A Role of CXCL1 Drives Osteosarcoma Lung Metastasis via VCAM-1 Production

Chiang-Wen Lee; Yao-Chang Chiang; Pei-An Yu; Kuo-Ti Peng; Miao-Ching Chi; Ming-Hsueh Lee; Mei-Ling Fang; Kuan-Han Lee; Lee-Fen Hsu; Ju-Fang Liu

doi:10.3389/fonc.2021.735277

A Role of CXCL1 Drives Osteosarcoma Lung Metastasis via VCAM-1 Production

Front Oncol. 2021 Oct 25:11:735277. doi: 10.3389/fonc.2021.735277. eCollection 2021.

Authors

Chiang-Wen Lee^{1

2

3}, Yao-Chang Chiang^{1

2

3}, Pei-An Yu^{1

4}, Kuo-Ti Peng^{1

5}, Miao-Ching Chi^{3

6

7}, Ming-Hsueh Lee^{6

8}, Mei-Ling Fang^{9

10}, Kuan-Han Lee¹¹, Lee-Fen Hsu^{6

8}, Ju-Fang Liu^{12

13}

Affiliations

¹ Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Puzi, Taiwan.
² Department of Nursing, Chang Gung University of Science and Technology, Puzi, Taiwan.
³ Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi, Taiwan.
⁴ Sports Medicine Center, Chang Gung Memorial Hospital at Chia Yi, Chiayi, Taiwan.
⁵ College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁶ Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi, Taiwan.
⁷ Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁸ Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
⁹ Center for Environmental Toxin and Emerging-Contaminant Research, Cheng Shiu University, Kaohsiung, Taiwan.
¹⁰ Super Micro Research and Technology Center, Cheng Shiu University, Kaohsiung, Taiwan.
¹¹ Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
¹² School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
¹³ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Abstract

Osteosarcoma, a common aggressive and malignant cancer, appears in the musculoskeletal system among young adults. The major cause of mortality in osteosarcoma was the recurrence of lung metastases. However, the molecular mechanisms of metastasis involved in osteosarcomas remain unclear. Recently, CXCL1 and CXCR2 have been crucial indicators for lung metastasis in osteosarcoma by paracrine releases, suggesting the involvement of directing neutrophils into tumor microenvironment. In this study, overexpression of CXCL1 has a positive correlation with the migratory and invasive activities in osteosarcoma cell lines. Furthermore, the signaling pathway, CXCR2/FAK/PI3K/Akt, is activated through CXCL1 by promoting vascular cell adhesion molecule 1 (VCAM-1) via upregulation of nuclear factor-kappa B (NF-κB) expression and nuclear translocation. The in vivo animal model further demonstrated that CXCL1 serves as a critical promoter in osteosarcoma metastasis to the lung. The correlated expression of CXCL1 and VCAM-1 was observed in the immunohistochemistry staining from human osteosarcoma specimens. Our findings demonstrate the cascade mechanism regulating the network in lung metastasis osteosarcoma, therefore indicating that the CXCL1/CXCR2 pathway is a worthwhile candidate to further develop treatment schemas.

Keywords: CXCL1; VCAM-1; metastasis; migration; osteosarcoma.