Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

Abstract

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) in the tumour microenvironment on the metastatic cascade is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-to-mesenchymal transition program in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix using a 3D-spheroid model. Moreover, a global Lcn2-deficiency attenuated breast cancer metastasis both in the MMTV-PyMT breast cancer model and in a xenograft model inoculating MCF-7 cells pre-treated with supernatants from wild type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild type PyMT tumour cells into Lcn2-lacking mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as putative therapeutic target.

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

“…1E). Treatment with MDA-CM also increased the transcriptional expression of the inflammatory and osteoclastogenic cytokines Interleukin (Il)1b and Il6, and of Lipocalin 2 (Lcn2), the latter known to have a pro-tumoral effect and to inhibit osteoblast differentiation (19,20) ( Supplementary Fig. 1F).…”

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

“…Recombinant mouse Lcn-2 was produced by transformation of E. coli with a pGEX-4T-3-NGAL plasmid as already described for human recombinant Lcn-2 [21]. In order to test efficient Lcn-2-catechol-iron complex formation, UV-visible spectroscopy (UV-vis) was used as previously described [44].…”

“…It represents both a biomarker of renal ischemic injury [15] including Cisplatin injury [16] and a renoprotective agent when exogenously administered [17][18][19]. Lcn-2 is expressed in MΦ upon contact to apoptotic cells [11,20,21]. Mechanistically, the induction of Lcn-2 was stimulated by apoptotic cell-secreted sphingosine-1-phophate (S1P) and the downstream activation of the STAT3 signaling pathway [20].…”

Co-expression network-based identification of biomarkers correlated with the lymph node metastasis of patients with head and neck squamous cell carcinoma

“…Meanwhile, it could inhibit the translocation of NF-κB into nucleus, representing a promising therapeutic target for colorectal cancer [20]. More importantly, LCN2 was validated to mediate the communications between tumor stroma and tumor cells, stimulating the epithelial-mesenchymal transition process in breast cancer [21]. KLK5 was a member of Kallikrein gene family and suggested to have close associations with tumorigenesis.…”