HMGB1 Positive Feedback Loop Between Cancer Cells and Tumor-Associated Macrophages Promotes Osteosarcoma Migration and Invasion

Changhe Hou; Ming Lu; Zixiong Lei; Shuangwu Dai; Wei Chen; Shaohua Du; Qinglin Jin; Zhongxin Zhou; Haomiao Li

doi:10.1016/j.labinv.2022.100054

HMGB1 Positive Feedback Loop Between Cancer Cells and Tumor-Associated Macrophages Promotes Osteosarcoma Migration and Invasion

Lab Invest. 2023 May;103(5):100054. doi: 10.1016/j.labinv.2022.100054. Epub 2023 Jan 10.

Authors

Changhe Hou¹, Ming Lu¹, Zixiong Lei¹, Shuangwu Dai¹, Wei Chen¹, Shaohua Du¹, Qinglin Jin¹, Zhongxin Zhou², Haomiao Li³

Affiliations

¹ Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
² Department of Vascular Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. Electronic address: 1145364046@qq.com.
³ Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. Electronic address: lihaom@mail.sysu.edu.cn.

PMID: 36801636
DOI: 10.1016/j.labinv.2022.100054

Abstract

Numerous studies have demonstrated the key roles of tumor-associated macrophages (TAMs) in osteosarcoma metastasis. Higher levels of high mobility group box 1 (HMGB1) promote osteosarcoma progression. However, whether HMGB1 is involved in the polarization of M2 macrophages into M1 macrophages in osteosarcoma remains largely unknown. Here, HMGB1 and CD206 mRNA expression levels were measured by a quantitative reverse transcription-polymerase chain reaction in osteosarcoma tissues and cells. HMGB1 and receptor for advanced glycation end products (RAGE) protein expression levels were measured by western blotting. Osteosarcoma migration was measured using transwell and wound-healing assays, while a transwell assay determined osteosarcoma invasion. Macrophage subtypes were detected using flow cytometry. HMGB1 expression levels were aberrantly enhanced in osteosarcoma tissues compared with normal tissues and were positively correlated with AJCC III and IV stages, lymph node metastasis, and distant metastasis. Silencing HMGB1 inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. Furthermore, reduced HMGB1 expression levels in conditioned media derived from osteosarcoma cells induced the polarization of M2 TAMs to M1 TAMs. In addition, silencing HMGB1 inhibited the liver and lung metastasis of tumors and reduced the expression levels of HMGB1, CD163, and CD206 in vivo. HMGB1 was found to regulate macrophage polarization through RAGE. Polarized M2 macrophages induced osteosarcoma migration and invasion, activating HMGB1 expression in osteosarcoma cells to form a positive feedback loop. In conclusion, HMGB1 and M2 macrophages enhanced osteosarcoma migration, invasion, and EMT through positive feedback regulation. These findings reveal the significance of tumor cell and TAM interactions in the metastatic microenvironment.

Keywords: HMGB1; M2 macrophage polarization; epithelial-mesenchymal transition; osteosarcoma; tumor-associated macrophage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Neoplasms* / genetics
Cell Line, Tumor
Cell Movement / genetics
Feedback
HMGB1 Protein* / genetics
HMGB1 Protein* / metabolism
Humans
Osteosarcoma* / genetics
Osteosarcoma* / pathology
Tumor Microenvironment / genetics
Tumor-Associated Macrophages / metabolism
Tumor-Associated Macrophages / pathology

Substances

HMGB1 Protein