…Both Th1 and Treg cells are reprogrammed by an activation of a lactate-driven epigenetic pathway, causing activation of T-bet or NF-kB/FoxP3 transcription factors. This lactate-based reprogramming of T-cell response leads to enhance malignancy of prostate tumors, thereby confirming the immunomodulatory role of lactate (51). Furthermore, cancer cell-derived lactate is able to polarize M1 macrophages into M2 ones, activating different signaling cascades (i.e., VEGF, arginase-1) in macrophages undergoing pro-tumor differentiation (57).…”

“…Interestingly, the MCT-mediating lactate influx and efflux activity involves protons (H + ), thereby leading to an apparent paradox. As several accessory cells in TME concur to decrease extracellular pH [due to the overexpression of carbonic anhydrases or proton pumps, commonly occurring in both cancer cells and CAFs (48,49)], lactate/H + -coupled transport by MCTs tends to drive lactate from the interstitium into tumor cells (50), allowing them to anabolize this nutrient (51). Furthermore, the physical association between carbonic anhydrases (CA) and lactate transporters MCT-1/4 plays a key role in the regulation of the directional flux of lactate, as well as in the protonation/deprotonation of proteins, thereby affecting their functions.…”

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

“…[51][52][53]). Considerable evidence suggests that this metabolic rewiring of metabolism in stromal cells contributes to cancer malignancies [51][52][53][54][55][56][57][58][59]. Our results suggest that as the Gleason grade increases, rewiring of glutamine metabolism in the stromal cell compartment contributes to advancing malignancy.…”

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

“…To date, it is widely accepted that cancer outcome does not only depend on the behavior of cancer cells, but also on the tumor microenvironment (TME) that coevolves with cancer cells, sustaining the enhancement of tumor malignancy. We previously demonstrated that cancer-associated fibroblasts (CAFs), the most represented stromal cells in the prostate TME, play an intriguing role during all stages of disease progression, including metastasis [14][15][16][17][18][19][20]. Herein, we show a selective action of WIN 55-212.2 mesylate, a synthetic cannabinoid with affinity for CB 1 and CB 2 higher than THC, on prostate cancer cell lines without affecting healthy counterpart.…”