Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy
Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy
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DOI：
10.1186/1471-2407-10-200
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发表时间：
2010-05-13
期刊：
影响因子：
3.8
通讯作者：
Jancar, Sonia
中科院分区：
文献类型：
--
作者：
de Oliveira, Soraya I.;Andrade, Luciana N. S.;Jancar, Sonia
背景：巨噬细胞吞噬凋亡细胞诱导抑制表型。我们小组以前的数据表明，这是通过血小板活化因子受体（PAF-R）介导的途径发生的。在本研究中，我们研究了凋亡细胞接种或诱导化疗药物（达卡巴嗪，DTIC）对肿瘤生长，微环境参数和生存的影响，以及与PAF-R拮抗剂（WEB 2170）治疗的效果。这些研究进行了小鼠肿瘤：埃利希肿瘤（EAT）和B16 F10 melanoma.Methods：肿瘤生长进行了评估，直接计数EAT细胞在腹水或通过测量实体瘤的体积。肿瘤微环境的参数，如表达环氧合酶-2（考克斯-2）、半胱天冬酶-3和半乳糖凝集素-3的细胞的频率，以及微血管密度，通过免疫组织化学测定。采用酶联免疫吸附法（ELISA）测定血管内皮生长因子（VEGF）和前列腺素E2（PGE 2）水平，Griess反应法测定一氧化氮（NO）水平。结果：EAT植入前接种凋亡细胞可刺激肿瘤生长。这种作用通过用WEB2170进行体内预处理而逆转。这种治疗也减少了肿瘤的生长，并通过减少PGE 2，VEGF和NO的产生来改变微环境。在B16 F10黑色素瘤中，WEB 2170单独或与DTIC联合显著减小肿瘤体积。荷瘤小鼠的存活率不受WEB 2170治疗的影响，但通过DTIC与WEB 2170的组合显著改善。肿瘤微环境元素是联合治疗的靶点，因为用WEB 2170或DTIC单独或联合治疗显著降低了肿瘤块内考克斯-2和半乳糖凝集素-3阳性细胞的相对频率和微血管密度。抗PAF-R的抗体染色了肿瘤内部的细胞，而不是体外生长的肿瘤细胞。在组织水平上，一些细胞（可能是巨噬细胞）染色阳性与抗体PAF-R。结论：我们建议，PAF-R依赖的途径被激活在实验性肿瘤生长，修改微环境和肿瘤巨噬细胞的表型，以这种方式有利于肿瘤生长。PAF-R拮抗剂和化疗药物的联合治疗可能代表了治疗某些肿瘤的新的和有前途的策略。
Background: Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma.Methods: Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclooxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry.Results: Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R.Conclusions: We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.