Iron Handling in Tumor-Associated Macrophages—Is There a New Role for Lipocalin-2?

Abstract

Carcinogenesis is a multistep process. Besides somatic mutations in tumor cells, stroma-associated immunity is a major regulator of tumor growth. Tumor cells produce and secrete diverse mediators to create a local microenvironment that supports their own survival and growth. It is becoming apparent that iron acquisition, storage, and release in tumor cells is different from healthy counterparts. It is also appreciated that macrophages in the tumor microenvironment acquire a tumor-supportive, anti-inflammatory phenotype that promotes tumor cell proliferation, angiogenesis, and metastasis. Apparently, this behavior is attributed, at least in part, to the ability of macrophages to support tumor cells with iron. Polarization of macrophages by apoptotic tumor cells shifts the profile of genes involved in iron metabolism from an iron sequestering to an iron-release phenotype. Iron release from macrophages is supposed to be facilitated by ferroportin. However, lipid mediators such as sphingosine-1-phosphate, released form apoptotic tumor cells, upregulate lipocalin-2 (Lcn-2) in macrophages. This protein is known to bind siderophore-complexed iron and thus, may participate in iron transport in the tumor microenvironment. We describe how macrophages handle iron in the tumor microenvironment, discuss the relevance of an iron-release macrophage phenotype for tumor progression, and propose a new role for Lcn-2 in tumor-associated macrophages.

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

“…By contrast, estrogens are known to produce reactive oxygen species (ROS) and are implicated in cellular carcinogenesis, as chronic oxidative stress promotes cell growth, survival and the tumorigenic potential of breast cancer cells (19). In the present study, we provide an update on the recent advances in the understanding of the reduction-oxidation (redox)-related molecular signaling and imbalance in the cellular redox state in malignant transformation of endometriosis (8,(20)(21)(22)(23)(24)(25)(26)(27). The pathogenesis of the malignant transformation of endometriosis remains obscure; however, the results of several studies support the hypothesis that the redox imbalance, inflammatory/immune response, cell cycle regulation and hormone activity are the deregulated functions and act in a dynamic epigenetic network (20,22,23,24).…”

Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection

“…7c ). Sporadic evidence for this hypothesis has been obtained from cancer studies (reviewed in [ 10 ]), but systemic studies investigating the role of apo- versus holo-Lcn2 in renal epithelial regeneration following various insults would be desirable. On the other hand, it is interesting to note that we have previously obtained evidence that siderophore Fe 3+ -loaded human holo-LCN2 binds with lower affinity to the N-terminus of human LCN2-R than apo-LCN2 [ 31 ].…”

“…Several studies have demonstrated that apo-Lcn2 induces apoptosis in Lcn2-R expressing cells [ 8 , 9 ], whereas holo-Lcn2 is anti-apoptotic and may even promote cell proliferation, e.g. in cancer cells [ 10 ]. Lcn2 is expressed in cells as a non-glycosylated ~22-kDa precursor and a glycosylated ~25-kDa mature Lcn2, but only the latter is secreted [ 6 , 11 ].…”

Role of iron in cancer development by viruses

“…Tumor‐associated macrophages (TAMs), which considered as a M2‐like phenotype, also contribute to carcinogenesis, particularly angiogenesis, metastasis, and suppression of antitumor responses . Indeed, TAM causes high ferroportin‐mediated iron release that provides higher iron availability in the tumor microenvironment . TAM stabilizes HIF and trigger expression of chemokines and chemokine receptors like CXCL12 and CXCR4 as well as vascular endothelial growth factor (VEGF) .…”

“…Moreover, TAM restrict an antitumor immune response through recruitment of immunosuppressive lymphocytes such as regulatory T cells to subvert tumoricidal lymphocyte function . Increased expression of Lipocalin‐2 (LCN‐2) was also found in TAM, which is thought to support tumor cell proliferation . Secreted LCN‐2 traffic iron through LCN2 receptor to the tumor cells can lead to increased LIP, thereby inducing antiapoptotic mediator Bcl‐2 .…”