Nitric oxide-mediated tumoricidal activity of murine microglial cells
Open accessAbstract
Experimental metastases in the brain of mice are infiltrated by microglia, and parabiosis experiments of green fluorescent protein (GFP(+)) and GFP(-) mice revealed that these microglia are derived from circulating monocytes (GFP(+), F4/80(+), and CD68(+)). These findings raised the question as to whether microglia (specialized macrophages) possess tumoricidal activity. C8-B4 murine microglia cells were incubated in vitro in medium (control) or in medium containing both lipopolysaccharide and interferon-γ. Control microglia were not tumoricidal against a number of murine and human tumor cells, whereas lipopolysaccharide/interferon-γ-activated microglia lysed murine and human tumor cells by release of nitric oxide. Parallel experiments with murine peritoneal macrophages produced identical results. Neither activated microglia nor activated macrophages lysed nontumorigenic murine or human cells. Collectively, these data demonstrate that brain metastasis-associated microglia are derived from circulating mononuclear cells and exhibit selective and specific tumoricidal activity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Sodium nitrite therapy may be an effective anti-tumor therapy through NO mediated radiosensitization or tumoricidal properties.
“As discussed above, sodium nitrite therapy may actually be an effective anti-tumor therapy through NO mediated radiosenitization or tumoricidal properties [278, 279].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [278]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · cited 1× · see citing works
“These so-called “resting” microglia were once thought to be largely inactive; however, recent work describes their active patrol of the healthy brain, using their motile processes to constantly survey the microenvironment [3,4].”
BackgroundMacrophage Diversity Enhances Tumor Progression and Metastasis
Qian, B., & Pollard, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.03.014 · Cited by 5,178 · cited 1× · see citing works
“A large body of evidence suggests that in some situations, macrophages can promote tumor growth, metastasis, and angiogenesis [13,14], whereas in others, macrophages are tumoricidal by selectively recognizing and destroying tumor cells [15–18].”
BackgroundATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · cited 1× · see citing works
“These so-called “resting” microglia were once thought to be largely inactive; however, recent work describes their active patrol of the healthy brain, using their motile processes to constantly survey the microenvironment [3,4].”
BackgroundOʼReilly, M. (1994) · Cell · doi:10.1016/0092-8674(94)90200-3 · Cited by 3,344 · cited 3× · see citing works
“Lipopolysaccharide (LPS) and interferon-γ (IFN-γ)–activated microglia isolated from the adult brain are more similar to macrophages infiltrating the central nervous system (CNS) than naive microglia of the brain [11].”
BackgroundDevelopment of Monocytes, Macrophages, and Dendritic Cells
Geissmann, F., Manz, M. G., Jung, S., Sieweke, M. H., Merad, M., & Ley, K. (2010) · Science · doi:10.1126/science.1178331 · Cited by 3,049 · cited 4× · see citing works
“Discussion Microglia are the major immune effector cells of the CNS and are commonly called the macrophages of the brain [1,2].”
BackgroundInfluentialHeterogeneity in the distribution and morphology of microglia in the normal adult mouse brain
Lawson, L. J., Perry, V. H., Dri, P., & Gordon, S. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90229-w · Cited by 2,045 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
Selection of Successive Tumour Lines for Metastasis
Fidler, I. J. (1973) · Nature New Biology · doi:10.1038/newbio242148a0 · Cited by 1,364 · cited 1× · see citing works
“The B16-BL6 cell line is a highly metastatic and invasive variant [32,33] derived from B16 mouse melanoma [34].”
BackgroundTrophic macrophages in development and disease
Pollard, J. W. (2009) · Nature Reviews Immunology · doi:10.1038/nri2528 · Cited by 1,178 · cited 1× · see citing works
“A large body of evidence suggests that in some situations, macrophages can promote tumor growth, metastasis, and angiogenesis [13,14], whereas in others, macrophages are tumoricidal by selectively recognizing and destroying tumor cells [15–18].”
BackgroundBreast Tumor Cell Lines From Pleural Effusions2
Cailleau, R., Young, R. K., Olivé, M., & Reeves, W. J. (1974) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/53.3.661 · Cited by 1,019 · cited 1× · see citing works
“The MDA-MB-231 is an ER-negative human breast carcinoma cell line [36] and was a gift from Dr R.”
Perry, V. H., Hume, D. A., & Gordon, S. (1985) · Neuroscience · doi:10.1016/0306-4522(85)90215-5 · Cited by 902 · see citing works
Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse.
Jat, P., Noble, M., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larsen, L., & Kioussis, D. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.12.5096 · Cited by 744 · see citing works
Role of Microglia in Central Nervous System Infections
Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R., & Peterson, P. K. (2004) · Clinical Microbiology Reviews · doi:10.1128/cmr.17.4.942-964.2004 · Cited by 723 · cited 1× · see citing works
“Interestingly, IFN-γ and LPS-activated monocytes are capable of recognizing elevated levels of PS and targeting these cells for lysis [53].”
BackgroundTurnover of resident microglia in the normal adult mouse brain
Lawson, L. J., Perry, V. H., & Gordon, S. (1992) · Neuroscience · doi:10.1016/0306-4522(92)90500-2 · Cited by 709 · see citing works
Utsugi, T., Schroit, A. J., Connor, J., Bucana, C. D., & Fidler, I. J. (1991) · PubMed · Cited by 594 · see citing works
Inflammatory Neurodegeneration and Mechanisms of Microglial Killing of Neurons
Brown, G. C., & Neher, J. J. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8105-9 · Cited by 526 · see citing works
Hume, D. A., Perry, V. H., & Gordon, S. (1983) · The Journal of Cell Biology · doi:10.1083/jcb.97.1.253 · Cited by 447 · cited 1× · see citing works
“Microglia and macrophages share molecular markers such as MAC1, F4/80, and FcIgG1/2b [6,7].”
BackgroundThe role of microglia in central nervous system immunity and glioma immunology
Yang, I., Han, S. J., Kaur, G., Crane, C., & Parsa, A. T. (2010) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2009.05.006 · Cited by 410 · see citing works
The origin and cell lineage of microglia: new concepts
Chan, W. Y., Kohsaka, S., & Rezaie, P. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.11.002 · Cited by 400 · cited 1× · see citing works
“Importantly, these data also corroborate previous reports that unlike other glial cells, such as astrocytes and oligodendrocytes that originate in the neuroectoderm, microglia are derived from circulating blood monocytes and are capable of repopulating the brain during pathologic conditions [25,26,30, 44,56–59].”
ResultCytokine Actions in the Central Nervous System
Benveniste, E. N. (1998) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(98)00015-x · Cited by 383 · cited 1× · see citing works
“Both macrophages and microglia can be potently activated by IFN-γ and LPS to express a variety of integral cell surface proteins necessary for immune function [16,43].”
BackgroundThe selection and characterization of an invasive variant of the B16 melanoma.
Hart, I. R. (1979) · PubMed · Cited by 374 · see citing works
Tumor Cell-Organ Microenvironment Interactions in the Pathogenesis of Cancer Metastasis
Langley, R. R., & Fidler, I. J. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0027 · Cited by 368 · cited 1× · see citing works
“The organ microenvironment can alter the ability of tumor cells to “seed” the organ and modify the response of metastatic tumor cells to therapy [48,49].”
Background(1985) · PubMed · Cited by 346 · see citing works
Microglia function in brain tumors
Watters, J. J., Schartner, J. M., & Badie, B. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20485 · Cited by 330 · cited 2× · see citing works
“Although the presence of macrophages and microglia has been reported in both clinical and experimental specimens of brain metastasis, their exact function is unclear [23–30].”
BackgroundXie, K., Huang, S., Dong, Z., Juang, S., Gutman, M., Xie, Q. W., Nathan, C., & Fidler, I. J. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.4.1333 · Cited by 320 · cited 2× · see citing works
“We have previously shown that this mechanism is also responsible for macrophageinduced tumor cell death [41,47].”
BackgroundThe “seed and soil” hypothesis revisited
Fidler, I. J., & Poste, G. H. (2008) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70201-8 · Cited by 319 · cited 1× · see citing works
“The organ microenvironment can alter the ability of tumor cells to “seed” the organ and modify the response of metastatic tumor cells to therapy [48,49].”
BackgroundMicroglial clearance function in health and disease
Napoli, I., & Neumann, H. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.06.046 · Cited by 312 · cited 1× · see citing works
“Importantly, these data also corroborate previous reports that unlike other glial cells, such as astrocytes and oligodendrocytes that originate in the neuroectoderm, microglia are derived from circulating blood monocytes and are capable of repopulating the brain during pathologic conditions [25,26,30, 44,56–59].”
ResultH‐2Kb‐tsA58トランスジェニックマウスから直接に無限増殖細胞系を得る方法
Jat, P., Noble, M., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larsen, L., & Kioussis, D. (1991) · Cited by 310 · see citing works
O'Brien, A. W. (1905) · The Elementary School Teacher · doi:10.1086/453500 · Cited by 303 · see citing works
Aldinucci, D., Gloghini, A., Pinto, A., Filippi, R. D., & Carbone, A. (2010) · The Journal of Pathology · doi:10.1002/path.2711 · Cited by 276 · cited 1× · see citing works
“Data suggest that these behavioral changes are largely dependent on the context of the specific tumor type and its microenvironment [19–22].”
BackgroundOxidative and Antioxidative Potential of Brain Microglial Cells
Dringen, R. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.1223 · Cited by 266 · cited 1× · see citing works
“Microglia-derived NO potentially harms cells, and it has been implicated in contributing to oxidative damage and subsequent cell death in a variety of neurologic pathologies [23].”
BackgroundMacrophages in experimental and human brain tumors
Morantz, R. A., Wood, G. W., Foster, M., Clark, M., & Gollahon, K. A. (1979) · Journal of neurosurgery · doi:10.3171/jns.1979.50.3.0305 · Cited by 239 · cited 3× · see citing works
“Although the presence of macrophages and microglia has been reported in both clinical and experimental specimens of brain metastasis, their exact function is unclear [23–30].”
BackgroundModulation of CD4 antigen on macrophages and microglia in rat brain.
Perry, V. H., & Gordon, S. (1987) · The Journal of Experimental Medicine · doi:10.1084/jem.166.4.1138 · Cited by 229 · cited 1× · see citing works
“It is largely recognized that some microglia develop from a pool of blood monocytes and can colonize the brain early in development [8–10].”
BackgroundLin, Q., Balasubramanian, K., Fan, D., Kim, S., Guo, L., Wang, H., Bar‐Eli, M., Aldape, K., & Fidler, I. J. (2010) · Neoplasia · doi:10.1593/neo.10602 · Cited by 228 · see citing works
Speculations on the Role of Ultraviolet Radiation in the Development of Malignant Melanoma4
Kripke, M. L. (1979) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/63.3.541 · Cited by 226 · cited 1× · see citing works
“The K-1735 C4 melanoma syngeneic to C3H-/HeN mice [35] was a gift from Dr M.”
MethodTherapy of Spontaneous Metastases by Intravenous Injection of Liposomes Containing Lymphokines
Fidler, I. J. (1980) · Science · doi:10.1126/science.7384789 · Cited by 202 · cited 1× · see citing works
“The B16-BL6 cell line is a highly metastatic and invasive variant [32,33] derived from B16 mouse melanoma [34].”
BackgroundFidler, I. J., & Schroit, A. J. (1988) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(88)90009-1 · Cited by 188 · cited 1× · see citing works
“However, we have previously demonstrated that tumor cells express higher levels of phosphatidylserine (PS) in the outer membrane leaflet, compared with cells of normal origin [15,52].”
BackgroundMolecular pathways and targets in cancer-related inflammation
Mantovani, A., Garlanda, C., & Allavena, P. (2010) · Annals of Medicine · doi:10.3109/07853890903405753 · Cited by 181 · cited 1× · see citing works
“Data suggest that these behavioral changes are largely dependent on the context of the specific tumor type and its microenvironment [19–22].”
BackgroundMicroglial progenitors with a high proliferative potential in the embryonic and adult mouse brain.
Alliot, F., Lecain, É., Grima, B., & Pessac, B. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.4.1541 · Cited by 174 · cited 1× · see citing works
“It is largely recognized that some microglia develop from a pool of blood monocytes and can colonize the brain early in development [8–10].”
BackgroundFrom bone marrow to microglia: barriers and avenues
Davoust, N., Vuaillat, C., Androdias, G., & Nataf, S. (2008) · Trends in Immunology · doi:10.1016/j.it.2008.01.010 · Cited by 173 · cited 1× · see citing works
“Importantly, these data also corroborate previous reports that unlike other glial cells, such as astrocytes and oligodendrocytes that originate in the neuroectoderm, microglia are derived from circulating blood monocytes and are capable of repopulating the brain during pathologic conditions [25,26,30, 44,56–59].”
ResultOvarian cancer creates a suppressive microenvironment to escape immune elimination
Yigit, R., Massuger, L. F. A. G., Figdor, C. G., & Torensma, R. (2010) · Gynecologic Oncology · doi:10.1016/j.ygyno.2010.01.019 · Cited by 168 · cited 1× · see citing works
“Data suggest that these behavioral changes are largely dependent on the context of the specific tumor type and its microenvironment [19–22].”
BackgroundCirculating Monocytes Expressing CD31
Kim, S., Kim, J., Papadopoulos, J. N., Kim, S. W., Maya, M., Zhang, F., He, J., Fan, D., Langley, R. R., & Fidler, I. J. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080819 · Cited by 153 · see citing works
Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide
Gibbons, H. M., & Dragunow, M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.02.032 · Cited by 142 · cited 2× · see citing works
“Recent work links microglial-induced neuronal toxicity to iNOS activity and iNOS expression is associated with microglia surrounding brain metastasis in humans [24,25,46].”
BackgroundMacrophages in experimental and human brain tumors
Morantz, R. A., Wood, G. W., Foster, M., Clark, M., & Gollahon, K. A. (1979) · Journal of neurosurgery · doi:10.3171/jns.1979.50.3.0298 · Cited by 131 · cited 3× · see citing works
“Although the presence of macrophages and microglia has been reported in both clinical and experimental specimens of brain metastasis, their exact function is unclear [23–30].”
BackgroundPaclitaxel-induced apoptosis in MCF-7 breast-cancer cells
Saunders, D. E., Lawrence, W. D., CHRISTENSEN, C. W., Wappler, N. L., Ruan, H., & Deppe, G. (1997) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19970117)70:2 · Cited by 121 · see citing works
Schackert, G., & Fidler, I. J. (1988) · PubMed · Cited by 117 · see citing works
Differential Reactions of Microglia to Brain Metastasis of Lung Cancer
He, B. P., Wang, J. J., Zhang, X., Wu, Y., Wang, M., Bay, B., & Chang, A. Y.-C. (2006) · Molecular Medicine · doi:10.2119/2006-00033.he · Cited by 99 · cited 3× · see citing works
“Recent work links microglial-induced neuronal toxicity to iNOS activity and iNOS expression is associated with microglia surrounding brain metastasis in humans [24,25,46].”
BackgroundFidler, I. J., & Nicolson, G. L. (1977) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/58.6.1867 · Cited by 91 · cited 1× · see citing works
“Reconstituting mice with a single injection of GFP bonemarrow cells will largely home to the liver and lungs; therefore, we used the parabiosis model, which allows for continuous release of bonemarrow cells into the circulation [42].”
MethodWu, Y., Mizukami, H., Matsuda, J., Saito, Y., Proia, R. L., & Suzuki, K. (2004) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2004.08.017 · Cited by 90 · see citing works
Romieu, R., Solis, M., Nardin, A., Goubau, D., Baron‐Bodo, V., Lin, R., Bernard Massie, B., Salcedo, M., & Hiscott, J. B. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1279 · Cited by 89 · see citing works
Xie, K., Huang, S., Dong, Z., Gutman, M., & Fidler, I. J. (1995) · PubMed · Cited by 84 · see citing works
Solis, M., Goubau, D., Romieu, R., Génin, P., Civas, A., & Hiscott, J. B. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.06.002 · Cited by 73 · see citing works
Zhang, M., & Olsson, Y. (1995) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(95)00227-9 · Cited by 70 · see citing works
Davoust, N., Vuaillat, C., Cavillon, G., Domenget, C., Hatterer, E., Bernard, A., Dumontel, C., Jurdic, P., Malcus, C., Confavreux, C., et al. (2006) · The FASEB Journal · doi:10.1096/fj.05-5593com · Cited by 62 · see citing works
Langley, R. R. (2009) · International Journal of Oncology · doi:10.3892/ijo_00000378 · Cited by 56 · see citing works
Xu, L., Xie, K., & Fidler, I. J. (1998) · Human Gene Therapy · doi:10.1089/hum.1998.9.18-2699 · Cited by 53 · cited 1× · see citing works
“Previous work from our laboratory revealed that tumoricidal activity of macrophages is mediated through NO release [41,55].”
BackgroundA spontaneously immortalized mouse microglial cell line expressing CD4
Alliot, F., Marty, M., Cambier, D., & Pessac, B. (1996) · Developmental Brain Research · doi:10.1016/0165-3806(96)00101-0 · Cited by 42 · cited 4× · see citing works
“Cell Line and Culture Conditions The spontaneously immortalized murine C8-B4 microglial cell line [6] was the gift of Dr D.”
BackgroundMethodInfluentialModel of malignant pleural effusion of human lung adenocarcinoma in SCID mice.
Yano, S., Nokihara, H., Hanibuchi, M., Parajuli, P., Shinohara, T., Kawano, T., & Sone, S. (1997) · PubMed · Cited by 36 · see citing works
Fan, D., Liaw, A., Denkins, Y. M., Collins, J. H., Arsdall, M. R. V., Chang, J. L., Chakrabarty, S., Nguyen, D., Kruzel, E., & Fidler, I. J. (2002) · Journal of Experimental Therapeutics and Oncology · doi:10.1046/j.1359-4117.2002.01053.x · Cited by 21 · cited 2× · see citing works
“The monolayers routinely contained greater than 98% pure peritoneal macrophages as assessed by morphologic and phagocytic criteria [40].”
BackgroundEue, I., Kumar, R., Dong, Z., Killion, J. J., & Fidler, I. J. (1998) · Journal of Immunotherapy · doi:10.1097/00002371-199809000-00002 · Cited by 20 · cited 5× · see citing works
“Assay for Nitrite Production Nitrite accumulation in the culture supernatant was measured in a colorimetric assay as described previously [41].”
BackgroundMethodInfluentialLipopolysaccharide extends the lifespan of mouse primary-cultured microglia
Kaneko, Y. S., Nakashima, A., Mori, K., Nagatsu, T., Nagatsu, I., & Ota, A. (2009) · Brain Research · doi:10.1016/j.brainres.2009.05.008 · Cited by 14 · cited 2× · see citing works
“LPS has been shown to extend the life span of cultured mouse microglia by increasing the expression of Bcl-xl and suppressing the induction of apoptosis and autophagy [12].”
Background
Flagged first, then by citations
2 of the 63 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W.-C., Li, P., Li, M., Wang, X., Zhang, C., et al. (2015) · Nature · doi:10.1038/nature15376 · Cited by 1,080 · see citing works
Alternatively activated microglia and macrophages in the central nervous system
Franco, R., & Fernández‐Suárez, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.003 · Cited by 650 · see citing works
“…(2009) MG5 Mouse 1997 Ohsawa et al. p53-deficient mice + + N/A N/A + + Kawahara et al. (2001) C8-B4 Mouse 1996 Alliot et al. Spontaneous + + + + + + Brantley et al. (2010), Moussaud and Draheim (2010), Moussaud et al. (2009) HAPI Rat 2001 Cheepsunthorn et al. Spontaneous + + + + + + Zheng et al.…”
BackgroundInfluentialDifferentiation of human and murine induced pluripotent stem cells to microglia-like cells
Pandya, H., Shen, M. J., Ichikawa, D. M., Sedlock, A. B., Choi, Y., Johnson, K. R., Kim, G., Brown, M. A., Elkahloun, A. G., Maric, D., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4534 · Cited by 405 · see citing works
The Evolving Landscape of Brain Metastasis
Valiente, M., Ahluwalia, M. S., Boire, A. A., Brastianos, P. K., Goldberg, S. B., Lee, E. Q., Rhun, É. L., Preusser, M., Winkler, F., & Soffietti, R. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.01.003 · Cited by 310 · see citing works
Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis
Poon, C. C., Sarkar, S., Yong, V. W., & Kelly, J. J. (2017) · Brain · doi:10.1093/brain/aww355 · Cited by 246 · see citing works
Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells
Sarkar, S., Döring, A., Zemp, F. J., Silva, C., Lun, X. Q., Wang, X., Kelly, J. J., Hader, W. J., Hamilton, M. G., Mercier, P., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3597 · Cited by 202 · see citing works
Brain metastases: pathobiology and emerging targeted therapies
Preusser, M., Capper, D., Ilhan‐Mutlu, A., Berghoff, A. S., Birner, P., Bartsch, R., Marosi, C., Zielinski, C. C., Mehta, M. P., Winkler, F., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0933-9 · Cited by 199 · see citing works
“Moreover, activated microglia are tumoricidal and lyse melanoma and carcinoma cells by release of nitric oxide [11], similar to the situation in gliomas [53].”
BackgroundZhang, J., Sarkar, S., Cua, R., Zhou, Y., Hader, W. J., & Yong, V. W. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr289 · Cited by 196 · see citing works
Boeck, A. D., Ahn, B. Y., D’Mello, C., Lun, X. Q., Menon, S. V., Alshehri, M. M., Szulzewsky, F., Shen, Y., Khan, L., Dang, N. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18569-4 · Cited by 181 · see citing works
The Biology of Brain Metastasis
Fidler, I. J. (2015) · The Cancer Journal · doi:10.1097/ppo.0000000000000126 · Cited by 179 · see citing works
“We determined the in vitro function of microglia by examining the ability of lipopolysaccharide + interferon γ–activated microglia to induce cytotoxicity in cancer cells.(111) Using the C8-B4 microglial cell line, we examined the effects of lipopolysaccharide + interferon γ–activated microglia on tumor cells and obser…”
BackgroundMethodBrain metastasis: Unique challenges and open opportunities
Lowery, F. J., & Yu, D. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.12.001 · Cited by 171 · see citing works
Wang, G., Zhong, K., Wang, Z., Zhang, Z., Tang, X., Tong, A., & Zhou, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.964898 · Cited by 129 · see citing works
Reactive Astrocytes in Brain Metastasis
Wasilewski, D., Priego, N., Torre, C. F., & Valiente, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00298 · Cited by 121 · see citing works
Inorganic nitrite therapy: historical perspective and future directions
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.042 · Cited by 113 · see citing works
Mukherjee, S., Baidoo, J., Sampat, S., Mancuso, A., David, L., Cohen, L. S., Zhou, S., & Banerjee, P. (2018) · Molecules · doi:10.3390/molecules23010201 · Cited by 101 · see citing works
“Therefore, we analyzed the possibility of activation of caspase3 (apoptosis) in the CD68high GBM cells in the tumors after treatment with TrLp or CLp, which could be a result of the observed M1 polarization of TAM and recruitment of activated NK cells, both of which are highly tumoricidal [14,15,48,50].”
BackgroundMukherjee, S., Fried, A., Hussaini, R., White, R., Baidoo, J., Yalamanchi, S., & Banerjee, P. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0792-5 · Cited by 100 · see citing works
Kuhn, S. P., Yang, J., & Ronchese, F. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00584 · Cited by 98 · see citing works
“In a similar manner, macrophages can eliminate tumors through secretion of cytotoxic factors (44, 45) and be associated with increased survival in patients (53), but more often they promote tumor growth (21, 54).”
BackgroundCharacterization of the inflammatory response to solid cancer metastases in the human brain
Berghoff, A. S., Lassmann, H., Preusser, M., & Höftberger, R. (2012) · Clinical & Experimental Metastasis · doi:10.1007/s10585-012-9510-4 · Cited by 88 · see citing works
Winkler, F. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1357-0 · Cited by 84 · see citing works
“Activated microglia is frequently found at and around human brain metastases [56], and can be tumoricidal and lysemelanoma and carcinoma cells by release of nitric oxide [57], similar to findings in gliomas [58].”
Mukherjee, S., Hussaini, R., White, R., Atwi, D., Fried, A., Sampat, S., Piao, L., Pan, Q., & Banerjee, P. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2130-3 · Cited by 81 · see citing works
“cytotoxic toward the surrounding tumor cells [12, 13, 26].”
BackgroundCurcumin changes the polarity of tumor‐associated microglia and eliminates glioblastoma
Mukherjee, S., Baidoo, J., Fried, A., Atwi, D., Dolai, S., Boockvar, J. A., Symons, M. H., Ruggieri, R., Raja, K. S., & Banerjee, P. (2016) · International Journal of Cancer · doi:10.1002/ijc.30398 · Cited by 79 · see citing works
Qiao, S., Qian, Y., Xu, G., Luo, Q., & Zhang, Z. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1389-9 · Cited by 76 · see citing works
Yokoi, K., Tanei, T., Godin, B., van de Ven, A. L., Hanibuchi, M., Matsunoki, A., Alexander, J. F., & Mauro Ferrari, B. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.11.015 · Cited by 64 · see citing works
“The authors thank Dr. Isaiah J. Fidler (MD Anderson Cancer Center, Houston, TX) for scientific review of the manuscript.”
BackgroundMethodInfluentialEmerging principles of brain immunology and immune checkpoint blockade in brain metastases
Fares, J., Ulasov, I. V., Timashev, P. S., & Lesniak, M. S. (2021) · Brain · doi:10.1093/brain/awab012 · Cited by 62 · see citing works
“47,48 In addition, the secretion of IL-10 and transforming growth factor beta (TGF b ) by myeloid cells and microglia induces the activity of M2 TAMs and regulatory T cells, which are known to suppress immune responses.”
BackgroundLocally sourced: site-specific immune barriers to metastasis
Correia, A. L. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00836-2 · Cited by 58 · see citing works
Steiner, N., Balez, R., Karunaweera, N., Lind, J. M., Münch, G. W., & Ooi, L. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2015.10.013 · Cited by 55 · see citing works
“Activated microglia behave similarly to macrophages by inducing cytotoxicity in a variety of cells through the release of NO (Brantley et al., 2010).”
Biology of brain metastases and novel targeted therapies: Time to translate the research
Fokas, E., Steinbach, J., & Rödel, C. M. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.10.005 · Cited by 55 · see citing works
Metabolism in the progression and metastasis of brain tumors
Tyagi, A., Wu, S.-Y., & Watabe, K. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215713 · Cited by 55 · see citing works
“Interestingly, studies show that resident microglia can selectively inhibit or promote tumor cell growth during colonization by upregulating tumoricidal (nitric oXide) or growth-supporting (neurotrophin-3) factors, respectively [68,69].”
BackgroundXu, L., Yao, Z., Wu, H., Wang, F., & Zhang, S. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.06.019 · Cited by 50 · see citing works
Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation
Benbenishty, A., Gadrich, M., Cottarelli, A., Lubart, A., Kain, D., Amer, M., Shaashua, L., Glasner, A., Erez, N., Agalliu, D., et al. (2019) · PLoS Biology · doi:10.1371/journal.pbio.2006859 · Cited by 50 · see citing works
Site‐specific metastasis: A cooperation between cancer cells and the metastatic microenvironment
Izraely, S., & Witz, I. P. (2020) · International Journal of Cancer · doi:10.1002/ijc.33247 · Cited by 49 · see citing works
“Activated microglia did not lyse non tumorigenic control cells.(249)”
BackgroundGlial Activation in the Early Stages of Brain Metastasis: TSPO as a Diagnostic Biomarker
O’Brien, E. R., Kersemans, V., Tredwell, M. J., Checa, B., Serres, S., Soto, M. S., Gouverneur, V., Leppert, D., Anthony, D. C., & Sibson, N. R. (2014) · Journal of Nuclear Medicine · doi:10.2967/jnumed.113.127449 · Cited by 46 · see citing works
“For example, microglial-induced tumor cytotoxicity has been demonstrated in vitro (30,31), but these cells have also been shown to facilitate metastatic colonization (29).”
BackgroundEffects of Taraxacum officinale on Fatigue and Immunological Parameters in Mice
Lee, B., Lee, J.-H., & An, H. (2012) · Molecules · doi:10.3390/molecules171113253 · Cited by 46 · see citing works
“In co-cultures of macrophages and lymphoma cells, NO generated from macrophages has been shown to inhibit cellular respiration in the target cells [19].”
BackgroundThe role of the immune system in brain metastasis.
Leibold, A. T., Monaco, G. N., & Dey, M. (2019) · PubMed · Cited by 46 · see citing works
Tumor microenvironment in lung cancer-derived brain metastasis
Liu, W., Powell, C. A., & Wang, Q. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002127 · Cited by 44 · see citing works
“On the one hand, microglia exercise anti-tumor immune function by secreting nitric oxide and lysing tumor cells, protecting the brain from colonization by metastatic cells.([91]) Also, M1-like microglia can act as antigen-presenting cells that stimulate activated CD8+ T cells and adaptive immune responses that kill tu…”
BackgroundResponse of the nitrergic system to activation of the neuroendocrine stress axis
Chen, H. C., Spiers, J. G., Sernia, C., & Lavidis, N. A. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00003 · Cited by 43 · see citing works
“Within the central nervous system, the iNOS-mediated release of NO by astrocytes and microglia has a major role in antimicrobial and tumoricidal activity in response to various inflammatory signals (Hua et al., 2002; Brantley et al., 2010).”
BackgroundIzraely, S., Ben‐Menachem, S., Sagi‐Assif, O., Telerman, A., Zubrilov, I., Ashkenazi, O., Meshel, T., Maman, S., Orozco, J. I. J., Salomon, M. P., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31745 · Cited by 43 · see citing works
Xue, J., Jiang, W., Chen, Y., Gong, F., Wang, M., Zeng, P. C., Xia, C., Wang, Q., & Huang, K. (2017) · The FASEB Journal · doi:10.1096/fj.201700008r · Cited by 39 · see citing works
“gondii infection and exhibits inhibitory activity on parasite proliferation (39, 40).”
BackgroundEmbracing rejection: Immunologic trends in brain metastasis
Farber, S. H., Tsvankin, V., Narloch, J. L., Kim, G. J., Salama, A. K. S., Vlahovic, G., Blackwell, K., Kirkpatrick, J. P., & Fecci, P. E. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1172153 · Cited by 37 · see citing works
“The nitric oxidemediated tumoricidal activity of metastatic tumor-infiltrating microglia has been well-described in vitro.(60) However, in vivo models have demonstrated microglial recruitment by tumor cells and subsequent secretion of pro-mitotic factors contributing to tumor cell proliferation.”
BackgroundThorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse
Lim, A. R., & Ghajar, C. M. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.007 · Cited by 35 · see citing works
Weidle, U. H., Birzele, F., Kollmorgen, G., & Rüger, R. (2016) · PubMed · Cited by 34 · see citing works
Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity
Sarkar, S., Poon, C. C., Mirzaei, R., Rawji, K. S., Hader, W. J., Bose, P., Kelly, J. J., Dunn, J. F., & Yong, V. W. (2018) · Scientific Reports · doi:10.1038/s41598-018-33306-0 · Cited by 33 · see citing works
Melanoma Brain Metastases: An Unmet Challenge in the Era of Active Therapy
Gorantla, V., Kirkwood, J., & Tawbi, H. (2013) · Current Oncology Reports · doi:10.1007/s11912-013-0335-3 · Cited by 32 · see citing works
“Microglia—the main immune effectors of the CNS—in vitro seem to exert tumoricidal effects through release of nitric oxide [44], but in vivo seem to support tumor proliferation by altering the microenvironment [45].”
BackgroundThe Implications of Hyponitroxia in Cancer
Oronsky, B. T., Fanger, G. R., Oronsky, N. C., Knox, S. J., & Scicinski, J. J. (2014) · Translational Oncology · doi:10.1016/j.tranon.2014.02.001 · Cited by 30 · see citing works
“[18] Brantley EC, Guo L, Zhang C, Lin Q, Yokoi K, Langley RR, Kruzel E, Maya M,”
BackgroundUltrasonography-Guided Intracardiac Injection
Balathasan, L., Beech, J. S., & Muschel, R. J. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.03.003 · Cited by 29 · see citing works
The Immune Microenvironment in Brain Metastases of Non-Small Cell Lung Cancer
Luo, L., Liu, P., Zhao, K., Zhao, W., & Zhang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.698844 · Cited by 24 · see citing works
“Microglia can lyse tumor cells by secreting NO and sheltering the brain from the metastatic cell colonization (33).”
BackgroundAn, S. S., Chi, K., Kang, S. C., Dubey, A. V., Park, D. W., Kwon, J. E., Jeong, Y. J., Kim, T., & Kim, I. (2015) · International Journal of Nanomedicine · doi:10.2147/ijn.s88289 · Cited by 24 · see citing works
“30 However, the general role of macrophages in tumorigenesis is widely disputed and data suggest that it may be largely dependent on the context of the specific tumor type.”
Kim, M.-C., Lee, G.-H., Kim, S.-J., Chung, W., Kim, S. S., Ko, S., & Um, J. (2011) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2011.576254 · Cited by 22 · see citing works
“Moreover, NO derived from Kupffer, NK, and endothelial cells also contributes to tumoricidal activity against many types of tumors.((28)) In this study, we demonstrated that NO production caused by DGBHT in mouse peritoneal macrophages could be highly stimulated in combination with rIFN-γ.”
BackgroundHung, Y., Wang, Y., & Lee, S. (2020) · The FASEB Journal · doi:10.1096/fj.201902818r · Cited by 20 · see citing works
Methionine enkephalin regulates microglia polarization and function
Xu, X., Gao, Y., Wen, L., Zhai, Z., Zhang, S., Shan, F., & Feng, J. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.08.037 · Cited by 18 · see citing works
The Role of Neurotrophin Signaling in Gliomagenesis
Alshehri, M. M., Robbins, S. M., & Senger, D. L. (2017) · Vitamins and hormones · doi:10.1016/bs.vh.2016.11.001 · Cited by 17 · see citing works
Melanoma Brain Metastases: Review of Histopathological Features and Immune-Molecular Aspects
Salvati, L., Mandalà, M., & Massi, D. (2020) · Melanoma Management · doi:10.2217/mmt-2019-0021 · Cited by 14 · see citing works
de Farias, J. O., Lima, S. M. D. F., & Rezende, T. M. B. (2020) · Clinical Oral Investigations · doi:10.1007/s00784-020-03629-2 · Cited by 11 · see citing works
Baik, J. S., Seo, Y. N., Lee, Y., Yi, J. M., Rhee, M. H., Park, M., & Kim, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213757 · Cited by 10 · see citing works
“In general, NO is known to have a tumoricidal effect [73,74].”
BackgroundBiology in prevention and treatment of brain metastases
Berghoff, A. S., & Preusser, M. (2013) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2013.852067 · Cited by 9 · see citing works
Nitric Oxide and Cancer: To Inhibit or To Induce iNOS: That Is the Question?
Kashfi, K., & Vannini, F. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816545-4.00005-0 · Cited by 7 · see citing works
Prostaglandin E2 potentiates interferon‐γ‐induced nitric oxide production in cultured rat microglia
Nagano, T., Nishiyama, R., Sanada, A., Mutaguchi, Y., Ioku, A., Umeki, H., Kishimoto, S., Yamanaka, D., Kimura, S. H., & Takemura, M. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13926 · Cited by 6 · see citing works
Winkler, F. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-12-811161-1.00003-7 · Cited by 6 · see citing works
Targeting Hyponitroxia in Cancer Therapy
Oronsky, B. T., Oronsky, N. C., Lybeck, M., Fanger, G. R., & Scicinski, J. J. (2015) · Springer eBooks · doi:10.1007/978-3-319-13611-0_3 · Cited by 3 · see citing works
Shim, D. H., Lim, J. W., & Kim, H. (2015) · Yonsei Medical Journal · doi:10.3349/ymj.2015.56.2.563 · Cited by 3 · see citing works
Zhou, Y., Lu, X., Zhang, Y., Li, C., Bai, Y., & Zhang, Z. (2022) · Combinatorial Chemistry & High Throughput Screening · doi:10.2174/1386207326666221111093915 · Cited by 2 · see citing works
[Tumor Cells and Micro-environment in Brain Metastases].
Zhong, W., & Hu, C. (2016) · Europe PMC (PubMed Central) · doi:10.3779/j.issn.1009-3419.2016.09.12 · Cited by 2 · see citing works
Brain Metastases and Microenvironment
Brito, M. A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-73119-9_17 · Cited by 2 · see citing works
Poole, A., Lun, X. Q., Robbins, S. M., & Senger, D. L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821310-0.00009-7 · Cited by 2 · see citing works
Interactions of silica nanoparticles with therapeutics for oxidative stress attenuation in neurons
White-Schenk, D., Shi, R., & Leary, J. F. (2015) · Proceedings of SPIE, the International Society for Optical Engineering/Proceedings of SPIE · doi:10.1117/12.2076048 · Cited by 1 · see citing works
“Upon activation, such cells release inflammatory factors, ROS, and RNS.(19) 0 10 20 30 40 50”
The Immunology of Brain Tumors
Fares, J., Petrosyan, E., Salhab, H. A., Dmello, C., & Fares, Y. (2023) · Interdisciplinary cancer research · doi:10.1007/16833_2023_132 · Cited by 1 · see citing works
Brain Metastases Cell Partners and Tumor Microenvironment
García‐Gómez, P., Priego, N., Álvaro‐Espinosa, L., & Valiente, M. (2019) · Springer eBooks · doi:10.1007/978-3-030-23417-1_5 · Cited by 1 · see citing works
Preusser, M., Ilhan‐Mutlu, A., Bartsch, R., Marosi, C., Zielinski, C. C., Berghoff, A. S., Birner, P., Mehta, M. P., Winkler, F., & Wick, W. (2012)
PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasisPreprint
Liu, Y., Sun, I.-M., Creixell, M., Brown, J., Kharbanda, S., Lee, J. J., Shahryari, V., Hake, K., O'Hara, J., Finn, K. J., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.25.707995
- Authors
- Brantley, E. C., Guo, L., Zhang, C., Lin, Q., Yokoi, K., Langley, R. R., Kruzel, E., Maya, M., Kim, S. W., Kim, S.-J., Fan, D., & Fidler, I. J.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Fidler, Isaiah J.
- Venue
- Translational Oncology
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 3
- Issue
- 6
- Pages
- 380-388
- ISSN
- 1936-5233 (ISSN-L)
- PMC
- PMC3000463
- OpenAlex
- W2103646648
- Cited by
- 71
- References
- 63
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 2 · 2013: 5 · 2012: 7
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA-16 672)
- National Cancer Institute (CA-16672, U54CA143837, P30CA016672)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- microglia, nitric oxide, tumoricidal activity, brain metastases, microglial origin, lipopolysaccharide, interferon-gamma, peritoneal macrophages, tumor cell lysis, parabiosis, F4/80, CD68
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
