958

CD40

CD40 molecule, TNF receptor superfamily member 5;CD40;CD40 molecule, TNF receptor superfamily member 5

B cell surface antigen CD40|B cell-associated molecule|CD40 antigen (TNF receptor superfamily member 5)|CD40 type II isoform|CD40L receptor|nerve growth factor receptor-related B-lymphocyte activation molecule|tumor necrosis factor receptor superfamily me

20q12-q13.2

protein-coding

OBJECTIVE; To investigate the expression of CD40 in gastric cancer and explore the correlation of CD40 with the outcome of patients. METHODS: The expression of CD40 was examined by immunohistochemistry in human gastric cancer tissues (73 cases) and adjacent normal gastric tissues (51 cases). CD40 mRNA was detected by RT-PCR in 11 gastric cancer and 11 adjacent normal gastric tissues. The patients were followed up for 60 months. The correlation of CD40 expression and the overall survival time were evaluated by Kaplan-Meier chart and Log-Rank test. Cox model was used for multivariate analysis. RESULTS: The immunoreactivity of CD40 increased in 35/73 gastric cancer tissues (47.9%) as compared to the tumor-free tissues (P = 0.0063). CD40 mRNA were detected in 72.7% (8/11) gastric cancer tissues, while not in all tumor-free tissues. After a 5-year follow-up, the survival rate was 57.9% (22/38) in CD40-negative patients, and 5.7% (2/35) in CD40-positive patients (P = 0.0022). The median survival time of patients with negative, positive, and strong CD40 expression was 56, 29 and 11 months respectively (P = 0.0085). Cox regression analysis suggested that CD40, lymph node metastasis and TNM stage were independent factors affecting the prognosis of gastric cancer patients. CONCLUSION: Normal and malignant gastric tissues are found to have its own unique CD40 expression patterns. CD40 may play a role in metastatic spread of gastric cancer and its expression may be used as an important survival predictor in human gastric cancer.

Anti-CD40 antibodies are in clinical development in patients with metastatic melanoma, a cancer that has been reported earlier to express CD40. The antitumor activity of anti-CD40 antibodies may be mediated by direct cytotoxic effects on CD40-positive melanoma cells or indirectly through modulation of host cells. In these studies, biopsies of patients with primary and metastatic melanoma, short-term cultures, and established melanoma cell lines were analyzed for CD40 expression using a combination of methods including immunohistochemistry, flow cytometry, and gene expression profiling, and the cytotoxic effects of the anti-CD40 antibody CP-870,893 on melanoma cell lines were tested using cell viability assays. CD40 was expressed at a higher frequency in metastatic melanoma lesions compared with primary melanomas. There was a variable expression of CD40 in synchronous and metachronous melanoma metastases. expression of CD40 was present in slightly over half of a large panel of short-term primary melanoma cultures, with a wide range of expression levels by flow cytometry. Similar results were obtained in established melanoma cell lines when analyzed at the mRNA level or by surface protein staining. In approximately one-third of cell lines, the expression of CD40 could be up-regulated with a histone deacetylase inhibitor. Treatment with increasing concentrations of CP-870,893 had no antitumor activity against either CD40-positive or negative melanoma cell lines. In conclusion, approximately one-third to one-half of melanomas expresses CD40 at variable levels. Direct exposure to a CD40-activating antibody does not lead to antitumor activity in melanoma cell lines, suggesting that the antitumor effects of these antibodies in the clinic may be indirectly mediated.

BACKGROUND: Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDAC) are well known. Genetic and epigenetic data were correlated with tumor biology to find specific alterations responsible for invasion and metastasis in pancreatic ductal adenocarcinomas. METHODS: A total of 16 human PDAC cell lines were used in murine orthotopic PDAC models. By means of standardized dissemination scores, local invasion and metastatic spread were assessed. mRNA and microRNA expression were studied by microarray and TaqMan low-density array. Quantitative real-time-polymerase chain reaction and flow cytometry were used for expression validation. RESULTS: CD40 was detected as a relevant target gene for differentially expressed miRNAs observed in highly invasive and metastatic PDAC only. A significant overexpression (P < .05) of CD40-related miRNAs miR-224 and miR-486 was detected in highly invasive and metastatic PDAC, whereas CD40 mRNA expression was not significantly altered. Instead, CD40 protein expression at cell surfaces of these highly invasive and metastatic PDAC was significantly reduced (P < .01). CONCLUSIONS: Epigenetic alterations with upregulated CD40-targeting miR-224 and miR-486 are related to downregulated CD40 protein expression at cell surfaces in highly invasive and metastatic PDAC. Thus, miRNA-regulated CD40 expression seems to play an important role in progression of PDAC. These data suggest a diagnostic and therapeutic potential for CD40 and/or its targeting miRNAs in PDAC.