Tumor refractoriness to endostatin anti-angiogenesis is associated with the recruitment of CD11b+Gr1+ myeloid cells and inflammatory cytokines
Tumor refractoriness to endostatin anti-angiogenesis is associated with the recruitment of CD11b+Gr1+ myeloid cells and inflammatory cytokines
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肿瘤对内皮抑素抗血管生成的耐药性与 CD11b Gr1 骨髓细胞和炎症细胞因子的募集有关
DOI：
10.1177/030089161309900613
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Hui Zhang, Zi Wang, Qian Peng, * Feng Luo
中科院分区：
文献类型：
--
作者：
Hui Zhang, Zi Wang, Qian Peng, * Feng Luo
抗血管生成治疗的主要挑战是肿瘤固有的难治性和治疗诱导的耐药的出现。最近，这种耐药性被认为与肿瘤微环境中的炎性变化有关。然而，在这一领域还没有关于内皮抑素对肿瘤微环境的影响的信息。我们建立了两种内皮抑制素治疗无效的肿瘤模型，并试图确定炎症变化在肿瘤对抗血管生成治疗无效的发展中的作用。方法采用小剂量或大剂量内皮抑素治疗3种小鼠移植瘤模型10 d。观察内皮抑素对肿瘤生长的影响，并确定内皮抑素治疗难治性肿瘤。进行流式细胞术以评估外周血和肿瘤中CD 11b + Gr 1+髓样细胞的存在。采用酶联免疫吸附试验测定外周血中炎性细胞因子水平。采用免疫组化法检测NF-κB、versican和缺氧诱导因子-1 α在肿瘤中的表达。结果LLC和B16 F1肿瘤是内皮抑素治疗无效的动物模型。在LLC荷瘤小鼠中，CD 11 b + Gr 1+髓系细胞固有地募集到外周血和肿瘤微环境中，并且血清G-CSF和TNF-α水平沿着肿瘤生长而升高。在B16 F1荷瘤小鼠中，CD 11b + Gr 1+骨髓细胞被内皮抑素获得性募集到外周血和肿瘤微环境中。另外，内皮抑素治疗后B16 F1荷瘤小鼠血清中G-CSF和TNF-α水平升高，肿瘤组织中NF-κB、versican和缺氧诱导因子-1 α表达升高。结论肿瘤可以是内源性生长，也可以是获得性生长，但内皮抑素治疗无效。CD 11b + Gr 1+髓系细胞和炎性细胞因子的募集可能在肿瘤对内皮抑素抗血管生成的难治性的发展中起重要作用。
Aims and background A major challenge in developing antiangiogenic therapies is tumor intrinsic refractoriness and the emergence of treatment-induced resistance. Recently, such resistance is considered to be associated with inflammatory changes in the tumor microenvironment. However, no information has been acquired about the effect of endostatin on tumor microenvironment in this field. We established two tumor models refractory to endostatin treatment and sought to determine the role of inflammatory changes in the development of tumor refractoriness to antiangiogenic therapy. Methods Three xenograft tumor murine models were treated with low-dose endostatin or high-dose endostatin for 10 days. The effect of endostatin on tumor growth was observed, and tumors refractory to endostatin treatment were defined. Flow cytometry were carried out to assess the presence of CD11b+Gr1+ myeloid cells in the peripheral blood and in the tumor. Inflammatory cytokine levels in peripheral blood were measured using the enzyme-linked immunosorbent assay. The expression of NF-κB, versican and hypoxia-inducible factor-1α in the tumor was evaluated using immunohistochemistry. Results LLC and B16F1 tumors were defined as animal models of refractoriness to endostatin treatment. CD11b+Gr1+ myeloid cells were inherently recruited into the peripheral blood and the tumor microenvironment in the LLC tumor-bearing mice, and levels of serum G-CSF and TNF-α were increased along with the progression of tumor growth. In the B16F1 tumor-bearing mice, CD11b+Gr1+ myeloid cells were acquiredly recruited by endostatin into the peripheral blood and the tumor microenvironment. Additionally, high levels of G-CSF and TNF-α in serum and high expression of NF-κB, versican and hypoxia-inducible factor-1α in tumor tissue were found in B16F1 tumor-bearing mice after endostatin administration. Conclusions A tumor can grow inherently or acquiredly with refractoriness to endostatin treatment in vivo. Recruitment of CD11b+Gr1+ myeloid cells and inflammatory cytokines may play an important role in the development of tumor refractoriness to endostatin anti-angiogenesis.
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DOI：
10.1158/1078-0432.ccr-11-1185
发表时间：
2011-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Carbone C;Moccia T;Zhu C;Paradiso G;Budillon A;Chiao PJ;Abbruzzese JL;Melisi D
通讯作者：
Melisi D
影响因子：
11.2
作者：
Franco, M;Man, S;Kerbel, RS
通讯作者：
Kerbel, RS
DOI：
10.1186/bcr2927
发表时间：
2011-08-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kim EJ;Choi MR;Park H;Kim M;Hong JE;Lee JY;Chun HS;Lee KW;Yoon Park JH
通讯作者：
Yoon Park JH
DOI：
10.1073/pnas.1014480108
发表时间：
2011-03-01
影响因子：
11.1
作者：
Keunen, Olivier;Johansson, Mikael;Niclou, Simone P.
通讯作者：
Niclou, Simone P.
影响因子：
1.9
作者：
Helan Wang;T. Ning;Mei Li;Zejun Lu;Xi Yan;Q. Peng;Na Lei;Hui Zhang;F. Luo
通讯作者：
Helan Wang;T. Ning;Mei Li;Zejun Lu;Xi Yan;Q. Peng;Na Lei;Hui Zhang;F. Luo