Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer
Open accessAbstract
Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis-associated macrophages is not known. Here we mapped and quantified hemosiderin-laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer.
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?
The iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo.
“This iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo [64,66,67,70,71,72].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [70]
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
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144 · see citing works
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994 · see citing works
Self-citationMANTOVANI, A., SOZZANI, S., LOCATI, M., ALLAVENA, P., & SICA, A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02302-5 · Cited by 5,528 · see citing works
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684 · see citing works
Self-citationDistinct role of macrophages in different tumor microenvironments
Lewis, C. E., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4005 · Cited by 2,225 · see citing works
Iron and cancer: more ore to be mined
Torti, S. V., & Torti, F. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3495 · Cited by 1,621 · see citing works
Schenck, J. F. (1996) · Medical Physics · doi:10.1118/1.597854 · Cited by 1,537 · see citing works
Macrophages and Therapeutic Resistance in Cancer
Ruffell, B., & Coussens, L. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.02.015 · Cited by 1,474 · see citing works
Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.
Leek, R., Lewis, C. E., Whitehouse, R. M., Greenall, M. J., Clarke, J., & Harris, A. L. (1996) · PubMed · Cited by 1,187 · see citing works
Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer
Lin, E. Y., Li, J.-F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D. A., Qian, H., Xue, X.-N., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1278 · Cited by 1,074 · see citing works
Imaging iron stores in the brain using magnetic resonance imaging
Haacke, E. M., Cheng, N. Y. C., House, M. J., Liu, Q., Neelavalli, J., Ogg, R. J., Khan, A., Ayaz, M., Kirsch, W., & Obenaus, A. (2005) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2004.10.001 · Cited by 995 · see citing works
Iron homeostasis in host defence and inflammation
Ganz, T., & Nemeth, E. (2015) · Nature Reviews Immunology · doi:10.1038/nri3863 · Cited by 843 · see citing works
Imaging macrophages with nanoparticles
Weissleder, R., Nahrendorf, M., & Pittet, M. J. (2014) · Nature Materials · doi:10.1038/nmat3780 · Cited by 809 · see citing works
The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer
Kalinowski, D. S., & Richardson, D. R. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.4.2 · Cited by 721 · see citing works
Medrek, C., Pontén, F., Jirström, K., & Leandersson, K. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-306 · Cited by 648 · see citing works
Zeisberger, S. M., Odermatt, B., Marty, C., Zehnder-Fjällman, A. H. M., Ballmer‐Hofer, K., & Schwendener, R. A. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603240 · Cited by 622 · see citing works
Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies
Bowman, R. L., Klemm, F., Akkari, L., Pyonteck, S. M., Sevenich, L., Quail, D. F., Dhara, S., Simpson, K., Gardner, E. E., Iacobuzio–Donahue, C. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.052 · Cited by 617 · see citing works
Self-citationMacrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer
Shree, T., Olson, O. C., Elie, B. T., Kester, J. C., Garfall, A. L., Simpson, K., Bell-McGuinn, K. M., Zabor, E. C., Brogi, E., & Joyce, J. A. (2011) · Genes & Development · doi:10.1101/gad.180331.111 · Cited by 541 · see citing works
Self-citationImmune surveillance: a balance between protumor and antitumor immunity
Ostrand‐Rosenberg, S. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.12.007 · Cited by 481 · see citing works
The role of iron in cell cycle progression and the proliferation of neoplastic cells
Le, N. (2002) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(02)00068-9 · Cited by 453 · see citing works
Magnetic-Susceptibility Measurement of Human Iron Stores
Brittenham, G. M., Farrell, D. E., Harris, J. W., Feldman, E. S., Danish, E. H., Muir, W. A., Tripp, J. H., & Bellon, E. M. (1982) · New England Journal of Medicine · doi:10.1056/nejm198212303072703 · Cited by 367 · see citing works
Gillis, P., & Koenig, S. H. (1987) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910050404 · Cited by 353 · see citing works
MRI of Tumor-Associated Macrophages with Clinically Applicable Iron Oxide Nanoparticles
Daldrup-Link, H. E., Golovko, D. M., Ruffell, B., DeNardo, D. G., Castaneda, R., Ansari, C., Rao, J., Tikhomirov, G. A., Wendland, M. F., Corot, C., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-3420 · Cited by 302 · see citing works
Macrophages as mediators of tumor immunosurveillance
Jaiswal, S., Chao, M. P., Majeti, R., & Weissman, I. L. (2010) · Trends in Immunology · doi:10.1016/j.it.2010.04.001 · Cited by 241 · see citing works
Yuan, Z.-Y., Luo, R., Peng, R., Wang, S., & Xue, C. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s61838 · Cited by 214 · see citing works
NMR relaxation times of blood: dependence on field strength, oxidation state, and cell integrity.
Gomori, J. M., Grossman, R. I., Yu-Ip, C., & Asakura, T. (1987) · PubMed · Cited by 213 · see citing works
Garbowski, M., Carpenter, J., Smith, G. C., et al. (2014) · Journal of Cardiovascular Magnetic Resonance · doi:10.1186/1532-429x-16-40 · Cited by 203 · see citing works
Iron Chelators in Cancer Chemotherapy
Buss, J. L., Greene, B. T., Turner, J., Torti, F. M., & Torti, S. V. (2004) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026043387269 · Cited by 199 · see citing works
Gomori, J. M., Grossman, R. I., Yu-Ip, C., & Asakura, T. (1987) · Journal of Computer Assisted Tomography · doi:10.1097/00004728-198707000-00025 · Cited by 195 · see citing works
Roland, C. L., Dineen, S. P., Lynn, K. D., Sullivan, L. A., Dellinger, M. T., Sadegh, L., Sullivan, J. P., Shames, D. S., & Brekken, R. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0280 · Cited by 189 · see citing works
Iron-based superparamagnetic nanoparticle contrast agents for MRI of infection and inflammation
Neuwelt, A., Sidhu, N., Hu, C.-A. A., Mlady, G., Eberhardt, S. C., & Sillerud, L. O. (2015) · American Journal of Roentgenology · doi:10.2214/ajr.14.12733 · Cited by 189 · see citing works
Valković, T., Dobrila, F., Melato, M., Sasso, F., Rizzardi, C., & Jonjić, N. (2001) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s004280100458 · Cited by 152 · see citing works
Iron levels in polarized macrophages: regulation of immunity and autoimmunity
Recalcati, S., Locati, M., Gammella, E., Invernizzi, P., & Cairo, G. (2012) · Autoimmunity Reviews · doi:10.1016/j.autrev.2012.03.003 · Cited by 150 · see citing works
Zhang, Y., Cheng, S., Zhang, M., Zhen, L., Pang, D., Zhang, Q., & Li, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076147 · Cited by 139 · see citing works
Gwak, J. M., Jang, M. H., Kim, D. I., Seo, A. N., & Park, S. Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125728 · Cited by 128 · see citing works
Iron Deprivation in Cancer––Potential Therapeutic Implications
Heath, J. L., Weiss, J. M., Lavau, C., & Wechsler, D. S. (2013) · Nutrients · doi:10.3390/nu5082836 · Cited by 121 · see citing works
Macrophages: central regulators of iron balance
Gammella, E., Buratti, P., Cairo, G., & Recalcati, S. (2014) · Metallomics · doi:10.1039/c4mt00104d · Cited by 95 · see citing works
Using T2-Weighted Sequences to More Accurately Characterize Breast Masses Seen on MRI
Westra, C., Dialani, V. M., Mehta, T. S., et al. (2014) · American Journal of Roentgenology · doi:10.2214/ajr.13.11266 · Cited by 83 · see citing works
Low-frequency low-field magnetic susceptibility of ferritin and hemosiderin
Allen, P. D., Pierre, T. G. S., Chua‐anusorn, W., Ström, V., & Rao, K. V. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(99)00104-0 · Cited by 82 · see citing works
Comparison of t2 relaxation in blood, brain, and ferritin
Brooks, R. A., Vymazal, J., Baumgarner, C. D., Tran, V., & Bulte, J. W. M. (1995) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.1880050414 · Cited by 76 · see citing works
THE NATURE OF STORAGE IRON IN IDIOPATHIC HEMOCHROMATOSIS AND IN HEMOSIDEROSIS
Richter, G. W. (1960) · The Journal of Experimental Medicine · doi:10.1084/jem.112.4.551 · Cited by 70 · see citing works
Wood, J. C., Zhang, P., Rienhoff, H. Y., et al. (2015) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2015.02.016 · Cited by 62 · see citing works
An, T., Sood, U., Pietruk, T., Cummings, G., Hashimoto, K., & Crissman, J. D. (1987) · PubMed Central · Cited by 59 · see citing works
Thulborn, K. R., Sorensen, A. G., Kowall, N. W., et al. (1990) · PubMed · Cited by 48 · see citing works
Thulborn, K. R., Sorensen, A. G., Kowall, N. W., et al. (1990) · American Journal of Roentgenology · doi:10.2214/ajr.154.5.2108542 · Cited by 45 · see citing works
MR imaging of tumor-associated macrophages
Daldrup-Link, H. E., & Coussens, L. M. (2012) · OncoImmunology · doi:10.4161/onci.19456 · Cited by 34 · see citing works
Associations and implications of cerebral microbleeds
Kleinig, T. J. (2013) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2012.12.002 · Cited by 24 · see citing works
Takada, S., Inoue, T., Niizuma, K., et al. (2011) · Neurologia medico-chirurgica · doi:10.2176/nmc.51.275 · Cited by 23 · see citing works
In vivo tissue characterization using magnetic techniques.
Aa, C., Vilela, G. R., Jb, F., de Araújo, D. B., Baffa, O., Elías, J., St Pierre, G., Il, A., & Covas, D. T. (2004) · PubMed · Cited by 12 · see citing works
Three‐Dimensional NMR microscopy of rat spleen and liver
Zhou, X. J., Magin, R. L., Alameda, J. C., et al. (1993) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910300114 · Cited by 11 · see citing works
Brain vascular lesions: a clinicopathologic, immunohistochemistry, and ultrastructural approach
Navarrete, M. G., Hernández, A. D., Collado-Ortiz, M. Á., et al. (2014) · Annals of Diagnostic Pathology · doi:10.1016/j.anndiagpath.2014.01.005 · Cited by 8 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [32]Sage D, Prodanov D, Tinevez J-Y, Schindelin J, editors. MIJ: making interoperability between ImageJ and Matlab possible. ImageJ User and Developer Conference; 2012; Luxembourg.
Cited by
Sorted by citations
Iron as a central player and promising target in cancer progression
Jung, M., Mertens, C., Tomat, E., & Brüne, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020273 · Cited by 268 · see citing works
Iron in the Tumor Microenvironment-Connecting the Dots
Pfeifhofer-Obermair, C., Tymoszuk, P., Petzer, V., Weiss, G., & Nairz, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00549 · Cited by 151 · see citing works
- Authors
- Leftin, A., Ben-Chetrit, N., Klemm, F., Joyce, J. A., & Koutcher, J. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Koutcher, Jason A.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-09-12
- Volume
- 12
- Issue
- 9
- Pages
- e0184765
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5595304
- OpenAlex
- W2754224034
- Cited by
- 36
- References
- 52
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 3
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- IRIS (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Cancer Institute (PO1 CA115675, P30 CA008748, 1F32CA206277)
- Department of Defense (PC120233)
- Breast Cancer Research Foundation
- Deutsche Forschungsgemeinschaft (KL 2491/1-1)
- Congressionally Directed Medical Research Programs (BC161705)
- Memorial Sloan-Kettering Cancer Center (Breast and Molecular Imaging Fund)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- hemosiderin, tumor-associated macrophages, breast cancer, iron accumulation, lung metastasis, brain metastases, iron metabolism, cellular MRI, macrophage imaging
- MeSH terms
- Animals, Cytoplasmic Granules, Female, Hemosiderin, Iron, Macrophages, Magnetic Resonance Imaging, Mammary Neoplasms, Experimental, Neoplasm Metastasis, Mice
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
