Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer
Abstract
The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
TAMs are found largely in hypoxic tumor regions and drive angiogenic response required for tumor survival and metastasis.
“Interestingly, TAMs are found largely within hypoxic regions of tumors and have been shown drive the angiogenic response that is required for tumor survival and metastasis [40,41].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [40]
Cites
Tumors: Wounds That Do Not Heal
Flier, J. S., Underhill, L. H., & Dvorak, H. F. (1986) · New England Journal of Medicine · doi:10.1056/nejm198612253152606 · Cited by 4,391 · cited 1× · see citing works
“inflammation and that of tumors, as proposed in the hypothesis that tumors are ‘‘wounds that never heal’’ (14).”
BackgroundTumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559 · see citing works
Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice
Bergers, G., Javaherian, K., Lo, K.-M., Folkman, J., & Hanahan, D. (1999) · Science · doi:10.1126/science.284.5415.808 · Cited by 988 · see citing works
Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., & Hanahan, D. (1999) · Genes & Development · doi:10.1101/gad.13.11.1382 · Cited by 946 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · 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-citationFunctional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., et al. (2014) · Nature · doi:10.1038/nature13490 · Cited by 3,046 · see citing works
Macrophage plasticity and polarization in tissue repair and remodelling
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A., & Locati, M. (2013) · The Journal of Pathology · doi:10.1002/path.4133 · Cited by 2,384 · see citing works
Microenvironmental regulation of tumour angiogenesis
De Palma, M., Biziato, D., & Petrova, T. V. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.51 · Cited by 1,847 · see citing works
The tumor microenvironment at a glance
Balkwill, F. R., Capasso, M., & Hagemann, T. (2012) · Journal of Cell Science · doi:10.1242/jcs.116392 · Cited by 1,857 · see citing works
DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., Gallagher, W. M., Wadhwani, N., Keil, S. D., Junaid, S. A., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8274.cd-10-0028 · Cited by 1,715 · see citing works
The role of myeloid cells in the promotion of tumour angiogenesis
Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2444 · Cited by 1,642 · see citing works
Lin, Y., Xu, J., & Lan, H. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0760-3 · Cited by 1,398 · see citing works
HIF transcription factors, inflammation, and immunity
Palazon, A., Goldrath, A. W., Nizet, V., & Johnson, R. S. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.008 · Cited by 1,195 · see citing works
Immune cell promotion of metastasis
Kitamura, T., Qian, B.-Z., & Pollard, J. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3789 · Cited by 1,158 · see citing works
Self-citationTrophic macrophages in development and disease
Pollard, J. W. (2009) · Nature Reviews Immunology · doi:10.1038/nri2528 · Cited by 1,178 · see citing works
Self-citationImmunological hallmarks of stromal cells in the tumour microenvironment
Turley, S. J., Cremasco, V., & Astarita, J. L. (2015) · Nature Reviews Immunology · doi:10.1038/nri3902 · Cited by 1,140 · see citing works
Macrophages in Tumor Microenvironments and the Progression of Tumors
Hao, N.-B., Lü, M.-H., Fan, Y.-H., Cao, Y.-L., Zhang, Z.-R., & Yang, S.-M. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/948098 · Cited by 1,003 · see citing works
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.02.034 · Cited by 926 · see citing works
Sansone, P., Storci, G., Tavolari, S., Guarnieri, T., Giovannini, C., Taffurelli, M., Ceccarelli, C., Santini, D., Paterini, P., Marcu, K. B., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32533 · Cited by 779 · see citing works
Macrophage polarization in pathology
Sica, A., Erreni, M., Allavena, P., & Porta, C. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1995-y · Cited by 673 · see citing works
Mazzieri, R., Pucci, F., Moi, D., Zonari, E., Ranghetti, A., Berti, A., Politi, L. S., Gentner, B., Brown, J. L., Naldini, L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.02.005 · Cited by 639 · see citing works
Chen, Q., Zhang, X. H.-F., & Massagué, J. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.025 · Cited by 619 · see citing works
Ostrand-Rosenberg, S., Sinha, P., Beury, D. W., & Clements, V. K. (2012) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2012.01.011 · Cited by 583 · see citing works
Tumor-associated macrophages: Functional diversity, clinical significance, and open questions
Biswas, S. K., Allavena, P., & Mantovani, A. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0367-7 · Cited by 551 · see citing works
An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
Palazon, A., Tyrakis, P. A., Macias, D., Veliça, P., Rundqvist, H., Fitzpatrick, S., Vojnovic, N., Phan, A. T., Loman, N., Hedenfalk, I., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.10.003 · Cited by 521 · see citing works
“Among them, macrophages actively contribute to the angiogenic switch (Lin et al., 2006) by secreting VEGF-A (Stockmann et al.”
BackgroundBuddingh, E. P., Kuijjer, M. L., Duim, R. A. J., Bürger, H., Agelopoulos, K., Myklebost, O., Serra, M., Mertens, F., Hogendoorn, P. C. W., Lankester, A. C., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2047 · Cited by 508 · see citing works
The pre-metastatic niche: finding common ground
Sceneay, J., Smyth, M. J., & Möller, A. (2013) · Cancer and Metastasis Reviews · doi:10.1007/s10555-013-9420-1 · Cited by 422 · see citing works
Dudley, A. C. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006536 · Cited by 424 · see citing works
Schmid, M. C., Avraamides, C. J., Dippold, H. C., Franco, I., Foubert, P., Ellies, L. G., Acevedo, L. M., Manglicmot, J. R. E., Song, X., Wrasidlo, W., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.016 · Cited by 378 · see citing works
Peterson, T. E., Kirkpatrick, N. D., Huang, Y., Farrar, C. T., Marijt, K. A., Kloepper, J., Datta, M., Amoozgar, Z., Seano, G., Jung, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525349113 · Cited by 317 · see citing works
Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy
Riera-Domingo, C., Audigé, A., Granja, S., Cheng, W.-C., Ho, P.-C., Baltazar, F., Stockmann, C., & Mazzone, M. (2020) · Physiological Reviews · doi:10.1152/physrev.00018.2019 · Cited by 310 · see citing works
Aging and cancer: The role of macrophages and neutrophils
Jackaman, C., Tomay, F., Duong, L., Abdol Razak, N. B., Pixley, F. J., Metharom, P., & Nelson, D. J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.03.008 · Cited by 251 · see citing works
The GAIT system: a gatekeeper of inflammatory gene expression
Mukhopadhyay, R., Jia, J., Arif, A., Ray, P. S., & Fox, P. L. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.03.004 · Cited by 216 · see citing works
Hypoxia-inducible factors: a central link between inflammation and cancer
Triner, D., & Shah, Y. M. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84430 · Cited by 199 · see citing works
Contribution of adipose tissue to development of cancer
Cozzo, A. J., Fuller, A. M., & Makowski, L. (2017) · Comprehensive Physiology · doi:10.1002/cphy.c170008 · Cited by 188 · see citing works
3D scaffolds in breast cancer research
Rijal, G., & Li, W. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2015.12.016 · Cited by 169 · see citing works
A versatile 3D tissue matrix scaffold system for tumor modeling and drug screening
Rijal, G., & Li, W. (2017) · Science Advances · doi:10.1126/sciadv.1700764 · Cited by 154 · see citing works
Proangiogenic Contribution of Adiponectin toward Mammary Tumor Growth <i>In vivo</i>
Landskroner-Eiger, S., Qian, B., Muise, E. S., Nawrocki, A. R., Berger, J. P., Fine, E. J., Koba, W., Deng, Y., Pollard, J. W., & Scherer, P. E. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2649 · Cited by 145 · see citing works
Self-citationClinical applications of iron oxide nanoparticles for magnetic resonance imaging of brain tumors
Iv, M., Telischak, N., Feng, D., Holdsworth, S. J., Yeom, K. W., & Daldrup-Link, H. E. (2015) · Nanomedicine · doi:10.2217/nnm.14.203 · Cited by 134 · see citing works
Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo
Joshi, S., Singh, A. R., Zulcic, M., Bao, L., Messer, K., Ideker, T., Dutkowski, J., & Durden, D. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095893 · Cited by 128 · see citing works
“The question which now strikes out to be answered is how this small GTPase, which is specifically expressed in the hematopoietic compartment, modulates tumor growth, metastasis and the M1 to M2 transition in macrophages? A growing body of evidence suggests that Mhs are frequently found to infiltrate tumors and have be…”
BackgroundMetastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches
Sleeboom, J. J. F., Eslami Amirabadi, H., Nair, P., Sahlgren, C. M., & den Toonder, J. M. J. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.033100 · Cited by 122 · see citing works
The dual roles of homeobox genes in vascularization and wound healing
Kachgal, S., Mace, K. A., & Boudreau, N. J. (2012) · Cell Adhesion & Migration · doi:10.4161/cam.22164 · Cited by 72 · see citing works
A bladder cancer microenvironment simulation system based on a microfluidic co-culture model
Liu, P.-F., Cao, Y.-W., Zhang, S.-D., Zhao, Y., Liu, X.-G., Shi, H.-Q., Hu, K.-Y., Zhu, G.-Q., Ma, B., & Niu, H.-T. (2015) · Oncotarget · doi:10.18632/oncotarget.6070 · Cited by 68 · see citing works
Hypoxia-inducible factors as key regulators of tumor inflammation
Mamlouk, S., & Wielockx, B. (2013) · International Journal of Cancer · doi:10.1002/ijc.27901 · Cited by 61 · see citing works
Heylman, C., Sobrino, A., Shirure, V. S., Hughes, C. C., & George, S. C. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214525295 · Cited by 53 · see citing works
Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer
Leftin, A., Ben-Chetrit, N., Klemm, F., Joyce, J. A., & Koutcher, J. A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0184765 · Cited by 36 · see citing works
Park, J.-H., Rasch, M. G., Qiu, J., Lund, I. K., & Egeblad, M. (2015) · Neoplasia · doi:10.1016/j.neo.2015.04.003 · Cited by 29 · see citing works
- Authors
- Lin, E. Y., Li, J.-F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D. A., Qian, H., Xue, X.-N., & Pollard, J. W.
- Affiliations
- Albert Einstein College of Medicine (US)
- Yeshiva University (US)
- 1Department of Developmental and Molecular Biology, Center of Reproductive Biology and Women's Health,
- 3Department of Epidemiology and Population Health, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York
- Venue
- Cancer Research
- Published
- 2006-12-01
- Volume
- 66
- Issue
- 23
- Pages
- 11238-11246
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2104104624
- Cited by
- 1,074
- References
- 4
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 37 · 2023: 46 · 2022: 59 · 2021: 68 · 2020: 66 · 2019: 37 · 2018: 58 · 2017: 46 · 2016: 55 · 2015: 63 · 2014: 70 · 2013: 89 · 2012: 78
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P-30-CA13330, CA 94173, P01CA100324, R01CA094173, CA 100324, P30CA013330)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor-associated macrophages, angiogenic switch, tumor angiogenesis, breast cancer, mammary tumors, PyMT mice, macrophage infiltration, tumor vasculature, precancerous lesions, tumor microenvironment
- MeSH terms
- Animals, Blood Vessels, Genotype, Macrophages, Mice, Transgenic, Neovascularization, Pathologic, Mammary Neoplasms, Animal, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Mice, Knockout, Disease Progression, Green Fluorescent Proteins, 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
