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Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
The metastatic role of the CXCL10-CXCR3 axis and its therapeutic potential in osteosarcoma
Benjamin B Gyau1,2, Junyan Wang1,2, Xiang Chen1,2
1Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Abstract:
The CXCL10-CXCR3 axis regulates immunity, tumorigenesis, and metastasis in multiple cancers. Yet, its roles in osteosarcoma (OS), the predominant pediatric malignant bone tumor, are not fully defined. Our prior work has shown that elevated serum CXCL10 levels correlate with poor OS prognosis. The current study delves deeper by investigating how CXCL10-mediated CXCR3 signaling influences OS growth and metastatic spread. In vitro, CXCL10 and related CXCR3 ligands (CXCL4, CXCL9, and CXCL11) enhanced OS tumor cell migration. In an orthotopic xenograft mouse model with a newly created CXCR3 knockout (KO) mutant, tumor growth and lung metastasis decreased significantly when compared with the parental cell line. Transfecting the transcript isoform CXCR3A, but not CXCR3B, into KO cells restored metastatic phenotypes in mice, highlighting isoform specificity. Pharmacological CXCR3 inhibition reduced OS cell migration in vitro and metastasis in vivo. Mechanistically, CXCL10 triggered AKT (S473) and PAK1 (S144) phosphorylation in OS cell lines, but not in the KO mutant, implicating the role of these kinases in CXCL10-mediated metastasis. Collectively, our data indicate the CXCL10-CXCR3 axis as a key metastatic driver in OS, suggesting CXCR3 as a viable therapeutic target for treating OS metastasis.
Insights
The CXCL10-CXCR3 axis promotes osteosarcoma (OS) growth and metastasis. Inhibiting CXCR3 signaling offers a potential therapeutic strategy for treating this pediatric bone cancer.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The CXCL10-CXCR3 axis is implicated in various cancers.
- Its specific role in osteosarcoma (OS), a pediatric bone tumor, requires further elucidation.
- Previous studies linked elevated serum CXCL10 to poor OS prognosis.
Purpose of the Study:
- To investigate the influence of CXCL10-CXCR3 signaling on OS tumor growth and metastasis.
- To identify potential therapeutic targets within this pathway for OS treatment.
Main Methods:
- In vitro cell migration assays with OS cells and CXCR3 ligands.
- Orthotopic xenograft mouse models using CXCR3 knockout mutants.
- Analysis of CXCR3 isoform (CXCR3A, CXCR3B) specific effects.
- Pharmacological inhibition of CXCR3.
- Western blot analysis of AKT and PAK1 phosphorylation.
Main Results:
- CXCL10 and other CXCR3 ligands enhanced OS cell migration in vitro.
- CXCR3 knockout significantly reduced OS tumor growth and lung metastasis in vivo.
- Restoration of CXCR3A, but not CXCR3B, in knockout cells re-established metastatic potential.
- CXCR3 inhibition decreased OS cell migration and metastasis.
- CXCL10 induced AKT and PAK1 phosphorylation in OS cells, dependent on CXCR3.
Conclusions:
- The CXCL10-CXCR3 axis is a critical driver of metastasis in osteosarcoma.
- CXCR3 isoform specificity is crucial for mediating these effects.
- Targeting CXCR3 presents a promising therapeutic avenue for managing OS metastasis.
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