Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.
Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.
复制标题
DOI：
10.1084/jem.20131195
复制
发表时间：
2013-12-16
期刊：
影响因子：
--
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Lotti F;Jarrar AM;Pai RK;Hitomi M;Lathia J;Mace A;Gantt GA Jr;Sukhdeo K;DeVecchio J;Vasanji A;Leahy P;Hjelmeland AB;Kalady MF;Rich JN
化疗刺激癌症相关的成纤维细胞分泌白细胞介素-17A，以提供维持线索，支持结直肠癌起始细胞的生长。许多实体癌显示出细胞层次结构，其中自我更新、致瘤干细胞或癌症起始细胞（CIC）位于顶端。尽管CIC通常表现出对常规癌症疗法的相对抗性，但它们也从也对细胞毒性疗法有反应的支持性基质成分接受关键的维持线索。为了探究化疗和CIC之间的相互作用，我们研究了人类结直肠癌中的细胞异质性。在细胞自主试验中，结直肠CIC对常规化疗具有耐药性，但癌症相关成纤维细胞（CAF）也增加了CIC的耐药性。对细胞毒性治疗前后患者的匹配结直肠癌标本进行比较分析，发现CAF显著增加。化疗处理的人CAF促进CIC自我更新和体内肿瘤生长，这与特异性细胞因子和趋化因子（包括白细胞介素-17A（IL-17 A））的分泌增加有关。外源性IL-17 A增加CIC自我更新和侵袭，靶向IL-17 A信号传导损害CIC生长。值得注意的是，IL-17 A在结肠直肠CAF中响应于化疗而过表达，其表达在未经培养的患者来源的标本中直接得到验证。这些数据表明，化疗诱导肿瘤微环境的重塑，以通过分泌因子支持肿瘤细胞等级。同时破坏CIC机制和与肿瘤微环境的相互作用可以优化癌症的治疗靶向。
Chemotherapy stimulates cancer-associated fibroblasts to secrete interleukin-17A to provide maintenance cues to support the growth of colorectal cancer-initiating cells. Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.
登录
查看更多内容
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
0.7
作者：
Desmoulière, A;Guyot, C;Gabbiani, C
通讯作者：
Gabbiani, C
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
50.3
作者：
Calon A;Espinet E;Palomo-Ponce S;Tauriello DV;Iglesias M;Céspedes MV;Sevillano M;Nadal C;Jung P;Zhang XH;Byrom D;Riera A;Rossell D;Mangues R;Massagué J;Sancho E;Batlle E
通讯作者：
Batlle E