Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma
Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma
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DOI：
10.1152/ajpregu.00320.2011
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发表时间：
2012-05-01
影响因子：
2.8
通讯作者：
Barnett, Carlton C., Jr.
中科院分区：
文献类型：
--
作者：
Benson, Douglas D.;Meng, Xianzhong;Barnett, Carlton C., Jr.
本森DD，孟X，富勒顿DA，摩尔EE，李JH，敖L，西利曼CC，巴内特CC，小。小鼠转移性胰腺癌间质炎性细胞的活化状态。Am J Physiol Regul Integr Comp Physiol 302：R1067-R1075，2012年。首次发表于2012年3月14日; doi：10.1152/ajpregu.00320.2011。巨噬细胞（肿瘤相关巨噬细胞，TAM）和中性粒细胞（肿瘤相关中性粒细胞，TAN）的组织学存在与实体瘤的不良临床结局有关。这种与预后恶化相关的确切机制尚不清楚。理论上，TAM被免疫调节至交替活化状态并促进肿瘤进展。类似地，TAN已显示促进血管生成和肿瘤脱离。在胰腺癌的免疫活性小鼠模型中，表征TAM和TAN的活化状态和促转移介质的产生。通过免疫荧光和免疫印迹对肝转移瘤标本进行评价。TAMS上调了交替活化的CD 206和CD 163标志物的表达（分别是对照的4.14 +/-0.55倍和7.36 +/-1.13倍，P < 0.001），但没有增加经典活化的巨噬细胞标志物CCR 2和CCR 5的表达。TAM还表达制瘤素M（OSM）。我们发现，TAN，而不是TAM，主要产生基质金属蛋白酶-9（MMP-9）在这种转移性肿瘤微环境中，而MMP-2的生产是泛肿瘤。此外，VEGF的表达增加与TAM共定位，而不是TAN。TAM和TAN可以作为不同的效应细胞，TAM表型上表现出交替活化并释放OSM和VEGF。TAN位于转移的侵袭性前沿，在那里它们与MMP-9共定位。对这些相互作用的进一步理解可能会导致胰腺癌的靶向治疗。
Benson DD, Meng X, Fullerton DA, Moore EE, Lee JH, Ao L, Silliman CC, Barnett CC, Jr. Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma. Am J Physiol Regul Integr Comp Physiol 302: R1067-R1075, 2012. First published March 14, 2012; doi:10.1152/ajpregu.00320.2011.-The histologic presence of macrophages (tumor-associated macrophages, TAMs) and neutrophils (tumor-associated neutrophils, TANs) has been linked to poor clinical outcomes for solid tumors. The exact mechanism for this association with worsened prognosis is unclear. It has been theorized that TAMs are immunomodulated to an alternatively activated state and promote tumor progression. Similarly, TANs have been shown to promote angiogenesis and tumor detachment. TAMs and TANs were characterized for activation state and production of prometastatic mediators in an immunocompetent murine model of pancreatic adenocarcinoma. Specimens from liver metastases were evaluated by immunofluorescence and immunoblotting. TAMS have upregulated expression of CD206 and CD163 markers of alternative activation, (4.14 +/- 0.55-fold and 7.36 +/- 1.13-fold over control, respectively, P < 0.001) but do not have increased expression of classically activated macrophage markers CCR2 and CCR5. TAMs also express oncostatin M (OSM). We found that TANs, not TAMs, predominantly produce matrix metalloproteinase-9 (MMP-9) in this metastatic tumor microenvironment, while MMP-2 production is pan-tumoral. Moreover, increased expression of VEGF colocalized with TAMs as opposed to TANs. TAMs and TANs may act as distinct effector cells, with TAMs phenotypically exhibiting alternative activation and releasing OSM and VEGF. TANs are localized at the invasive front of the metastasis, where they colocalize with MMP-9. Improved understanding of these interactions may lead to targeted therapies for pancreas adenocarcinoma.