TY - JOUR
T1 - Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance article
AU - Che, Yun
AU - Wang, Jingnan
AU - Li, Yuan
AU - Lu, Zhiliang
AU - Huang, Jianbing
AU - Sun, Shouguo
AU - Mao, Shuangshuang
AU - Lei, Yuanyuan
AU - Zang, Ruochuan
AU - Sun, Nan
AU - He, Jie
N1 - Funding Information:
The work was supported by The CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001), National Key Basic Research Development Plan (2015CB553901), Chinese Academy of Medical Sciences Central Public-interest Scientific Institution Basal Research Fund (2016ZX310196).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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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U2 - 10.1038/s41419-018-0808-2
DO - 10.1038/s41419-018-0808-2
M3 - Article
C2 - 29988148
AN - SCOPUS:85049742497
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - 759
ER -