Nerve growth factor promote VCAM-1-dependent monocyte adhesion and M2 polarization in osteosarcoma microenvironment: Implications for larotrectinib therapy

Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In...

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Bibliographic Details
Published in:International journal of biological sciences 2024, Vol.20 (11), p.4114-4127
Main Authors: Lin, Syuan-Ling, Yang, Shang-Yu, Tsai, Chun-Hao, Fong, Yi-Chin, Chen, Wei-Li, Liu, Ju-Fang, Lin, Chih-Yang, Tang, Chih-Hsin
Format: Article
Language:English
Subjects:
Animals
Bone Neoplasms - drug therapy
Bone Neoplasms - metabolism
Bone Neoplasms - pathology
Cell Adhesion - drug effects
Cell Line, Tumor
Humans
Macrophages - metabolism
Mice
Mice, Nude
Monocytes - drug effects
Monocytes - metabolism
Nerve Growth Factor - metabolism
Osteosarcoma - drug therapy
Osteosarcoma - metabolism
Osteosarcoma - pathology
Pyrazoles - pharmacology
Pyrazoles - therapeutic use
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Tumor Microenvironment - drug effects
Vascular Cell Adhesion Molecule-1 - metabolism
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Summary:Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.
ISSN:1449-2288
1449-2288
DOI:10.7150/ijbs.95463