Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.
Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.
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DOI：
10.1371/journal.pone.0027729
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ghansah T
中科院分区：
文献类型：
--
作者：
Pilon-Thomas S;Nelson N;Vohra N;Jerald M;Pendleton L;Szekeres K;Ghansah T
胰腺癌是最具侵袭性的癌症之一，肿瘤诱导的髓系来源的抑制细胞(MDSC)参与了其发病机制和无效的治疗。作为对细胞因子/趋化因子受体激活的响应，src同源2结构域含肌醇5‘-磷酸酶-1(SHIP-1)影响磷脂酰肌醇-3-激酶(PI3K)信号事件，从而调节免疫平衡。我们假设来自小鼠胰腺癌细胞的因子导致SHIP-1表达下调，这可能有助于MDSC的扩张，并抑制CD8+T细胞免疫反应。因此，我们试图确定SHIP-1在实体瘤进展中的作用，例如小鼠胰腺癌。免疫活性C57BL/6小鼠接种Panc02细胞(荷瘤[TB]小鼠)和磷酸盐缓冲盐水(PBS)(对照小鼠)。对Panc02培养上清液的细胞仪珠阵(CBA)分析检测到促炎细胞因子，如IL-6、IL-10和MCP-1。CBA检测显示，TB小鼠血清促炎因子IL-6和MCP-1水平显著升高。QRT-PCR和Western印迹分析显示，结核小鼠脾细胞Ship-1的表达在体内下调。Western印迹分析还检测到结核小鼠脾细胞SHIP-1活性降低，AKT-1和BAD过度磷酸化增加，bcl2表达上调。在体外，qRT-PCR和Western印迹分析检测到与Panc02细胞共培养的对照脾细胞SHIP-1mRNA和蛋白表达降低。流式细胞仪检测结果显示，结核小鼠外周血和脾细胞中的MDSC明显扩增。经AutoMACS分选的TB MDSC经免疫印迹分析显示AKT-1过度磷酸化，bcl2过度表达。TB MDSC在体外可显著抑制抗原特异性CD8+T细胞免疫反应。SHIP-1可能调节影响MDSC扩张和功能的免疫发育，从而促进胰腺肿瘤的进展。因此，SHIP-1可以作为一个潜在的治疗靶点，帮助胰腺癌患者恢复免疫平衡，改善治疗反应。
Pancreatic cancer is one of the most aggressive cancers, with tumor-induced myeloid-derived suppressor cells (MDSC) contributing to its pathogenesis and ineffective therapies. In response to cytokine/chemokine receptor activation, src homology 2 domain-containing inositol 5′-phosphatase-1 (SHIP-1) influences phosphatidylinositol-3-kinase (PI3K) signaling events, which regulate immunohomeostasis. We hypothesize that factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8+ T cell immune responses. Therefore, we sought to determine the role of SHIP-1 in solid tumor progression, such as murine pancreatic cancer. Immunocompetent C57BL/6 mice were inoculated with either murine Panc02 cells (tumor-bearing [TB] mice) or Phosphate Buffer Saline (PBS) (control mice). Cytometric Bead Array (CBA) analysis of supernatants of cultured Panc02 detected pro-inflammatory cytokines such as IL-6, IL-10 and MCP-1. TB mice showed a significant increase in serum levels of pro-inflammatory factors IL-6 and MCP-1 measured by CBA. qRT-PCR and Western blot analyses revealed the in vivo down-regulation of SHIP-1 expression in splenocytes from TB mice. Western blot analyses also detected reduced SHIP-1 activity, increased AKT-1 and BAD hyper-phosphorylation and up-regulation of BCL-2 expression in splenocytes from TB mice. In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein expression in control splenocytes co-cultured with Panc02 cells. Flow cytometry results showed significant expansion of MDSC in peripheral blood and splenocytes from TB mice. AutoMACS sorted TB MDSC exhibited hyper-phosphorylation of AKT-1 and over-expression of BCL-2 detected by western blot analysis. TB MDSC significantly suppressed antigen-specific CD8+ T cell immune responses in vitro. SHIP-1 may regulate immune development that impacts MDSC expansion and function, contributing to pancreatic tumor progression. Thus, SHIP-1 can be a potential therapeutic target to help restore immunohomeostasis and improve therapeutic responses in patients with pancreatic cancer.
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影响因子：
10.5
作者：
Liu, QR;Sasaki, T;Penninger, JM
通讯作者：
Penninger, JM
影响因子：
11.2
作者：
Bunt, Stephanie K.;Yang, Linglin;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
4.4
作者：
Ghansah, T;Paraiso, KHT;Kerr, WG
通讯作者：
Kerr, WG
影响因子：
4.4
作者：
Gabhann, Joan Ni;Higgs, Rowan;Jefferies, Caroline A.
通讯作者：
Jefferies, Caroline A.
肌醇磷酸酶 SHIP-1 受到 Fli-1 的负向调节，其缺失会加速白血病的发生。
影响因子：
20.3
作者：
Lakhanpal, Gurpreet K.;Vecchiarelli-Federico, Laura M.;Ben-David, Yaacov
通讯作者：
Ben-David, Yaacov