Integrin alphavbeta6 promotes tumor tolerance in colorectal cancer.

Tumor immune tolerance plays a critical role in tumor cell survival; the establishment of tumor immune tolerance is incompletely understood yet. Integrin alphavbeta6 (avb6) is involved in tumor growth and metastasis. This study aimed to observe the effect of avb6 on the development of tumor tolerance in colorectal cancer (CRC). In this study, 28 CRC patients were recruited. The frequencies of tolerogenic dendritic cells (TolDC), regulatory T cells (Treg), and CD8+ T cells in surgically removed CRC tissue were assessed by flow cytometry. The levels of avb6 in CRC tissue were measured by enzyme-linked immunoassay (ELISA). The effect of avb6 on inducing TolDCs and Tregs was evaluated with the cell culture model. The results showed that in surgically removed CRC tissue, we detected higher frequencies of TolDC and Tregs, lower frequency CD8+ T cells and high levels of avb6 as compared with non-CRC tissue. CRC protein extracts could induce TolDC development that could be blocked by anti-avb6 antibody. CRC-derived DCs could convert naïve CD4+ T cells to Tregs. Peripheral CD8+ T cells from CRC patients still retained the ability to produce granzyme B and to proliferate in response to CRC tumor antigen in culture that was abolished by the presence of CRC-derived Tregs. We conclude that CRC-derived avb6 is involved in the establishment of tumor immune tolerance in local tissues.

The identification of miR-375 as a potential biomarker in distal gastric adenocarcinoma.

MicroRNAs (miRNAs) are endogenous small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level and play an important role in carcinogenesis. Herein, we characterized the global expression of miRNA in distal gastric adenocarcinomas and determined if circulating miRNAs could be used as biomarkers for distal gastric adenocarcinoma. We used a microarray screening system to detect dysregulated miRNAs in distal gastric adenocarcinoma tissues. The expression of a subset of five aberrantly expressed miRNAs (miR-375, -196b, -204, -18b, and -93) were further quantified in an independent set of clinical samples of distal gastric adenocarcinoma by real-time quantitative RT-PCR (rt-qRT-PCR). We also used rt-qRT-PCR to investigate the expression levels of putative miRNA biomarkers in serum and tumor cell lines. In our study, the expression of a subset of microRNAs was altered in distal gastric adenocarcinoma compared to normal tissue, miR-375 was significantly downregulated in distal gastric adenocarcinoma tissues, to a level that was significantly lower than cardia adenocarcinoma (p < 0.05). The circulating serum levels of miR-375 in patients who had distal gastric adenocarcinoma were also much lower than normal controls (p < 0.001). As a biomarker, miR-375 yielded a receiver operating characteristic area under the curve of 0.835. The specificity and sensitivity was 80% and 85%, respectively, in the discrimination of distal gastric adenocarcinoma from control, at a normalized cutoff of 0.218. The expression of miR-375 was downregulated both in distal gastric adenocarcinoma tissues and serum of patients with distal gastric adenocarcinoma. These data suggest miR-375 is a potential biomarker for distal gastric adenocarcinoma.

Immunoglobulin kappa and immunoglobulin lambda are required for expression of the anti-apoptotic molecule Bcl-xL in human colorectal cancer tissue.

OBJECTIVE: Aberrant expression of immunoglobulin (Ig) by cancer cells has been documented in a number of malignant tumors but its biological significance is unclear. Cancer cells overexpress anti-apoptotic molecules such as Bcl-xL. The present study aimed to examine the role of expression of Ig light-chain Igk and Iglambda in maintaining the high levels of Bcl-xL in colorectal cancer cells. MATERIAL AND METHODS: Thirty patients with colorectal cancer were recruited to this study. Expression of Igk, Iglambda and Bcl-xL in surgically removed cancer tissue was examined by immunohistochemistry and/or flow cytometry. Using the HT29 cell line as a study platform, RNA interference (RNAi) was employed to knock out the genes of Igk and Iglambda in the cancer cell line; the expression of Bcl-xL in HT29 cells was subsequently analyzed. RESULTS: Human colorectal cancer cells, but not normal colorectal tissue, expressed both Igk and Iglambda in the cytoplasm. High levels of Bcl-xL were detected in cancer cells. Using RNAi to knock out the genes of Igk and/or Iglambda, Bcl-xL expression in HT29 cells was significantly suppressed and the cells became apoptotic. CONCLUSION: The results suggest that expression of Igk and Iglambda is required to stabilize Bcl-xL expression in cancer cells.

[Clinical analysis of 38 elderly patients with early double primary cancers].

OBJECTIVE: To study the clinical features and proper treatment of 38 elderly patients with early double primary cancers. METHODS: Thirty-eight elderly patients with early double primary cancers treated from January 1980 to March 2003 were retrospectively reviewed for involved organs, treatment and prognosis. RESULTS: Digestive tract was the most frequently involved, followed by urogenital system and lung. Long-term results of endoscopic mucosal resection (EMR), operation and radiotherapy were superior to other methods. The prognosis of gastrointestinal carcinoma was better than that of prostate carcinoma and hematopoietic system. The operation rate decreased with increasing age. The 5-year survival rates of EMR, operation and radiotherapy were 85.7%, 71.1% and 75.0%, respectively. The medium survival time was 120 months in first cancer and 39 months in the second primary cancer. The 5-year survival rates of the first cancer and second primary cancer were 88.6% and 53.8%. CONCLUSION: Yearly follow-up for elderly patients with endoscopy, beta ultrasonic scan and X-ray contribute to finding of early double primary cancers. Operation is the best treatment of early double primary cancers. Endoscopic mucosal resection is especially suitable for old patients with digestive tract and bladder cancer.

Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells.

AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl4-induced hepatic fibrosis in rats. METHODS: We constructed a rat model of CCl4-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real-time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy. RESULTS: OM attenuated CCl4-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis. CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect.