Background and Objectives This study was conducted to investigate whether and how macrophages recruited to tumor microenvironments (tumor‐associated macrophages, TAMs) were involved in angiogenesis and lymphangiogenesis of gastric cancer (GC). Methods TAMs, microvessel density (MVD), and lymphatic vessel density (LVD) in 115 cases of GC tissue were assessed by immunohistochemistry (IHC) staining of CD68, CD34, and D2‐40, respectively. Preoperative blood samples from 43 patients were obtained to detect serum levels of vascular endothelial growth factor (VEGF) and VEGF‐C. A co‐culture system was also developed to study effects and underlying mechanisms of THP‐1 macrophages on SGC7901 GC cells. Results TAMs numbers were closely related to serosa invasion, lymph node metastasis and tumor, nodes, and metastases stage and a positive correlation existed between the TAMs count and MVD and LVD. Additionally, TAMs were associated with preoperative serum levels of VEGF and VEGF‐C, the expression of VEGF and VEGF‐C protein in macrophages was up‐regulated in the co‐culture system, and inhibition of the NF‐κB pathway in macrophages induced a significant reduction in the expression of VEGF and VEGF‐C in both macrophages and GC cells (all P < 0.05). Conclusions TAMs may promote angiogenesis and lymphangiogenesis of GC, possibly by enhancing VEGF and VEGF‐C expression. J. Surg. Oncol. 2012; 106:462–468. © 2012 Wiley Periodicals, Inc.
Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.
Background Cardamonin, a chalcone isolated from Alpiniae katsumadai , has anti-inflammatory and anti-tumor activities. However, the molecular mechanism by which cardamonin inhibits breast cancer progression largely remains to be determined. Methods CCK-8 and Hoechst 33258 staining were used to detect cell growth and apoptosis, respectively. HIF-1α driven transcription was measured by luciferase reporter assay. Glucose uptake and lactate content were detected with 2-NBDG and L-Lactate Assay Kit. Cell metabolism assays were performed on Agilent’s Seahorse Bioscience XF96 Extracellular Flux Analyzer. Mitochondrial membrane potential was measured with JC-1 probe. DCFH-DA was used to measure ROS level. Protein expression was detected by western blotting assay. Immunohistochemistry was performed to measure the expression of HIF-1α, LDHA and CD31 in tumor tissues. Results Cardamonin inhibited growth of the triple negative breast cancer cell line MDA-MB-231 in vitro and in vivo by suppressing HIF-1α mediated cell metabolism. Cardamonin inhibited the expression of HIF-1α at mRNA and protein levels by repressing the mTOR/p70S6K pathway, and subsequently enhanced mitochondrial oxidative phosphorylation and induced reactive oxygen species (ROS) accumulation. We also found that cardamonin inhibited the Nrf2-dependent ROS scavenging system which further increased intracellular ROS levels. Eventually, accumulation of the intracellular ROS induced apoptosis in breast cancer cells. In addition, cardamonin treatment reduced glucose uptake as well as lactic acid production and efflux, suggesting its function in repressing the glycolysis process. Conclusions These results reveal novel function of cardamonin in modulating cancer cell metabolism and suppressing breast cancer progression, and suggest its potential for breast cancer treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1351-4) contains supplementary material, which is available to authorized users.
Most colorectal carcinomas (CRCs) arise from adenomas through an archetypal pathogenic pathway, the adenomacarcinoma-metastasis sequence. Aberrant expression of -catenin, p16, E-cadherin and c-myc appears to have played important roles in the development and/or progression of CRC, but their precise distribution pattern and associations in different pathologic loci along CRC's pathogenic pathway have not been thoroughly examined. In this study, a tissue microarray (TMA) containing 85 advanced CRCs in different Dukes stages was constructed. In each of 85 cases, tissue specimens from normal mucosa and primary carcinomas in different layers of the bowel wall were included in the TMA. Tissue specimens from matched adenoma, lymph node metastases and distant metastases were obtained from 22, 21 and 21 cases, respectively. Expression patterns of -catenin, p16, E-cadherin and c-myc were evaluated by immunohistochemistry. The results revealed that nuclear expression of -catenin, p16 and c-myc was quantitatively increased from normal mucosa to premalignant adenoma, primary carcinoma and lymph node metastatic carcinoma; the frequency of nuclear overexpression of -catenin and p16 in lymph node metastases was significantly higher than that in distant metastases (p < 0.05). These results suggest an association between nuclear overexpression of -catenin and/or p16 and CRC lymph node metastasis but not distant metastasis. The results also showed that correlative high nuclear expression of -catenin and c-myc was observed in primary carcinomas involving the serosa and lymph node metastases (p < 0.05) but not in other pathologic regions of CRCs, suggesting that the tumor microenvironment in different pathologic loci of colorectal tumorigenesis and progression may influence cmyc responsiveness to -catenin/Tcf activation. © 2003 Wiley-Liss, Inc. Key words: colorectal carcinoma; heterogeneity; immunohistochemistry; fluorescence in situ hybridizationColorectal carcinoma (CRC) is one of the most common malignancies and a major cause of cancer death in the developed countries. 1 The incidence of CRC varies greatly around the world, with the highest incidence in the Western world and the lowest in India. 2 In urban Shanghai, China, the incidence of CRC increased rapidly and doubled over a 23-year period (1972-1994). 3 It is now widely accepted that most CRCs arise from adenomas through a process described as the adenoma-carcinoma-metastasis sequence. Tumorigenesis and progression of CRC is believed to be influenced by the genetic accumulation of abnormalities of numerous tumor suppressor genes and oncogenes, including nuclear overexpression of -catenin, p16 and c-myc and loss expression of membranous E-cadherin. 4 -8 However, it is well known that the distribution pattern of gene expression detected by immunohistochemistry in tumor tissue, especially in certain histologically and genetically heterogeneous tumors, is often substantially varied. Germane to the present study, previous studies have documented heterogeneous expression ...
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