Cancer cell‑induced tissue inhibitor of metalloproteinase‑1 secretion by cancer‑associated fibroblasts promotes cancer cell migration

Nakai,Nozomu; Hara,Masayasu; Takahashi,Hiroki; Shiga,Kazuyoshi; Hirokawa,Takahisa; Maeda,Yuzo; Yanagita,Takeshi; Ando,Nanako; Takasu,Korehito; Suzuki,Takuya; Maeda,Anri; Ogawa,Ryo; Matsuo,Yoichi; Takiguchi,Shuji

doi:10.3892/or.2022.8323

Cancer cell‑induced tissue inhibitor of metalloproteinase‑1 secretion by cancer‑associated fibroblasts promotes cancer cell migration

Authors:
- Nozomu Nakai
- Masayasu Hara
- Hiroki Takahashi
- Kazuyoshi Shiga
- Takahisa Hirokawa
- Yuzo Maeda
- Takeshi Yanagita
- Nanako Ando
- Korehito Takasu
- Takuya Suzuki
- Anri Maeda
- Ryo Ogawa
- Yoichi Matsuo
- Shuji Takiguchi
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Affiliations: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, Mizuho‑cho, Mizuho‑ku, Nagoya 467‑8601, Japan
Published online on: April 27, 2022 https://doi.org/10.3892/or.2022.8323
Article Number: 112

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Abstract

Cancer‑associated fibroblasts (CAFs) are one of the major components of the cancer stroma in the tumor microenvironment. The interaction between cancer cells and CAFs (cancer‑stromal interaction; CSI) promotes tumor progression, including metastasis. Recently, the tissue inhibitor of metalloproteinase‑1 (TIMP‑1) was reported to promote cancer cell migration and metastasis, which is contrary to its anticancer role as an inhibitor of matrix metalloproteinase. Moreover, CAF‑derived TIMP‑1 is reported to regulate CAF activity. In the present study, we investigated the effect of TIMP‑1 on colon cancer cell migration in vitro. The TIMP‑1 secretion levels from the CAFs and cancer cell lines were comparatively measured to determine the main source of TIMP‑1. Furthermore, the effect of CSI on TIMP‑1 secretion was investigated using the Transwell co‑culture system. Cancer cell migration was evaluated using the wound‑healing assay. The results demonstrated that TIMP‑1 promoted the migration of LoVo cells, a colon cancer cell line, whereas TIMP‑1 neutralization inhibited the enhanced migration. The TIMP‑1 levels secreted from the cancer cells were approximately 10 times less than those secreted from the CAFs. TIMP‑1 secretion was higher in CAFs co‑cultured with cancer cells than in monocultured CAFs. Furthermore, the migration of LoVo cells increased upon co‑culturing with the CAFs. TIMP‑1 neutralization partially inhibited this enhanced migration. These results suggest that CAFs are the primary source of TIMP‑1 and that the TIMP‑1 production is enhanced through CSI in the tumor microenvironment, which promotes cancer cell migration.

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