Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling

• Published in: Free radical biology & medicine 2019-01, Vol.130, p.163-173
• Main Authors: Cruz-Bermúdez, Alberto, Laza-Briviesca, Raquel, Vicente-Blanco, Ramiro J., García-Grande, Aránzazu, Coronado, Maria José, Laine-Menéndez, Sara, Alfaro, Cristina, Sanchez, Juan Cristobal, Franco, Fernando, Calvo, Virginia, Romero, Atocha, Martin-Acosta, Paloma, Salas, Clara, Garcia, José Miguel, Provencio, Mariano
• Format: Article
• Language: English
• Subjects: A549 Cells; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Cancer; Cancer associated fibroblasts mitochondria; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cellular Reprogramming; Coculture Techniques; Fibrosis; Glycolysis; Humans; Lung - pathology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metabolism; Neoplasm Staging; OXPHOS; Reactive Oxygen Species - metabolism; Reverse Warburg effect; Signal Transduction; Transforming Growth Factor beta - metabolism; Tumor Microenvironment
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.10.450

Lung cancer is a major public health problem due to its high incidence and mortality rate. The altered metabolism in lung cancer is key for the diagnosis and has implications on both, the prognosis and the response to treatments. Although Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor microenvironment, little is known about their role in lung cancer metabolism. We studied tumor biopsies from a cohort of 12 stage IIIA lung adenocarcinoma patients and saw a positive correlation between the grade of fibrosis and the glycolysis phenotype (Low PGC-1α and High GAPDH/MT-CO1 ratio mRNA levels). These results were confirmed and extended to other metabolism-related genes through the in silico data analysis from 73 stage IIIA lung adenocarcinoma patients available in TCGA. Interestingly, these relationships are not observed with the CAFs marker α-SMA in both cohorts. To characterize the mechanism, in vitro co-culture studies were carried out using two NSCLC cell lines (A549 and H1299 cells) and two different fibroblast cell lines. Our results confirm that a metabolic reprogramming involving ROS and TGF-β signaling occurs in lung cancer cells and fibroblasts independently of α-SMA induction. Under co-culture conditions, Cancer-Associated fibroblasts increase their glycolytic ability. On the other hand, tumor cells increase their mitochondrial function. Moreover, the differential capability among tumor cells to induce this metabolic shift and also the role of the basal fibroblasts Oxphos Phosphorylation (OXPHOS) function modifying this phenomenon could have implications on both, the diagnosis and prognosis of patients. Further knowledge in the mechanism involved may allow the development of new therapies. [Display omitted] •The fibroblast component of NSCLC tumors correlates with their glycolytic phenotype.•There is a process of metabolic reprogramming in both fibroblast and tumor cells.•The metabolic reprogramming occurs independently of Alpha-SMA expression in CAFs.•Fibroblast with a decreased OXPHOS function facilitates the phenomenon.•ROS and TGFβ are involved in this process.