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    Free Radical Biology and Medicine
    journal homepage:
    Original article
    Cancer-associated fibroblasts modify lung cancer metabolism involving ROS T and TGF-β signaling
    Alberto Cruz-Bermúdeza, , Raquel Laza-Briviescaa,1, Ramiro J. Vicente-Blancoa,1, Aránzazu García-Grandeb, Maria José Coronadoc, Sara Laine-Menéndezd, Cristina Alfaroa, Juan Cristobal Sancheza, Fernando Francoa, Virginia Calvoa, Atocha Romeroa,
    Paloma Martin-Acostae,f, Clara Salase, José Miguel Garciaa, Mariano Provencioa,
    a Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain b Flow Cytometry Core Facility, Hospital Universitario Puerta de Hierro Majadahonda Calle, Madrid, Spain
    c Confocal Microscopy Core Facility, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
    d Mitochondrial and neuromuscular disease laboratory, Instituto de Investigación Hospital "12 de Octubre" (i+12), Madrid, Spain
    e Departamento de Patología, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
    f Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
    Metabolism Reverse Warburg effect Cancer associated fibroblasts mitochondria
    Lung cancer is a major public health problem due to its high incidence and mortality rate. The altered meta-bolism 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 mi-croenvironment, 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 induc-tion. 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.
    1. Introduction
    One of the tumor cell´s hallmarks is its altered metabolism, adapted to support a rapid cell growth [1]. This, from a basic standpoint, is achieved by an increase in aerobic glycolysis, known as the Warburg effect, which allows the contribution of intermediary metabolites used in anabolic processes [2,3]. In fact, one of the most important systems