Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
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DOI：
10.1016/j.ccr.2014.04.005
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发表时间：
2014-06-16
期刊：
影响因子：
50.3
通讯作者：
Kalluri R
中科院分区：
文献类型：
--
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
胰腺导管腺癌（PDAC）与显著的纤维化和基质肌成纤维细胞有关，但其功能作用仍不清楚。构建了能够在胰腺癌中删除αSMA⁺肌成纤维细胞的转基因小鼠。在非侵袭性前体（胰腺上皮内瘤变，PanIN）阶段或PDAC阶段开始清除肌成纤维细胞，都会导致侵袭性、未分化的肿瘤，其缺氧情况加重、上皮 - 间质转化增强以及癌症干细胞增多，动物存活率降低。在PDAC患者中，肿瘤中肌成纤维细胞较少也与存活率降低相关。在肌成纤维细胞缺失的小鼠肿瘤中观察到免疫监视受抑制，CD4⁺Foxp3⁺调节性T细胞增加。虽然肌成纤维细胞缺失的肿瘤对吉西他滨没有反应，但抗CTLA4免疫疗法逆转了疾病加速并延长了动物的存活时间。这项研究强调了在针对PDAC中癌相关成纤维细胞时需谨慎。
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts but their functional contribution remains unknown. Transgenic mice with ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either non-invasive precursor (PanIN) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, with diminished animal survival. In PDAC patients, lower myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblasts depleted mouse tumors. While myofibroblasts depleted tumors did not respond to Gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
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影响因子：
50.3
作者：
Cooke VG;LeBleu VS;Keskin D;Khan Z;O'Connell JT;Teng Y;Duncan MB;Xie L;Maeda G;Vong S;Sugimoto H;Rocha RM;Damascena A;Brentani RR;Kalluri R
通讯作者：
Kalluri R
影响因子：
11.5
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50.3
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Guerra C;Collado M;Navas C;Schuhmacher AJ;Hernández-Porras I;Cañamero M;Rodriguez-Justo M;Serrano M;Barbacid M
通讯作者：
Barbacid M
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA