Breaking the 'harmony' of TNF-α signaling for cancer treatment.
Breaking the 'harmony' of TNF-α signaling for cancer treatment.
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DOI：
10.1038/onc.2011.567
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发表时间：
2012-09-13
期刊：
影响因子：
8
通讯作者：
Goukassian, D. A.
中科院分区：
文献类型：
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作者：
Sasi, S. P.;Yan, X.;Enderling, H.;Park, D.;Gilbert, H-Y;Curry, C.;Coleman, C.;Hlatky, L.;Qin, G.;Kishore, R.;Goukassian, D. A.
肿瘤坏死因子-α（TNF-α）与两种不同的受体TNFR 1/p55和TNFR 2/p75结合。TNF-α参与肿瘤生长、存活、分化、侵袭、转移、细胞因子和促血管生成因子的分泌过程。我们已经表明，TNFR 2/p75信号通过调节几种血管生成生长因子促进缺血诱导的血管生成。我们推测TNFR 2/p75可能促进肿瘤生长和血管生成。在野生型（WT）、p75敲除（KO）和双p55 KO/p75 KO小鼠肿瘤异种移植模型中评价小鼠刘易斯肺癌（LLC 1）和/或小鼠黑素瘤B16细胞的生长。与WT和p55 KO/p75 KO小鼠相比，LLC和B16肿瘤中p75 KO小鼠的肿瘤生长均显著降低（2倍）。肿瘤生长抑制与VEGF表达和毛细血管密度的降低以及骨髓（BM）来源的内皮祖细胞（EPCs）并入功能性毛细血管网络以及LLC异种移植物中凋亡细胞的增加相关。肿瘤组织的基因阵列分析显示，促进肿瘤血管生成和细胞存活的途径中的基因表达减少。在培养的LLC中通过shRNA阻断p75导致TNF介导的细胞凋亡增加，以及血管生成生长因子（VEGF、HGF、PLGF）和SDF-1α受体CXCR 4的组成性和TNF介导的表达减少。总之，p75对于高度血管化的鼠肺肿瘤异种移植物中的肿瘤血管生成和存活是必需的。阻断p75表达可能导致肿瘤消退。这可能代表了新的和有效的治疗肺肿瘤和潜在的其他来源的肿瘤。
Tumor necrosis factor-alpha (TNF-α) binds to two distinct receptors, TNFR1/p55 and TNFR2/p75. TNF-α is implicated in the processes of tumor growth, survival, differentiation, invasion, metastases, secretion of cytokines and pro-angiogenic factors. We have shown that TNFR2/p75 signaling promotes ischemia-induced angiogenesis via modulation of several angiogenic growth factors. We hypothesized that TNFR2/p75 may promote tumor growth and angiogenesis. Growth of mouse Lewis lung carcinoma (LLC1) and/or mouse melanoma B16 cell was evaluated in wild type (WT), p75 knockout (KO) and double p55KO/p75KO mouse tumor xenograft models. Compared to WT and p55KO/p75KO mice, growth of tumors in p75KO mice was significantly decreased (two-fold) in both LLC and B16 tumors. Tumor growth inhibition was correlated with decreases in VEGF expression and capillary density, as well as bone marrow (BM)-derived endothelial progenitor cells (EPCs) incorporation into the functional capillary network, and an increase in apoptotic cells in LLC xenografts. Gene array analysis of tumor tissues showed a decrease in gene expression in pathways that promote tumor angiogenesis and cell survival. Blocking p75 by shRNA in cultured LLCs led to increases in TNF-mediated apoptosis, as well as decreases in the constitutive and TNF-mediated expression of angiogenic growth factors (VEGF, HGF, PLGF), and SDF-1α receptor CXCR4. In summary, p75 is essential for tumor angiogenesis and survival in highly vascularized murine lung tumor xenografts. Blocking p75 expression may lead to tumor regression. This may represent new and effective therapy against lung neoplasms and potentially tumors of other origin.
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影响因子：
--
作者：
Eisenthal, Avi;Schwartz, Ignat;Issakov, Josephine;Klausner, Yossef;Misonzhnik, Faina;Lifschitz-Mercer, Beatriz
通讯作者：
Lifschitz-Mercer, Beatriz
通过预防新血管形成，体内肿瘤休眠。
影响因子：
15.3
作者：
Gimbrone, M A Jr;Leapman, S B;Cotran, R S;Folkman, J
通讯作者：
Folkman, J
影响因子：
11.4
作者：
Asahara, T;Takahashi, T;Isner, JM
通讯作者：
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影响因子：
56.9
作者：
Gao, Dingcheng;Nolan, Daniel J.;Mittal, Vivek
通讯作者：
Mittal, Vivek
影响因子：
5.3
作者：
Gupta, S;Chiplunkar, S;Gollapudi, S
通讯作者：
Gollapudi, S