Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer

Candido, Saverio; Maestro, Roberta; Polesel, Jerry; Catania, Alessia; Maira, Francesca; Signorelli, Salvatore Santo; McCubrey, James A.; Libra, Massimo

doi:10.18632/oncotarget.1738

Cited by 99 publications

(132 citation statements)

References 110 publications

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“…However, recent studies have indicated that NGAL has potential role in cancer development and that it may have pro-oncogenic or anti-oncogenic functions. In particular, it has been reported that the NGAL mRNA transcript and protein levels were higher in bladder cancer tissues than those in their normal counterparts (27). Accordingly, 50.5% of cases displayed NGAL transcript levels higher than the 75 th percentile of the 'normal' values, suggesting its role as a diagnostic marker (27).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, it has been reported that the NGAL mRNA transcript and protein levels were higher in bladder cancer tissues than those in their normal counterparts (27). Accordingly, 50.5% of cases displayed NGAL transcript levels higher than the 75 th percentile of the 'normal' values, suggesting its role as a diagnostic marker (27). These are in agreement with the results of previous investigations in which NGAL and MMP-9 were overexpressed in urothelial bladder carcinomas, suggesting their role as early diagnostic markers for this tumor type (14).…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of MMP-2, MMP-9, TIMP-1, TIMP-2, NGAL and MMP-9/NGAL complex in urine and sera from patients with bladder cancer

Ricci¹,

Bruzzese²,

Carlo³

2015

Oncology Letters

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Abstract. The identification of biomarkers in urine or serum samples from patients with bladder cancer is urgently required for the development of non-invasive methods for the diagnosis of bladder carcinoma and to facilitate follow-up surveillance, to combat the high progression and recurrence rates of this type of cancer. The current study measured the content of matrix metalloproteinase (MMP)-2 and -9, as well as tissue inhibitor of metalloproteinase (TIMP)-1 and -2 in the urine and sera of 41 patients with bladder cancer by ELISA. The association between levels of MMP-2 and -9 and TIMP-1 and -2, and tumor grade and stage were investigated to verify whether these molecules are involved in tumor differentiation. Statistical analysis of the data revealed that urinary TIMP-1 levels were significantly higher in the high grade group compared with those of the low grade samples (P=0.022). The results also revealed a significantly differing distribution of TIMP-1 expression between Ta and T1 stage specimens (P=0.040). The corresponding area under the curves (AUCs) were 0.72, with a sensitivity of 0.70 and specificity of 0.75. In addition, neutrophil gelatinase-associated lipocalin (NGAL) and MMP-9/NGAL complex levels in the sera were measured. All molecules evaluated were detected in the sera of the patients studied. In particular, tumors staged as non-muscle invasive (Ta and T1), demonstrated significantly higher NGAL levels compared with those of muscle invasive (>T1) bladder cancer (32.8 ng/ml vs. 16.2 ng/ml; P=0.029). The discriminatory ability of NGAL expression was confirmed by receiver operating characteristic curve analysis that revealed an AUC of 0.75, a sensitivity of 0.88 and a specificity of 0.67. These data indicated that urinary TIMP-1 and serum NGAL may be useful non-invasive biomarkers to provide clinical information for bladder cancer disease management. Multicenter, prospective studies are required to confirm these preliminary results. IntroductionBladder cancer (BCa) is one of the most common urologic malignancies worldwide; with a higher frequency amongst males than females (1). The two major environmental risk factors for BCa are high exposure to tobacco smoke, and occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons (2,3). Furthermore, exposure to ionizing radiation, a variety of lifestyle choices, occupations, dietary factors, drugs, urologic pathologies, family history and genetic polymorphisms may increase the risk of bladder carcinoma (1-3). There are two clinical phenotypes of bladder carcinoma: Non-invasive and invasive BCa. Non-invasive BCa includes the papillary carcinoma phenotype (Ta) and flat carcinoma in situ (cis). Ta bladder carcinoma is superficial and rarely invades the basement membrane or metastasizes, but is associated with a high risk of local recurrence; while invasive bladder carcinoma has a high risk of disease progression, including muscle invasion and metastasis, and mortality. Ta tumorigenesis typically occurs via a mol...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of MMP-2, MMP-9, TIMP-1, TIMP-2, NGAL and MMP-9/NGAL complex in urine and sera from patients with bladder cancer

Ricci¹,

Bruzzese²,

Carlo³

2015

Oncology Letters

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“…by guest www.bloodjournal.org From a growing number of studies have provided evidence that a variety of solid tumors are characterized by overexpression of LCN2. [28][29][30][31] Previously, LCN2 has been implicated in the pathobiology of another MPN, chronic myeloid leukemia, where this iron-containing protein has been shown not only to promote BCR/ABL 1 hematopoiesis but also to inhibit the residual reservoir of normal hematopoietic progenitor cells, thereby likely contributing to the clonal dominance of the malignant clone. 14,18 Beyond its effects on tumor cells, LCN2 expression has also been implicated as a mediator of renal, pulmonary, and cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Lü

Xia

Liu

et al. 2015

Blood

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Key Points• LCN2 acts to generate reactive oxygen species, leading to increased DNA strand breaks and apoptosis in normal CD34 1 cells.• LCN2 promotes the generation of osteoblasts but diminishes adipogenesis, resembling the composition of the MF marrow microenvironment.Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34 1 cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. (Blood. 2015;126(8):972-982)

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“…Additional functions of lipocalins include, but are not limited to; cryptic coloration, olfaction, pheromone transport, retinol transport and may even aid in enzymatic synthesis of prostaglandins [1,9,40]. However, more recent studies indicate that lipocalins have a variety of activities which we will briefly summarize.…”

Section: Novel Functions Of Ngal/lipocalinsmentioning

confidence: 95%

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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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.

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Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer

Cited by 99 publications

References 110 publications

Evaluation of MMP-2, MMP-9, TIMP-1, TIMP-2, NGAL and MMP-9/NGAL complex in urine and sera from patients with bladder cancer

Evaluation of MMP-2, MMP-9, TIMP-1, TIMP-2, NGAL and MMP-9/NGAL complex in urine and sera from patients with bladder cancer

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

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