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Theranostics 2019; 9(10):2950-2966. doi:10.7150/thno.29617 This issue Cite

Research Paper

CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages

Pengling Jiang^1,3,4, Wenjuan Gao², Tiansi Ma², Rongrong Wang², Yongjun Piao², Xiaoli Dong², Peng Wang², Xuehui Zhang^3,5, Yanhua Liu^2,6, Weijun Su^2,6, Rong Xiang^2,6, Jin Zhang^1,3,4✉, Na Li^2,6✉

1. Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;
2. School of Medicine, Nankai University, 94 Weijin Road, Tianjin, China;
3. Tianjin's Clinical Research Center for Cancer, Tianjin, China;
4. Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China;
5. Department of Blood Transfusion, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;
6. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, Tianjin, China.

✉ Corresponding authors: Dr. Jin Zhang, zhangjincom; Dr. Na Li, lina08edu.cn.

Abstract

Rationale: Bone is one of the most common metastatic sites of breast cancer. CD137 (4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study.

Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo.

Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 blocking antibody (NP-αCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis.

Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.

Keywords: liposomal nanoparticles, anti-CD137 antibody, Fra1, breast cancer, bone metastasis, metastatic niche.

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