The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
Purpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear.Experimental Design: The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A coculture system was established, and functional assays, including ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis. A xenograft gastric cancer model and a lymph node metastasis model were established to study the function of CXCR2 in vivo.Results: CXCR2 expression is associated with the prognosis of patients with gastric cancer (P ¼ 0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells. Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop. Gastric cancer cells secrete TNF-a to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer in vitro and in vivo.Conclusions: Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.
BackgroundPancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer.MethodsThe effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine.ResultsGambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment.ConclusionsThese results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0579-0) contains supplementary material, which is available to authorized users.
In this population-based retrospective study, we aimed to investigate the association between age at diagnosis and prognosis of pancreatic cancer (PC) patients using data from the National Cancer Institute’s Surveillance, Epidemiology, and the End Results database. Different factors for stratification, like race, sex, year of diagnosis, pathological grade, American Joint Committee on Cancer stage, historic stage, and tumour location, were included to compare the survival rates of patients of different age groups, and the five-year survival rate was calculated. Multivariate analysis using Cox regression was performed to control for confounder bias, and the hazard ratio was calculated. In total, 126,066 patients were enrolled in this study. The five-year PC-specific survival of patients aged 20–40 years was almost three times that of patients aged >40 years. Stratified by race, sex, year of diagnosis, pathological grade, clinical stage, and tumour location, a descending trend of survival was observed with an increase in age. On multivariate analysis, the mortality risk of PC patients aged 40–80 years was twice that of patients aged <40 years; however, patients aged >80 years had a mortality risk three times that of patients aged <40 years. The survival rate of PC patients has improved in the last few decades. Age at diagnosis is a significant and negative prognostic factor for PC, and patients diagnosed at a relatively earlier stage had the best survival.
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