Author(s): Akiko Kogure 1, Yutaka Naito 2, Yusuke Yamamoto 3, Masakazu Yashiro 4, Tohru Kiyono 5, Kazuyoshi Yanagihara 6, Kosei Hirakawa 4, Takahiro Ochiya 1,*
Cancer-associated fibroblasts (CAFs) are the major stromal components in various types of malignancies [1-3]. They are a heterogeneous population and originate from several stromal cell types, including resident fibroblasts, endothelial cells, pericytes, and bone marrow-derived cells [1,4]. CAFs play a pivotal role in cancer development and progression by enhancing cancer cell invasion, remodeling the extracellular matrix and mediating the inflammatory environment [1-3]. Several reports have suggested that stromal components, including CAFs, are potential therapeutic targets for cancer treatment and could be used to improve cancer diagnosis [5-7].
Growing evidence suggests that CAFs undergo aerobic glycolysis and produce various types of metabolites to support tumor growth . Lactate is shuttled from CAFs via MCT4, and that mechanism is utilized by cancer cells for promoting the Krebs cycle as well as anabolic metabolism and cell proliferation . It has also been reported that reprogrammed CAFs in the metastatic niche by tumor-derived extracellular vesicles (EVs) create a metabolic environment that supports tumor metastasis [9-11]. Targeting strategies of tumor stroma might diminish the nutrient balance within the tumor, leading to novel effective therapies for cancer treatment. However, several studies demonstrated that CAFs have many various subtypes with distinct functions and phenotypes during cancer progression [12-15]. These CAF phenotypes differ according to the cancer subtype and aggressiveness [13,15]. Although it is possible that the malignant properties of cancer cells exert a different effect on glucose metabolism in fibroblasts within the tumor microenvironment, it remains unclear whether the metastatic potential of cancer cells can be used to metabolically reprogram surrounding stromal cells.
We previously reported that highly metastatic gastric cancer (GC) cells more strongly affected the fibroblast phenotypes than did GC cells with low metastatic potential . In this model, highly metastatic GC cells induced glycolysis-related gene expression in fibroblasts, but GC cells with low metastatic potential did not, suggesting that highly metastatic cancer cells potentially reprogram the metabolic status of surrounding fibroblasts. Here, with a metastatic model of diffuse-type gastric cancer (DGC), we investigated how the difference in glucose metabolism appeared by comparing DGC cells with high and low metastatic potential. Our study revealed that cancer cells with high metastatic capacity can strongly induce metabolic reprogramming. These results might provide novel information regarding the formation of a metabolic microenvironment for tumor metastasis.
Materials and methods
HSC-44PE and 44As3 cell lines were used as described previously . Two human normal gastric fibroblasts (NFs) were immortalized by infection with retroviruses expressing mutant Cdk4, cyclin D1 and human telomerase reverse transcriptase, as previously described; the resultant lines were named iNF-58 and iNF-60 . Briefly, GC cell lines were cultured in RPMI-1640 (Thermo Fisher Scientific, Rockford, IL) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Gibco, Thermo Fisher Scientific) and 1% Antibiotic-Antimycotic (Thermo Fisher Scientific) at 37°C in 5% CO 2 . iNF-58 and iNF-60 cells were cultured in Dulbecco's modified Eagle...