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.
Keywords: TAM; iron; iron-trafficking; lipocalin-2; tumor microenvironment; tumor stroma.