Abstract
Stromal fibroblasts, which occupy a major portion of the tumor microenvironment, play an important role in cancer metastasis. Thus, targeting of these fibroblasts activated by cancer cells (carcinoma‐associated fibroblasts; CAFs) might aid in the improved treatment of cancer metastasis. NIH3T3 fibroblasts cocultured with MCF7 cells displayed enhanced migration compared to NIH3T3 fibroblasts cultured alone. We used this system to identify the small‐molecule inhibitors responsible for their enhanced migration, a characteristic of CAFs. We selected β‐arrestin1, which showed high expression in cocultured cells, as a molecular target for such inhibitors. Cofilin, a protein downstream of β‐arrestin1, is activated/dephosphorylated in this condition. The small‐molecule ligands of β‐arrestin1 obtained by chemical array were then examined using a wound healing coculture assay. RKN5755 was identified as a selective inhibitor of activated fibroblasts. RKN5755 inhibited the enhanced migration of fibroblasts cocultured with cancer cells by binding to β‐arrestin1 and interfering with β‐arrestin1‐mediated cofilin signaling pathways. Therefore, these results demonstrate the role of β‐arrestin1 in the activation of fibroblasts and inhibiting this protein by small molecule inhibitor might be a potential therapeutic target for the stromal fibroblast activation (cancer–stroma interaction).
Highlights
Treatment of metastatic breast cancer, which is often incurable, faces the challenge of the tumor microenvironment
Migration of fibroblast cells was enhanced when cancer cells were cocultured We examined the migration of fibroblast cells by a traditional wound healing assay
We demonstrate that NIH3T3 fibroblasts migrate faster when cocultured with MCF7 breast cancer cells
Summary
Treatment of metastatic breast cancer, which is often incurable, faces the challenge of the tumor microenvironment. A number of studies examining tumor microenvironments have made it clear that fibroblasts, which comprise a major component of cancerous stroma, play an important role in cancer metastasis [1]. The cross-talk that occurs between stromal fibroblasts and cancer cells leads to morphological changes in normal fibroblastic cells. Fibroblasts that are activated by cancer cells are called carcinoma-associated fibroblasts (CAFs), and they are known to guide cancer cell migration by mechanically modifying tumor stroma [2]. Recent studies have described how the interaction of CAFs with the cancer cells can lead to chemotherapy resistance [3, 4]. A combination of conventional therapy, along with CAF- directed therapy, might lead to improved treatment of breast cancer metastasis
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