期刊
BRITISH JOURNAL OF CANCER
卷 117, 期 12, 页码 1787-1797出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.354
关键词
TYRO3; AXL; leiomyosarcoma; TAM receptors; GAS6; tyrosine kinase inhibitor; sarcoma
类别
资金
- National Cancer Institute: LYric [DGOS-INCA 4664]
- NetSARC INTERSARC
- RREPS
- Agence Nationale de la Recherche: LabEx DEvweCAN [ANR-10-LABX-0061]
- Eurosarc [FP7-278742]
- La Ligue contre le Cancer de L'Ardeche
- Association pour la recherche sur le cancer
- Agence Nationale de la Recherche (ANR) [ANR-10-LABX-0061] Funding Source: Agence Nationale de la Recherche (ANR)
Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
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