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

Autor: Peng Wang, Rongrong Wang, Na Li, Yanhua Liu, Wenjuan Gao, Weijun Su, Tiansi Ma, Xiaoli Dong, Rong Xiang, Xuehui Zhang, Jin Zhang, Pengling Jiang, Yongjun Piao
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Medicine (miscellaneous)
Osteoclasts
Bone Neoplasms
Breast Neoplasms
metastatic niche
Models
Biological
Monocytes
Metastasis
Cell Line
anti-CD137 antibody
03 medical and health sciences
Mice
Tumor Necrosis Factor Receptor Superfamily
Member 9
0302 clinical medicine
Breast cancer
breast cancer
Osteoclast
Cell Movement
Fra1
Medicine
Macrophage
Animals
Neoplasm Metastasis
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
bone metastasis
Tumor microenvironment
business.industry
Monocyte
Bone metastasis
Cell Differentiation
liposomal nanoparticles
medicine.disease
Up-Regulation
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Tumor necrosis factor alpha
business
Proto-Oncogene Proteins c-fos
Research Paper
Zdroj: Theranostics
ISSN: 1838-7640
Popis: 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.
Databáze: OpenAIRE
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