Targeting of cancer‑associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment

Li,Minmin; Li,Mei; Yin,Tao; Shi,Huashan; Wen,Yuan; Zhang,Binglan; Chen,Meihua; Xu,Guangchao; Ren,Kexin; Wei,Yuquan

doi:10.3892/mmr.2016.4868

Targeting of cancer‑associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment

Authors:
- Minmin Li
- Mei Li
- Tao Yin
- Huashan Shi
- Yuan Wen
- Binglan Zhang
- Meihua Chen
- Guangchao Xu
- Kexin Ren
- Yuquan Wei
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Affiliations: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, State Key Laboratory of Biotherapy, West China Hospital and School of Life Science, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: February 4, 2016 https://doi.org/10.3892/mmr.2016.4868
Pages: 2476-2484
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cancer‑associated fibroblasts (CAFs), key components of the tumor stroma, can regulate tumorigenesis by altering the tumor microenvironment in variety of ways to promote angiogenesis, recruit inflammatory immune cells and remodel the extracellular matrix. Using a murine xenograft model of colon carcinoma, the present study observed that oxaliplatin increased the accumulation of CAFs and stimulated the production of cytokines associated with CAFs. When oxaliplatin was combined with the small‑molecule dipeptidyl peptidase inhibitor PT‑100, which inhibits CAFs by targeting fibroblast activation protein (FAP), the accumulation of CAFs was markedly reduced, xenograft tumor growth was significantly suppressed and the survival of the mice increased, compared to those of mice treated with oxaliplatin or PT‑100 alone. Furthermore, the xenograft tumor tissues of mice treated with oxaliplatin and PT‑100 contained lower numbers of tumor‑associated macrophages and dendritic cells, expressed lower levels of cytokines associated with CAFs and had a lower density of CD31+ endothelial cells. The present study demonstrated that pharmacological inhibition of CAFs improved the response to chemotherapy, reduced the recruitment of immune tumor‑promoting cells and inhibited angiogenesis. Combining chemotherapy with agents which target CAFs may represent a novel strategy for improving the efficacy of chemotherapy and reducing chemoresistance.

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