NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis.

Hao Liu,Liping Yang,Min Qi,Jianglin Zhang

doi:10.1042/bsr20181604

Abstract

Tumor-associated macrophages (TAMs) play substantial roles in tumor growth, invasion, and metastasis. Nuclear factor of activated T cell (NFAT1) has been shown to promote melanoma growth and metastasis in vivo. We herein aim to investigate whether NFAT1 is capable to promote melanoma growth and metastasis by influencing TAM properties. Melanoma-conditioned TAMs were obtained from human monocytes after incubation with conditioned medium from A375 cell culture. The phenotype of the macrophages was detected. Cell proliferation, migration, and invasion were evaluated. Human malignant melanoma tissues exhibited increased CD68+-macrophage infiltration and NFAT1 expression compared with the normal pigmented nevus tissues. Melanoma-conditioned TAMs displayed M2-like phenotype. Melanoma-conditioned TAMs also promoted proliferation, migration, and invasion of human malignant melanoma cell lines A375 and WM451. Furthermore, NFAT1 expression in TAMs was significantly increased compared with the M0 group. NFAT1 overexpression significantly strengthened the melanoma-conditioned TAM-mediated promotion of cell migration and invasion in A375 and WM451 cells, whereas NFAT1 knockdown exerted the opposite effects. Moreover, NFAT1 overexpression in melanoma-conditioned TAMs promoted CD68+-macrophage infiltration, tumor growth, and metastasis in vivo. NFAT1 may play a critical role in enhancing the TAM-mediated promotion of growth and metastasis in malignant melanoma.

Highlights

Melanoma is the most aggressive and the deadliest form of skin cancer [1]
These results suggested that melanoma-conditioned tumor-associated macrophage (TAM) displayed M2-like phenotype
The results showed that the capacity of melanoma-conditioned TAMs to promote cell migration and invasion of A375 and WM451 cells was significantly enhanced by nuclear factor of activated T cell (NFAT1) overexpression (Figure 5D,E) but suppressed by NFAT1 knockdown (Figure 6A,B) compared with their corresponding control

Summary

Introduction

Melanoma is the most aggressive and the deadliest form of skin cancer [1]. Despite rapid progress in the treatment, malignant melanoma still presents a major clinical challenge. The melanoma progression and pathogenesis strongly depends on the fine-tuned interactions between melanoma cancer cells and the various stromal cells in the host [5]. Tumor-associated macrophages (TAMs) have been shown to play substantial roles in tumor growth, invasion, and metastasis [6,7,8,9]. Convincing evidence has highlighted the association of increased TAMs infiltration with poor prognosis and worse pathological characteristics in diverse cancers, including colon cancer, breast cancer, bladder cancer, and melanoma [10,11,12,13,14]. TAMs generally acquire M2-like properties [16,17]

Methods

Results

Conclusion