Gefitinib Inhibits Invasion and Metastasis of Osteosarcoma via Inhibition of Macrophage Receptor Interacting Serine-Threonine Kinase 2. Mol Cancer Ther 2020 Jun;19(6):1340-1350
Date
05/07/2020Pubmed ID
32371577DOI
10.1158/1535-7163.MCT-19-0903Scopus ID
2-s2.0-85085903901 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Most patients with osteosarcoma have subclinical pulmonary micrometastases at diagnosis. Mounting evidence suggests that macrophages facilitate metastasis. As the EGFR has been implicated in carcinoma-macrophage cross-talk, in this study, we asked whether gefitinib, an EGFR inhibitor, reduces osteosarcoma invasion and metastatic outgrowth using the K7M2-Balb/c syngeneic murine model. Macrophages enhanced osteosarcoma invasion in vitro, which was suppressed by gefitinib. Oral gefitinib inhibited tumor extravasation in the lung and reduced the size of metastatic foci, resulting in reduced metastatic burden. Gefitinib also altered pulmonary macrophage phenotype, increasing MHCII and decreasing CD206 expression compared with controls. Surprisingly, these effects are mediated through inhibition of macrophage receptor interacting protein kinase 2 (RIPK2), rather than EGFR. Supporting this, lapatinib, a highly specific EGFR inhibitor that does not inhibit RIPK2, had no effect on macrophage-promoted invasion, and RIPK2-/- macrophages failed to promote invasion. The selective RIPK2 inhibitor WEHI-345 blocked tumor cell invasion in vitro and reduced metastatic burden in vivo In conclusion, our results indicate that gefitinib blocks macrophage-promoted invasion and metastatic extravasation by reprogramming macrophages through inhibition of RIPK2.
Author List
Maloney C, Kallis MP, Edelman M, Tzanavaris C, Lesser M, Soffer SZ, Symons M, Steinberg BMAuthor
Caroline Maloney MD, PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Bone Neoplasms
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
Macrophages
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Neoplasm Invasiveness
Osteosarcoma
Receptor-Interacting Protein Serine-Threonine Kinase 2
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
