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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

Yun Che, Jingnan Wang, Yuan Li, Zhiliang Lu, Jianbing Huang, Shouguo Sun, Shuangshuang Mao, Yuanyuan Lei, Ruochuan Zang, Nan Sun, Jie He

Cell Death Dis. 2018 Jul 9;9(7):759.

PMID: 29988148

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP393105538	Tiplaxtinin		393105-53-8	Price

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