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    In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123+BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-?, TNF-?, IL-6, macrophage inflammatory protein-1?, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-? and TGF-?. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423–34. ©2011 AACR. cancerres.aacrjournals.org


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    In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123+BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-?, TNF-?, IL-6, macrophage inflammatory protein-1?, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-? and TGF-?. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423–34. ©2011 AACR.
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    VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (P < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest VEGFA levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/RUNX1 protein (AML1/ETO). Overexpression of AML1/RUNX1 led to downregulation of VEGFA expression, whereas blocking of AML1/RUNX1 with siRNAs resulted in increased VEGFA expression. Cotransfection of AML1/RUNX1 and VEGFA promoter luciferase promoter constructs resulted in a decrease in VEGFA promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of VEGFA on three AML1/RUNX1 binding sites. Silencing of AML1/ETO caused a decrease in VEGFA mRNA expression and a decrease in secreted VEGFA protein levels in AML1/ETO-positive Kasumi-1 cells. Taken together, these data pinpoint to a model whereby in normal cells AML1/RUNX1 acts as a repressor for VEGFA, while in AML cells VEGFA expression is upregulated due to AML1/RUNX1 aberrations, for example, AML1/ETO. In conclusion, these observations give insight in the regulation of VEGFA at the mRNA level in AML. Cancer Res; 71(7); 2761–71. ©2011 AACR.

    cancerres.aacrjournals.org


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    VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (P < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest VEGFA levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/RUNX1 protein (AML1/ETO). Overexpression of AML1/RUNX1 led to downregulation of VEGFA expression, whereas blocking of AML1/RUNX1 with siRNAs resulted in increased VEGFA expression. Cotransfection of AML1/RUNX1 and VEGFA promoter luciferase promoter constructs resulted in a decrease in VEGFA promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of VEGFA on three AML1/RUNX1 binding sites. Silencing of AML1/ETO caused a decrease in VEGFA mRNA expression and a decrease in secreted VEGFA protein levels in AML1/ETO-positive Kasumi-1 cells. Taken together, these data pinpoint to a model whereby in normal cells AML1/RUNX1 acts as a repressor for VEGFA, while in AML cells VEGFA expression is upregulated due to AML1/RUNX1 aberrations, for example, AML1/ETO. In conclusion, these observations give insight in the regulation of VEGFA at the mRNA level in AML. Cancer Res; 71(7); 2761–71. ©2011 AACR.
    cancerres.aacrjournals.org   ...Read On

    Prognostic Significance of Preoperative Bowel Obstruction in Stage III Colorectal Cancer.

    Ann Surg Oncol. 2011 Mar 3;

    Authors: Katoh H, Yamashita K, Wang G, Sato T, Nakamura T, Watanabe M

    BACKGROUND: Previous studies have suggested a detrimental prognostic effect of preoperative obstruction proximal to colorectal cancer (CRC). If such a detrimental effect is preserved in each stage of advanced (stage II or III) CRC, we can identify high-risk patients. METHODS: We enrolled 641 patients with pathologically confirmed advanced CRC (stage II, n = 207; stage III, n = 434) who had undergone curative resection of the primary lesion. The association of preoperative obstruction with clinicopathologic parameters was evaluated. Kaplan-Meier analysis and Cox proportional hazard models were used to estimate the effect of preoperative obstruction on disease-free survival in each stage. RESULTS: Preoperative obstruction was seen in 63 patients (9.8%) (stage II, n = 16; stage III, n = 47). Multivariable analysis showed that preoperative obstruction was significantly associated with preoperative elevation of carcinoembryonic antigen level in patients with colon cancer (odds ratio = 3.59; P < 0.001), while it was correlated with poor differentiation in patients with rectal cancer (odds ratio = 3.99; P = 0.016). Preoperative obstruction was a significant prognostic factor in stage III CRC (P < 0.001), but not in stage II disease. Multivariable prognostic analysis showed that preoperative obstruction was a remnant independent prognostic factor in stage III CRC. This finding was confirmed by separate analyses of colon and rectal cancer. Preoperative obstruction was associated with systemic recurrence (P = 0.003) rather than peritoneal or local recurrence. CONCLUSIONS: These findings suggest that preoperative obstruction may predict worse long-term prognosis in patients with stage III CRC and may be a potential clinical marker to identify patients with high-risk stage III CRC.

    PMID: 21369738 [PubMed - as supplied by publisher]

    www.ncbi.nlm.nih.gov


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