1.
Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy.
Candido, S, Abrams, SL, Steelman, LS, Lertpiriyapong, K, Fitzgerald, TL, Martelli, AM, Cocco, L, Montalto, G, Cervello, M, Polesel, J, et al
Biochimica et biophysica acta. 2016;(3):438-448
Abstract
Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
2.
Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections.
Nasioudis, D, Witkin, SS
Medical microbiology and immunology. 2015;(4):471-9
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL), an essential component of the antimicrobial innate immune system, is present in neutrophils and multiple other tissues. It prevents iron acquisition by microorganisms by sequestering iron-loaded bacterial siderophores. NGAL also modulates neutrophil functions. Its production is inducible following Toll-like receptor 4 activation and release of pro-inflammatory cytokines. NGAL is employed clinically in the diagnosis of acute kidney injury and may be useful in general in the differential diagnosis of a bacterial-mediated infectious process. Elevated levels of NGAL have been detected in the blood of patients with bacterial urinary tract infection, community-acquired pneumonia, sepsis, as well as in the cerebrospinal fluid and peritoneal fluid of patients with bacterial meningitis and peritonitis. Some bacteria have developed resistance to NGAL-mediated iron sequestration by production of modified siderophores that are not recognized by NGAL.
3.
Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene.
Bolignano, D, Donato, V, Lacquaniti, A, Fazio, MR, Bono, C, Coppolino, G, Buemi, M
Cancer letters. 2010;(1):10-6
Abstract
The small 25 kDa peptide, neutrophil gelatinase-associated lipocalin (NGAL), first known as an antibacterial factor of natural immunity, and an acute phase protein, is currently one of the most interesting and enigmatic proteins involved in the process of tumor development. The aim of the present review is to point out the main contradictory, sometimes even paradoxical, effects attributed to NGAL in human neoplasias. For instance, acting as an intracellular iron carrier and protecting MMP9 from proteolytic degradation, NGAL has a clear pro-tumoral effect, as has already been observed in different tumors (e.g. breast, stomach, oesophagus, brain) in humans. Moreover, in thyroid carcinomas, NGAL is strongly induced by NF-kB, an important factor involved both in tumor growth and in the link between chronic inflammation and neoplastic development. However, on the contrary, some studies have demonstrated that NGAL can inhibit the pro-neoplastic factor HIF-1alpha, FA-Kinase phosphorylation and also VEGF synthesis, thus suggesting that, in alternative conditions, NGAL also, paradoxically, has an anti-tumoral and anti-metastatic effect in neoplasias of, for example, the colon, ovary and pancreas. Finally, in the field of clinical oncology, attention is currently focused on the potential use of NGAL levels in making an early diagnosis, establishing a prognosis and predicting response to different treatments.
4.
Decreased serum lipocalin-2 levels in human immunodeficiency virus-infected patients: increase during highly active anti-retroviral therapy.
Landrø, L, Damås, JK, Flo, TH, Heggelund, L, Ueland, T, Tjønnfjord, GE, Espevik, T, Aukrust, P, Frøland, SS
Clinical and experimental immunology. 2008;(1):57-63
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Abstract
Although neutrophil gelatinase-associated lipocalin (NGAL) may play a pivotal role in the innate immune response, there are currently no data on NGAL levels in human immunodeficiency virus (HIV)-infected patients. In this study we aimed to examine the regulation of NGAL in HIV infection. The regulation of NGAL in HIV infection was examined by different experimental approaches, including studies in peripheral blood and mononuclear cells (MNC) from bone marrow aspirates before and during highly active anti-retroviral therapy (HAART). We found that: before initiating HAART, HIV-infected patients (n = 37) had significantly decreased serum NGAL levels compared with healthy controls (n = 26); (ii) during HAART, there was a gradual and significant increase in NGAL concentrations reaching levels comparable to those in healthy controls after 12 months; (iii) this increase was seen primarily in virological responders to HAART (HIV RNA level <200 copies/ml after 24 months); (iv) phytohaemagglutinin-stimulated NGAL release in MNC cells from bone marrow aspirates was decreased in untreated HIV-infected patients compared with healthy controls, but increased after 26 weeks on HAART; and (v) there was a significant positive correlation between neutrophil counts and NGAL levels at all time-points during HAART. We have shown decreased NGAL levels in HIV-infected patients, potentially reflecting decreased number and function of neutrophils as well as impaired bone marrow myelopoiesis. These abnormalities were reversed by successful HAART. Our findings underscore further the involvement of neutrophils and innate immunity in HIV-related immunodeficiency.