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Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment

Mertens, Christina; Mora, Javier; Ören, Bilge; Grein, Stephan; Winslow, Sofia; Scholich, Klaus; Weigert, Andreas; Malmström, Per LU ; Forsare, Carina LU and Fernö, Mårten LU , et al. (2018) In OncoImmunology 7(3).
Abstract

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... (More)

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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Contribution to journal
publication status
published
subject
keywords
iron, iron-trafficking, lipocalin-2, TAM, tumor microenvironment, tumor stroma
in
OncoImmunology
volume
7
issue
3
publisher
Landes Bioscience
external identifiers
  • scopus:85038825678
ISSN
2162-4011
DOI
10.1080/2162402X.2017.1408751
language
English
LU publication?
yes
id
53059963-07ca-4916-832c-37907c5ffba6
date added to LUP
2018-01-03 12:20:39
date last changed
2018-04-05 03:00:20
@article{53059963-07ca-4916-832c-37907c5ffba6,
  abstract     = {<p>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.</p>},
  articleno    = {e1408751},
  author       = {Mertens, Christina and Mora, Javier and Ören, Bilge and Grein, Stephan and Winslow, Sofia and Scholich, Klaus and Weigert, Andreas and Malmström, Per and Forsare, Carina and Fernö, Mårten and Schmid, Tobias and Brüne, Bernhard and Jung, Michaela},
  issn         = {2162-4011},
  keyword      = {iron,iron-trafficking,lipocalin-2,TAM,tumor microenvironment,tumor stroma},
  language     = {eng},
  number       = {3},
  publisher    = {Landes Bioscience},
  series       = {OncoImmunology},
  title        = {Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment},
  url          = {http://dx.doi.org/10.1080/2162402X.2017.1408751},
  volume       = {7},
  year         = {2018},
}