Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy
| العنوان: | Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy |
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| المؤلفون: | Arman Jahangiri, Brandyn A. Castro, Shruti Shrivastav, Gary Kohanbash, Manish K. Aghi, William S. Chen, Maxim Sidorov, M De Lay, Daniel Hoffman, Patrick M. Flanigan, Smita Mascharak, Ruby Kuang, Hideho Okada, Garima Yagnik, Jeffrey Wagner |
| المصدر: | Oncogene, vol 36, iss 26 Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, genetic structures, Angiogenesis, Nude, Drug Resistance, Angiogenesis Inhibitors, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Macrophage, Aetiology, Inbred BALB C, Cancer, Mice, Inbred BALB C, Tumor, Neovascularization, Pathologic, Brain Neoplasms, Cell cycle, 3. Good health, Bevacizumab, 030220 oncology & carcinogenesis, Original Article, Female, Biotechnology, Clinical Sciences, Oncology and Carcinogenesis, Macrophage polarization, Mice, Nude, Down-Regulation, Biology, Cell Line, 03 medical and health sciences, Rare Diseases, Growth factor receptor, Cell Line, Tumor, Glioma, otorhinolaryngologic diseases, Genetics, medicine, Animals, Humans, Oncology & Carcinogenesis, Macrophage Migration-Inhibitory Factors, Molecular Biology, Neovascularization, Cell Proliferation, Pathologic, Tumor microenvironment, Macrophages, medicine.disease, Xenograft Model Antitumor Assays, eye diseases, Brain Disorders, Brain Cancer, 030104 developmental biology, Drug Resistance, Neoplasm, Immunology, Cancer research, Neoplasm, Macrophage migration inhibitory factor, sense organs, Glioblastoma |
| الوصف: | Anti-angiogenic therapies for cancer such as VEGF neutralizing antibody bevacizumab have limited durability. While mechanisms of resistance remain undefined, it is likely that acquired resistance to anti-angiogenic therapy will involve alterations of the tumor microenvironment. We confirmed increased tumor-associated macrophages in bevacizumab-resistant glioblastoma patient specimens and two novel glioblastoma xenograft models of bevacizumab resistance. Microarray analysis suggested downregulated macrophage migration inhibitory factor (MIF) to be the most pertinent mediator of increased macrophages. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naive tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Media from macrophages exposed to bevacizumab-resistant tumor cell conditioned media increased glioma cell proliferation compared with media from macrophages exposed to bevacizumab-responsive tumor cell media, suggesting that macrophage polarization in bevacizumab-resistant xenografts is the source of their aggressive biology and results from a secreted factor. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naive patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b24c15f0cc0cfb3ed39238ff84c6be87Test https://doi.org/10.1038/onc.2017.1Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b24c15f0cc0cfb3ed39238ff84c6be87 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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