Background & Aims: Macrophages (Mu) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor Mu are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue Mu pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating Mu in human hepatocellular carcinoma (HCC). Methods: Flow cytometry analyses were performed to examine the presence and phenotype of proliferating Mu in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating Mu. The underlying regulatory mechanisms were examined using human monocytederived Mu. Results: Tumor-infiltrating Mu exhibited a significantly higher proliferative capacity than Mu in non-tumor tissues. A higher level of Mu proliferation was positively correlated with Mu density in the tumor and a poor prognosis in patients with HCC. Proliferating Mu were less differentiated (with increased CD206 expression) and were induced by the tumor cell-derived soluble small molecule, adenosine, but not proteins, lipids, or large peptides. Mechanistic studies demonstrated that autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) released by tumor-stimulated Mu could enhance A2A receptor expression on Mu and function synergistically with adenosine to elicit Mu proliferation in HCC. Conclusions: Local Mu proliferation is an important mechanism for Mu accumulation in HCC tissues. Tumor-derived adenosine functions synergistically with autocrine GM-CSF released from activated Mu, which promotes Mu proliferation. Thus, selective modulation of Mu accumulation at the source may provide a novel strategy for cancer therapy. Lay summary: Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.
As an indispensable factor in preventing the recirculation of tissue lymphocytes to the lymphatic and blood systems, the integrin CD103 has enabled the characterization of lymphocyte populations in non-lymphoid tissues and organs. However, the expression, distribution, and clinical significance of CD103 + tumor-infiltrating lymphocytes (TILs) in esophageal squamous cell carcinoma (ESCC) remain unclear. In the present study, we included tumor and adjacent non-tumor tissue specimens from 198 patients with ESCC who had undergone surgical resection. Immunohistochemistry and immunofluorescence were used to detect CD103 + TIL distribution, as well as the co-expression of CD103 and T cell markers and functional molecules. Kaplan-Meier analysis and the Cox proportional hazards model were used to estimate the prognostic value of CD103 + TILs. The results showed that CD103 + TILs were predominantly located in adjacent non-tumor tissues compared with tumor tissues (P < 0.0001). Immunofluorescence double staining revealed that CD8 + T cells, but not CD4 + T cells, comprised the majority of CD103-expressing cells. Most of these CD103-expressing cells co-expressed CTLA-4 and granzyme B rather than the exhaustion marker PD-1. High density of intratumoral CD103 + TIL is associated with longer overall survival (OS) and disease-free survival (DFS) in both the internal (OS, P = 0.0004 and DFS, P = 0.0002) and external (OS, P = 0.038 and DFS, P = 0.12) cohorts. Multivariate Cox analysis showed the density of CD103 + TILs was an independent positive prognostic factor for OS (hazards ratio [HR] = 0.406;
Macrophages (Mϕ) are prominent components of solid tumours and exhibit distinct phenotypes in different microenvironments. Previously, we found that tumours could alter the normal developmental process of Mϕ to trigger transient activation of monocytes in the peritumoural stroma of human hepatocellular carcinoma (HCC). In the present study, we showed that a fraction of monocytes in the peritumoural stroma, but not in HCC cancer nests, expressed surface c-Met molecules. Monocytes exposed to tumours strongly expressed c-Met proteins with kinetics similar to their activation status, and significant correlations were found between c-Met levels and HLA-DR expression on tumour-infiltrating monocytes. NF-κB-mediated autocrine TNF-α stimulated the expression of c-Met on activated monocytes, and by interacting with its ligand hepatocyte growth factor (HGF), c-Met increased the motility and matrix metalloproteinase (MMP) 9-producing capacity of tumour-associated monocytes. The intensity of c-Met expression on tumour-infiltrating monocytes was associated with high mortality and reduced survival of patients with HCC. Therefore, the expression of c-Met on activated monocytes/Mϕ may represent a novel mechanism by which a tumour actively and precisely regulates the distribution and functions of these cells to facilitate disease progression.
Interleukin-25 (IL-25) is a recently identified member of the proinflammatory IL-17 cytokine family; however, its role in human tumors remains largely unknown. The aim of this study was to investigate the cellular source and clinical significance of IL-25 in gastric cancer (GC) in situ. The results demonstrated that macrophages (Mφs) were the primary IL-25-expressing cells (IL-25+) in GC in situ. Moreover, IL-25+ cells were highly enriched in the intra-tumoral (IT) region of GC tissues (p < 0.001). The production of IL-25 in Mφs exposed to culture supernatant from gastric cancer cell line SGC7901 in vitro was induced by transforming growth factor-β1, and their density in the IT region was positively associated with those of other effector immune cells, namely, CD4+ T cells, CD8+ T cells and CD103+T cells (p < 0.01). This suggested that macrophages might produce IL-25 to create an antitumor micromilieu in GC tissues. The level of IL-25+IT cells was positively associated with histological grade (p < 0.001) and found to be an independent predictor of favorable survival (p = 0.024) in patients with GC after radical resection. These findings suggest that IL-25+IT cells may be a novel therapeutic target in those patients.
Salmonella typhimurium is a pathogenic gram-negative bacterium, which is found primarily in the intestinal lumen. it often causes diarrhea in infants and young children and leads to food poisoning. Drug resistance of Salmonella typhimurium presented serious complications in clinical patients. in this study, we investigated the antibiotic susceptibility of Salmonella typhimurium standard strain L forms to the third and forth generation cephalosporins, in order to control and eliminate Salmonella typhimurium L forms in infection treatment. Salmonella typhimurium L forms were induced by β-lactam antibiotic cefazolin in the culture medium of bacterial L forms. the antibiotic susceptibility of Salmonella typhimurium L forms was analyzed by K-B drug susceptibility testing. The change trend of drug susceptibility and resistance of Salmonella typhimurium L forms was obtained in accordance with USA clinical and laboratory standards institute (CLSI) evaluation data and statistical analysis. Drug resistance of Salmonella typhimurium L forms showed little increasing trend compared with their parent bacteria. The L form inhibition zone was smaller than in the parent bacteria. However, the drug susceptibility of L forms of Salmonella typhimurium to the third and forth generation cephalosporins remained sensitive.the antibiotic susceptibility of Salmonella typhimurium L forms to the third and forth generation cephalosporins remains sensitive, and the combined use of multi-antibiotics is a convenient and effective method to reduce Salmonella typhimurium L forms occurrence. Because of the immature immunity of infants and young children, bacterial acquired antibiotic resistance and poor sanitation, Salmonella typhimurium (S. typhimurium) has become the main pathogen in nosocomial and foodborne infection 1-3. Salmonella typhimurium possesses endotoxin, enterotoxin and extracellular enzymes as well as other pathogenic factors, so that Salmonella typhimurium has strong pathogenicity 4,5. After the use of antibiotics, it was easy to make Salmonella typhimurium form into cell wall-defective bacteria named bacterial L forms 6-8. BacteriaL L forms still have the ability to cause disease, such as leading to the delay of chronic infection, and decreased susceptibility to antibacterial drugs which act on cell walls 9,10. In these experiments, we studied the resistance of Salmonella typhimurium standard strain L forms to advanced cephalosporins and judged the susceptibility degree of Salmonella typhimurium L forms to the third and fourth generation cephalosporins, in order to guide the rational use of clinical antibacterial drugs. The study will provide the basic theory for controlling Salmonella typhimurium infection. Materials and Methods Bacterial strain. Salmonella typhimurium standard strain CMCC50115 was purchased from the National Institute for the Control of Pharmaceutical and Biological Products.
Epithelial ovarian cancer (EOC) is a common ovarian cancer in gynecological cancers today. It has been found that microRNAs and long‐chain noncoding RNA (lncRNA) regulate the gene transcriptional expression in cells. However, it is not well understood that the upstream and downstream regulatory molecules of lncRNA HOX antisense intergenic RNA (HOTAIR). The effects of miR‐200c overexpression on the invasion and nude mouse tumorigenicity, as well as lncRNA HOTAIR and snail expression of EOC SKOV3 cells, should be further explored. The expression of miR‐200c and lncRNA HOTAIR was detected by reverse transcription PCR (RT‐PCR) in EOC SKOV3 cells. The whole miR‐200c gene fragment was cloned into a lentiviral plasmid vector. The miR‐200c expression in transducted SKOV3 cells with reconstructed miR‐200c lentivirus was significantly higher than the negative control (P < .01). The lentivirus‐miR‐200c‐SKOV3 cells show that the invasion ability was significantly decreased compared with the negative control (P < .01). The nude mouse tumorigenicity was significantly decreased compared with that of the control group (P < .01). The snail protein expression in lentivirus‐miR‐200c‐SKOV3 xenograft tumor was significantly decreased compared with the negative control lentivirus‐SKOV3 group (P < .05). The miR‐200c overexpression significantly decreased the expressions of lncRNA HOTAIR and snail, but increased E‐cadherin expression in the lentivirus‐miR‐200c transducted SKOV3 cells of xenograft tumor, compared with the negative control (P < .05). The miR‐200c overexpression in SKOV3 cells with transducted lentivirus‐miR‐200c can inhibit lncRNA HOTAIR expression, decrease snail, increase E‐cadherin and significantly reduce the invasion and tumorigenicity of EOC SKOV3 cells. These results suggest that the miR‐200c and lncRNA HOTAIR could be effective therapeutic targets for human epithelial ovarian cancer treatment.
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