Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment
Open accessAbstract
While the importance of iron for tumor development is widely appreciated, the exact sources of tumor-supporting iron largely remain elusive. The possibility that iron might be provided by stromal cells in the tumor microenvironment was not taken into account so far. In the present study, we show that tumor-associated macrophages (TAM) acquire an iron-release phenotype upon their interaction with tumor cells, thereby increasing the availability of iron in the tumor microenvironment. Mechanistically, TAM expressed elevated levels of the high-affinity iron-binding protein lipocalin-2 (LCN-2), which appeared to be critical for the export of iron from TAM, and in turn enhanced tumor cell proliferation. Moreover, in PyMT-mouse tumors as well as in primary human breast tumors LCN-2 was predominantly expressed in the tumor stroma as compared to tumor cells. LCN-2 expression in the stroma further correlated with enhanced tumor proliferation in vivo. Our data suggest a dominant role of TAM in the tumor iron-management and identify LCN-2 as a critical iron transporter in this context. Targeting the LCN-2 iron export mechanism selectively in stromal cells might open for future iron-targeted tumor therapeutic approaches.
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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 [66]
Under these conditions, TAM expressed higher levels of the high-affinity iron-binding protein lipocalin-2 (Lcn-2).
“Under these conditions, TAM expressed higher levels of the high-affinity iron-binding protein lipocalin-2 (Lcn-2).”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [66]
Pro-inflammatory macrophages are prone to iron retention, displaying an iron sequestering phenotype characterized by enhanced iron uptake and storage, but attenuated release.
“Pro-inflammatory macrophages are prone to iron retention. They display an iron sequestering phenotype characterized by enhanced iron uptake and storage, but attenuated release [64,65,66,67].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [66]
TAM adopt an iron-release phenotype due to their interaction with dying tumor cells, whereby iron availability was increased within the tumor microenvironment.
“Recently, we provided evidence that TAM adopt an iron-release phenotype due to their interaction with dying tumor cells, whereby iron availability was increased within the tumor microenvironment [66].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [66]
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References 37 · Cited by 85
- Authors
- Mertens, C., Mora, J., Ören, B., Grein, S., Winslow, S., Scholich, K., Weigert, A., Malmström, P., Forsare, C., Fernö, M., Schmid, T., Brüne, B., & Jung, M.
- Affiliations
- Goethe University Frankfurt (DE)
- Temple University (US)
- Lund University (SE)
- Corresponding author
- Jung, Michaela
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-12-22
- Volume
- 7
- Issue
- 3
- Pages
- e1408751
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5790355
- OpenAlex
- W2770884032
- Cited by
- 85
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 18 · 2020: 21 · 2019: 8 · 2018: 5
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Funders
- Deutsche Krebshilfe (111578)
- Fritz Thyssen Stiftung (Az.10.12.2.156)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- neutrophil gelatinase-associated lipocalin, tumor-associated macrophages, iron transport, tumor microenvironment, iron metabolism, tumor stroma, breast cancer, tumor cell proliferation, iron export
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