Abstract
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.
Highlights
Osteosarcoma is the most common malignant bone tumor in children [1]
We demonstrate that macrophages promote the invasion of osteosarcoma cells in vitro and, through clodronate depletion, implicate pulmonary macrophages in the outgrowth of preexisting lung metastases in vivo
We provide compelling evidence that treatment with gefitinib inhibits macrophage-promoted invasion in vitro and inhibits tumor cell extravasation and metastatic outgrowth in vivo, likely as a result of alteration of macrophage phenotype
Summary
Osteosarcoma is the most common malignant bone tumor in children [1]. Osteosarcoma is highly metastatic, and based on historical data, more than 80% of patients developed pulmonary metastases after surgical removal of the primary tumor as monotherapy [2]. Despite the addition of chemotherapy to the treatment algorithm, up to 40% of newly diagnosed patients who present with localized disease will develop metastases [3]. This high metastatic rate is thought to result from subclinical micrometastatic disease present in the lungs. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
