Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.
Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.
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DOI：
10.1038/s41419-018-0808-2
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发表时间：
2018-07-09
影响因子：
9
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Che Y;Wang J;Li Y;Lu Z;Huang J;Sun S;Mao S;Lei Y;Zang R;Sun N;He J
术前化疗是治疗食管鳞状细胞癌的有效手段。获得性化疗耐药是改善患者预后的主要障碍。癌症相关成纤维细胞（CAF）是肿瘤微环境的主要组成部分，在肿瘤发展中起着至关重要的作用;这些细胞也是癌症的潜在治疗靶点。利用蛋白质芯片，我们确定了一个关键的分泌细胞因子，派-1，从CAFs预处理顺铂诱导后的DNA损伤的CAFs。肿瘤微环境中的派-1促进肿瘤生长并减弱顺铂治疗的效果。细胞外派-1激活AKT和ERK 1/2信号通路，抑制caspase-3活性和活性氧积累。替普拉替宁作为派-1抑制剂与顺铂在体内外均具有协同作用。在临床样本中，CAF中派-1高表达的ESCC患者的无进展生存期明显较差。总之，我们的研究结果表明，派-1分泌的顺铂激活的CAFs促进肿瘤生长，并减少顺铂的影响，在旁分泌的方式，建立了一个临床前的基本原理，以这种细胞因子为目标，以进一步提高食管鳞状细胞癌的临床反应。
Preoperative chemotherapy is a promising strategy for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired resistance to chemotherapy is a major obstacle in improving patient prognosis. Cancer-associated fibroblasts (CAFs) are the primary components of the tumor microenvironment and play a crucial role in tumor development; these cells are also potential therapeutic targets for cancer. Using protein arrays, we identified a key secreted cytokine, PAI-1, from CAFs pretreated with cisplatin that was induced after DNA damage of CAFs. The PAI-1 in the tumor microenvironment promoted tumor growth and attenuated the effects of cisplatin treatment. Extracellular PAI-1 activated the AKT and ERK1/2 signaling pathways and inhibited caspase-3 activity and reactive oxygen species accumulation. Tiplaxtinin as a PAI-1 inhibitor could play synergistic effects with cisplatin in vitro and in vivo. In clinical samples, ESCC patients with high expression of PAI-1 in CAFs presented a significantly worse progression-free survival. Taken together, our results showed that PAI-1 secreted from cisplatin-activated CAFs promoted tumor growth and reduced the effects of cisplatin in a paracrine manner, establishing a preclinical rationale to target this cytokine to further improve the clinical response of esophageal squamous cell carcinoma.
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影响因子：
8
作者：
通讯作者：
--
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
DOI：
10.1084/jem.20131195
发表时间：
2013-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
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
通讯作者：
Rich JN
癌症相关成纤维细胞分泌的尿激酶纤溶酶原激活剂通过 PI3K/AKT 和 ERK 信号传导诱导食管鳞状细胞癌肿瘤进展
影响因子：
--
作者：
Tian B;Chen X;Zhang H;Li X;Wang J;Han W;Zhang LY;Fu L;Li Y;Nie C;Zhao Y;Tan X;Wang H;Guan XY;Hong A
通讯作者：
Hong A
影响因子：
5.7
作者：
Gomes-Giacoia E;Miyake M;Goodison S;Rosser CJ
通讯作者：
Rosser CJ