Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.
Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.
复制标题
DOI：
10.1016/j.celrep.2017.03.038
复制
发表时间：
2017-04-04
期刊：
影响因子：
8.8
通讯作者：
Joyce JA
中科院分区：
文献类型：
--
作者：
Olson OC;Kim H;Quail DF;Foley EA;Joyce JA
抗有丝分裂剂，包括紫杉醇，破坏微管动力学，并导致长期的有丝分裂停滞和随后的细胞死亡。尽管这些药物在乳腺癌和其他肿瘤类型中具有广泛的用途，但临床反应仍然可变。肿瘤相关巨噬细胞（TAM）抑制紫杉醇诱导的乳腺癌细胞有丝分裂停滞的持续时间，并促进早期有丝分裂滑移。这与组蛋白H2 AX（γ H2 AX）磷酸化形式的减少、p53活化减少和间期癌细胞死亡减少相关。TAM以对MAPK/ERK激酶（MEK）抑制敏感的方式促进有丝分裂滑移后的癌细胞活力。主要组织相容性复合物II类低（MHCIIlo）TAMs的急性消耗增加了紫杉醇诱导的癌细胞DNA损伤和凋亡，导致干预试验的更大疗效。MEK抑制阻断了TAM的保护能力，并表型模拟了TAM消耗对泰素治疗的影响。TAM抑制紫杉醇的细胞毒性作用，部分通过癌细胞中有丝分裂停滞的细胞非自主调节，靶向TAM-癌细胞相互作用增强紫杉醇功效。Olson等研究了肿瘤相关巨噬细胞（TAM）如何抑制乳腺癌细胞中紫杉醇诱导的有丝分裂停滞的持续时间并促进早期有丝分裂滑移。TAM通过对MEK抑制敏感的机制促进有丝分裂滑移后的癌细胞活力。在临床前乳腺癌模型中MHCIIlo TAM的急性消耗增加了紫杉醇诱导细胞凋亡的能力并改善了治疗反应。
Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these drugs in breast cancer and other tumor types, clinical response remains variable. Tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. This correlates with a decrease in the phosphorylated form of histone H2AX (γH2AX), decreased p53 activation, and reduced cancer cell death in interphase. TAMs promote cancer cell viability following mitotic slippage in a manner sensitive to MAPK/ERK kinase (MEK) inhibition. Acute depletion of major histocompatibility complex class II low (MHCIIlo) TAMs increased Taxol-induced DNA damage and apoptosis in cancer cells, leading to greater efficacy in intervention trials. MEK inhibition blocked the protective capacity of TAMs and phenocopied the effects of TAM depletion on Taxol treatment. TAMs suppress the cytotoxic effects of Taxol, in part through cell non-autonomous modulation of mitotic arrest in cancer cells, and targeting TAM-cancer cell interactions potentiates Taxol efficacy. Olson et al. examine how tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. TAMs promote cancer cell viability following mitotic slippage through a mechanism that is sensitive to MEK inhibition. Acute depletion of MHCIIlo TAMs in a preclinical breast cancer model increased the ability of Taxol to induce apoptosis and improved therapeutic response.
登录
查看更多内容
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
48
作者：
Chittajallu DR;Florian S;Kohler RH;Iwamoto Y;Orth JD;Weissleder R;Danuser G;Mitchison TJ
通讯作者：
Mitchison TJ
影响因子：
11.2
作者：
Orth JD;Kohler RH;Foijer F;Sorger PK;Weissleder R;Mitchison TJ
通讯作者：
Mitchison TJ
影响因子：
8
作者：
Menendez, JA;Vellon, L;Lupu, R
通讯作者：
Lupu, R
影响因子：
82.9
作者：
通讯作者：
--