br In addition as well as
In addition, as well as for membrane 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 .
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 . 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).
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.
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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