Abstract
M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that all-trans retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages in vitro ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. Cancer Immunol Res; 5(7); 547-59. ©2017 AACR.
Highlights
Osteosarcoma accounts for 60% of all malignant childhood bone tumors [1]
M2 tumor-associated macrophages (TAM) promote metastasis of osteosarcoma cells in vivo To study the role of macrophages in osteosarcoma metastasis, we injected K7M2 WT osteosarcoma cells together with RAW264.7 macrophage cells into the tail vein of mice and examined the numbers of pulmonary metastatic nodules
We demonstrated that M2 polarization of TAMs promoted pulmonary metastasis of osteosarcoma cells
Summary
Osteosarcoma accounts for 60% of all malignant childhood bone tumors [1]. With combined treatment (neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy), the 5-year survival rate of patients with no metastatic disease at diagnosis is 60% to 70% [2]; for patients who present with metastasis, the chance of survival drops to less than 30% [3]. Treatment-refractory pulmonary metastasis is the major complication of osteosarcoma. Microenvironment determines tumor progression and metastasis [4]. The presence and density of tumor-associated macrophages (TAM) correlates with tumor cell proliferation, invasion, metastasis, and poor prognosis [5, 6]. M2-type TAMs are key drivers of tumors behavior, affecting tumor progression and Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
