Abstract
We have previously shown that Neutrophil Gelatinase-Associated Lipocalin (NGAL) is strongly expressed in thyroid carcinomas, especially of anaplastic type, where it protects neoplastic cells from serum deprivation-induced apoptosis and enhances tumor invasivity by regulating MMP-9 activity. Here we demonstrate that NGAL-containing conditioned medium from human anaplastic thyroid carcinoma (ATC) cells is able to induce monocyte migration via up-regulation of a number of different chemokines. The enhanced chemokines transcription is due to the NGAL-mediated intracellular iron uptake. Very importantly, mice tumor allografts raised from subcutaneous injection of syngeneic colon carcinoma cell lines, expressing high levels of NGAL, show a dense leukocyte infiltrate which strongly decreases in tumor allografts from NGAL-depleted cell injected mice.Our results indicate that the NGAL promotes leukocytes recruitment in tumor microenvironment through iron-mediated chemokines production.
Highlights
The tumor microenvironment plays a pivotal role in the establishment and further development of cancer [1]
To study the potential chemoattractant activity of Neutrophil Gelatinase-Associated Lipocalin (NGAL), we tested the ability of the conditioned medium from human anaplastic thyroid carcinoma (ATC)-derived BHT101 cells, containing large amounts of NGAL [20], to induce human monocytic THP-1 cells chemotaxis in transwell migration assays
In the present paper we demonstrate that NGAL secreted by neoplastic cells supports immune cells chemotaxis in tumor microenvironment
Summary
The tumor microenvironment plays a pivotal role in the establishment and further development of cancer [1] It is constituted of a number of different cell types including stromal fibroblasts, endothelial cells and immune cells which synergistically with neoplastic cells deeply contribute to tumor growth and to the multiple stages of tumor progression [2]. Tumor infiltrating immune cells induce the synthesis of a number of growth factors, cytokines, chemokines and pro-inflammatory mediators that stimulate proliferation of neoplastic and stromal cells [6]. One of the main actors in the inflammatory process is NF-κB which, by regulating the expression and the function of different cytokines and chemokines in inflammatory cells, stimulates the growth and its own activity in epithelial cells. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is an ironbinding acute phase protein [10,11,12] under NF-κB transcriptional regulation [13,14,15], strongly over-expressed in many human tumors [16,17,18,19] including thyroid cancer, where it is able to mediate critical NF-κB functions, such as the resistance to serum withdrawal-induced apoptosis [15] and the metastatic activity of anaplastic thyroid carcinoma cells [20]
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