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    In addition, as well as for membrane 1428935-60-7 potential, there is a differential effect of the co-culture with different fibroblast 1428935-60-7 for ROS. The co-culture with the AF produces a greater increase of ROS in the tumor cells than the co-culture with CF1. On the contrary, the increase of ROS in both fibroblasts was similar.
    The differences in basal ROS levels between tumor cells might ex-plain why this metabolic reprogramming is restricted to the H1299 cells, while A549 cells are not capable of producing this effect. Reinforcing our results, the role of ROS in this phenomenon has been pointed out previously as the starting mechanism for this process [10].
    On the other hand, it has been described how an increase of ROS in the cell media produces an increase of the fibroblast TGF-β levels [44]. Our results showed an increase of TGF-β mRNA levels for all the cell lines when co-cultured (Fig. 5D). Again, the effect on the tumor cell line is greater when it is co-cultured with the AF. In turn TGF-β levels are key in the metabolic reprogramming towards an increase of fibroblast glycolysis and production of lactic acid, substrate for the tumor cells [26,36]. When we incubate the cells with TGF-β we see a similar effect to that produced by the co-culture; tumor cells increase the MIMP while fibroblasts reduce it. On the other hand TGF-β induces an increase of ROS in the two cell lines similar to that induced by the co-culture (Fig. 5E).
    4. Conclusions
    This study provides a better understanding of the actual tumor metabolism as it focuses on functional studies and takes into account that tumor cells are not isolated but are in constant communication to other cell types forming a particular microenvironment. Our results support the existence of the Reverse Warburg Effect in lung cancer. Interestingly, this process is restrained to some tumor cell lines; it is not necessarily associated to fibroblast activation; may be modified by different fibroblasts and implies an alteration of ROS and TGF-β levels. Out of all the previously stated information, knowing the metabolic 
    relationships between different cell types may provide: improvements in diagnosis through better interpretation of PET images; identification of different groups of patients according to their metabolic micro-environment that could have different prognoses; or even the discovery of key therapeutic targets for developing new drugs.
    Conflict of interest
    The authors declare no conflicts of interest.
    Work in the authors’ laboratories is supported by ‘‘Instituto de Salud Carlos III’’ PI13/01806 and PIE14/0064 to M.P. A.C-B, received a Spanish Lung Cancer Group fellowship. R.L-B, is supported by Comunidad Autónoma de Madrid “Garantía juvenil” contract.
    Appendix A. Supplementary material
    Supplementary data associated with this article can be found in the online version at doi:10.1016/j.freeradbiomed.2018.10.450.
    [5] S. Pavlides, D. Whitaker-Menezes, R. Castello-Cros, N. Flomenberg,
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    [36] C. Guido, D. Whitaker-menezes, C. Capparelli, R. Balliet, Z. Lin, R.G. Pestell, et al., Metabolic reprogramming of cancer-associated fibroblasts by TGF- β drives tumor growth Connecting TGF- β signaling with “ Warburg-like” cancer metabolism and L-lactate production, Cell Cycle 11 (2012) 3019–3035.
    [41] R.M. Balliet, C. Capparelli, C. Guido, T.G. Pestell, U.E. Martinez-outschoorn, Z. Lin, et al., Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth Understanding the aging and cancer connection 4065–4073, 2011.
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    Original Articles
    Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in T human gastric cancer
    Jing Zhaia,1, Jiajia Shenb,1, Guiping Xiea,1, Jiaqi Wuc, Mingfang Hec, Lili Gaod, Yifen Zhangd, Xuequan Yaoa, Lizong Shena,∗ a Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
    b Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China