Background Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. Methods To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. Results Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. Conclusions Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0972-8) contains supplementary material, which is available to authorized users.

In contrast to mitochondria in healthy cells, which utilize oxidative phosphorylation, malignant cells undergo elevated glycolysis for energy production using glucose. The objectives of this study were to evaluate whether the expression of various molecules, including pyruvate dehydrogenase kinase-1 (PDK-1), is involved in the altered glucose metabolism associated with gastric cancer prognosis and to assess the role of a therapeutic agent in targeting glucose metabolism in gastric cancer. Immunohistochemistry was performed on gastric cancer tissues obtained from 152 patients who underwent curative resection to assess the expression of hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (GLUT-1), hexokinase-2 (HK-2) and PDK-1. In an in vitro analysis, the lactate production and glucose uptake levels, cellular viability and 5-fluorouracil (5-FU) responses were evaluated before and after treatment with dichloroacetate (DCA), a PDK-1 inhibitor, in the MKN45 and AGS gastric cancer cell lines and in the non-cancerous HEK293 cell line. GLUT-1 and PDK-1 expression was significantly associated with tumor progression, although only PDK-1 expression was an independent prognostic factor for patients who received 5-FU adjuvant treatment. There was no significant difference in cell viability between the HEK293 and gastric cancer cell lines following DCA treatment. However, DCA treatment reduced lactate production and increased responsiveness to 5-FU in MKN45 cells, which expressed high levels of PDK-1 in comparison to the other cell lines. Thus, PDK-1 may serve as a biomarker of poor prognosis in patients with gastric cancer. In addition, PDK-1 inhibitors such as DCA may be considered an additional treatment option for patients with PDK-1-expressing gastric cancers.

Objective The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Background Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. Methods One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro.Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Results Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P \ 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P \ 0.001) and overall survival (P \ 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings. Conclusions The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.

Although the survival of gastric cancer (GC) patients has gradually improved, the outcomes of advanced GC patients remain unsatisfactory despite standard treatment with conventional chemotherapy or targeted agents. Several studies have shown that cancer-associated fibroblasts (CAFs), a major component of tumor stroma in GC, may have significant roles in GC progression and resistance to treatments. CAFs are a major source of various secreted molecules in the tumor microenvironment, which stimulate cancer cells and other noncancerous components of GC. Surprisingly, these factors could be involved in gastric carcinogenesis. Cytokines, including interleukin-6 and interleukin-11, or growth factors, such as fibroblast growth factor produced from CAFs, can directly activate GC cells and consequently lead to the development of an aggressive phenotype. Galectin-1 or hepatocyte growth factor can be involved in CAF-derived neovascularization in GC. In addition, recent studies showed that CAFs can affect tumor immunity through M2 polarization of tumor-associated macrophages. Finally, the current study aimed to introduce several inhibitory agents and evaluate their suppressive effects on CAFs in patients with GC progression. However, further studies are required to evaluate their safety and select appropriate patients for application in clinical settings.

BackgroundDiscoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that utilizes collagen as a ligand, is a key molecule in the progression of solid tumors as it regulates the interaction of cancer cells with the tumor stroma. However, the clinical relevance of DDR1 expression in gastric carcinoma is yet to be investigated. Here, we assessed the role of DDR1 in mediating the aggressive phenotype of gastric carcinoma and its potential as a therapeutic target.MethodsWe conducted DDR1 immunohistochemistry using a tissue microarray of 202 gastric carcinoma specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis, and cell migration in gastric cancer cell lines, and tumor growth in a xenograft animal model of gastric cancer.ResultsOur results showed that 50.5% of gastric cancer tissues are positive for DDR1 expression, and positive DDR1 expression was significantly correlated with a poor prognosis (P = 0.015). In a subgroup analysis, DDR1 expression was prognostically meaningful only in patients receiving adjuvant treatment (P = 0.013). We also demonstrated that collagen was able to activate DDR1 and increase the clonogenicity and migration of gastric cancer cells. We observed that a DDR1 inhibitor, 7rh benzamide, suppressed tumor growth in gastric cancer xenografts.ConclusionsOur findings suggest a key role for DDR1 signaling in mediating the aggressive phenotype of gastric carcinoma. Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3051-9) contains supplementary material, which is available to authorized users.

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Coumarins comprise a group of natural phenolic compounds found in a variety of plant sources. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further. The purpose of this study is to investigate cellular protective activity of coumarin compound, fraxin extracted from Weigela florida var. glabbra, under oxidative stress, to identify genes expressed differentially by fraxin and to compare antioxidative effect of fraxin with its structurally related chemicals. Of the coumarins, protective effects of fraxin against cytotoxicity induced by H2O2 were examined in human umbilical vein endothelial cells (HUVECs). Fraxin showed free radical scavenging effect at high concentration (0.5 mM) and cell protective effect against H2O2-mediated oxidative stress.

BackgroundCudrania tricuspidata extract is an important traditional herbal remedy for tumors, inflammation, gastritis, and liver damage and is predominantly used in Korea, China, and Japan. However, the anti-inflammatory effects of the extract have not yet been conclusively proved.MethodsIn this study, we investigated the effects of the CHCl3 fraction (CTC) of a methanol extract of C. tricuspidata on the lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophage cells and mouse peritoneal macrophages, and the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in RAW 264.7 macrophage cells.ResultsWe observed that the protein expression levels of inducible NO synthase and COX-2 enzymes were markedly inhibited by CTC in a concentration-dependent manner. In addition, CTC reduced the production of TNF-α, IL-1β, and IL-6 in the LPS-stimulated RAW 264.7 macrophage cells.ConclusionsOur results show that the C. tricuspidata extract could modulate macrophage-mediated inflammatory functions such as the overproduction of cytokines, NO, and PGE2. The CTC was found to be the active fraction in this context.