Genetic ablation of epidermal EGFR reveals the dynamic origin of adverse effects of anti-EGFR therapy.
Genetic ablation of epidermal EGFR reveals the dynamic origin of adverse effects of anti-EGFR therapy.
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DOI：
10.1126/scitranslmed.3005773
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发表时间：
2013-08-21
影响因子：
17.1
通讯作者：
Yuspa SH
中科院分区：
文献类型：
--
作者：
Mascia F;Lam G;Keith C;Garber C;Steinberg SM;Kohn E;Yuspa SH
接受抗egfr药物治疗的癌症患者经常出现不明原因的剂量限制性瘙痒性皮疹。本研究的目的是通过对吉非替尼治疗患者皮肤和全身变化的临床研究来确定因果关系，并利用这些研究来建立和表征一个小鼠模型，该模型概括了抗egfr治疗引起的人皮疹综合征。我们检查了患者在吉非替尼治疗前后的血浆，并记录了与皮疹程度或瘙痒存在相关的趋化因子和白细胞计数的变化。我们通过在表皮中消融EGFR建立平行小鼠模型。这些小鼠出现了与人类皮疹相似的皮肤损伤。在病变发展之前，我们检测到皮肤中趋化因子mRNA表达的增加与巨噬细胞和肥大细胞的早期浸润以及嗜酸性粒细胞、T细胞和中性粒细胞的后期浸润有关。随着皮肤表型的进化，血液计数和循环趋化因子的变化重现了在吉非替尼治疗的患者中看到的变化。将突变小鼠与TNFα受体、MyD88、NOS2、CCR2、T或B细胞缺失的小鼠杂交，均不能逆转皮肤表型。然而，局部巨噬细胞的消耗提供了部分解决方案，这表明该模型可以识别出可能有效预防皮肤对抗egfr药物产生麻烦和剂量限制反应的靶点。这些结果强调了EGFR信号在维持皮肤免疫稳态中的重要性，并确定了巨噬细胞对癌症化疗严重不良后果的贡献。表皮表皮生长因子受体消融术引起局部皮疹和全身炎症综合征
Cancer patients treated with anti-EGFR drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients’ plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts that were associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Prior to lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells and neutrophils. As the skin phenotype evolved, changes in blood counts and circulating chemokines reproduced those seen in the gefitinib-treated patients. Crossing the mutant mice with mice deficient for TNFα receptors, MyD88, NOS2, CCR2, T or B cells failed to reverse the skin phenotype. However, local depletion of macrophages provided partial resolution, suggesting that this model can identify targets that may be effective in preventing the troublesome and dose limiting skin response to anti-EGFR drugs. These results highlight the importance of EGFR signaling in maintaining skin immune-homeostasis and identify a macrophage contribution to a serious adverse consequence of cancer chemotherapy. Epidermal EGFR ablation causes a localized cutaneous rash and a systemic inflammatory syndrome
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影响因子：
4.4
作者：
Pastore, S;Mascia, F;Girolomoni, G
通讯作者：
Girolomoni, G
影响因子：
10.3
作者：
Han, S. S.;Lee, M.;Ryu, M. H.
通讯作者：
Ryu, M. H.
影响因子：
45.3
作者：
Peréz-Soler, R;Saltz, L
通讯作者：
Saltz, L
影响因子：
4.4
作者：
Cataisson, C;Pearson, AJ;Yuspa, SH
通讯作者：
Yuspa, SH
影响因子：
6
作者：
Mascia, F;Mariani, V;Pastore, S
通讯作者：
Pastore, S