Impaired lymphatic function accelerates cancer growth.
Impaired lymphatic function accelerates cancer growth.
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DOI：
10.18632/oncotarget.9953
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Eikesdal HP
中科院分区：
文献类型：
--
作者：
Steinskog ES;Sagstad SJ;Wagner M;Karlsen TV;Yang N;Markhus CE;Yndestad S;Wiig H;Eikesdal HP
淋巴管生成增加是癌症发展和进展的共同特征，然而淋巴管生成受损对肿瘤生长的影响是难以捉摸的。将C3 HBA乳腺癌和KHT-1肉瘤细胞系原位植入Chy小鼠体内，这些细胞系携带血管内皮生长因子受体-3的杂合失活突变，导致真皮淋巴管生成受损。在Chy小鼠的两种癌症模型中均观察到肿瘤生长加速，与肿瘤周围淋巴管生成减少一致。在患有C3 HBA肿瘤的Chy小鼠中，从肿瘤周围区域观察到受损的淋巴洗脱，并且巨噬细胞的数量显著减少。虽然检测到较少的巨噬细胞，但CD 163 + M2巨噬细胞的分数保持恒定，导致Chy小鼠中M2/M1比率向更高的方向转变。野生型和Chy小鼠之间的适应性免疫细胞没有观察到差异。有趣的是，C3 HBA肿瘤中促炎和抗炎巨噬细胞相关细胞因子的水平降低，表明先天免疫应答受损。然而，IL-6在C3 HBA肿瘤间质液中显著升高，用抗IL-6受体抗体托珠单抗治疗可抑制乳腺癌生长。总的来说，我们的数据表明，受损的淋巴管生成削弱了抗肿瘤免疫力，有利于肿瘤生长在癌症发展的早期阶段。
Increased lymphangiogenesis is a common feature of cancer development and progression, yet the influence of impaired lymphangiogenesis on tumor growth is elusive. C3HBA breast cancer and KHT-1 sarcoma cell lines were implanted orthotopically in Chy mice, harboring a heterozygous inactivating mutation of vascular endothelial growth factor receptor-3, resulting in impaired dermal lymphangiogenesis. Accelerated tumor growth was observed in both cancer models in Chy mice, coinciding with reduced peritumoral lymphangiogenesis. An impaired lymphatic washout was observed from the peritumoral area in Chy mice with C3HBA tumors, and the number of macrophages was significantly reduced. While fewer macrophages were detected, the fraction of CD163+ M2 macrophages remained constant, causing a shift towards a higher M2/M1 ratio in Chy mice. No difference in adaptive immune cells was observed between wt and Chy mice. Interestingly, levels of pro- and anti-inflammatory macrophage-associated cytokines were reduced in C3HBA tumors, pointing to an impaired innate immune response. However, IL-6 was profoundly elevated in the C3HBA tumor interstitial fluid, and treatment with the anti-IL-6 receptor antibody tocilizumab inhibited breast cancer growth. Collectively, our data indicate that impaired lymphangiogenesis weakens anti-tumor immunity and favors tumor growth at an early stage of cancer development.
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影响因子：
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作者：
Chen MF;Kuan FC;Yen TC;Lu MS;Lin PY;Chung YH;Chen WC;Lee KD
通讯作者：
Lee KD
影响因子：
20.3
作者：
Duluc, Dorothee;Delneste, Yves;Jeannin, Pascale
通讯作者：
Jeannin, Pascale
DOI：
10.1126/science.1176009
发表时间：
2009-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hynes RO
通讯作者：
Hynes RO
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
11.5
作者：
Howe, Louise R.;Subbaramaiah, Kotha;Dannenberg, Andrew J.
通讯作者：
Dannenberg, Andrew J.