Neutrophil Gelatinase–Associated Lipocalin: A Novel Suppressor of Invasion and Angiogenesis in Pancreatic Cancer

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa secreted acute phase protein, which is also up-regulated in multiple cancers, including breast, lung, and pancreas. Recently, NGAL has been proposed as an early biomarker in pancreatic cancer (PaCa). However, its biological role in PaCa is unknown. In this study, we examined in vitro and in vivo the functional role of NGAL in PaCa. Well-to moderately differentiated PaCa cells (AsPC-1, BxPC-3, and Capan-2) expressed high levels of NGAL but moderately to poorly differentiated PaCa cells (PANC-1 and MIAPaCa-2) expressed undetectable NGAL levels. Immunohistochemistry of untreated tissue microarray showed specific NGAL staining in resected PaCa specimens (P = 0.0167). Stable NGAL overexpression (MIAPaCa-2 and PANC-1) significantly blocked PaCa cell adhesion and invasion in vitro and vice versa with stable PaCa clones (BxPC-3 and AsPC-1). Moreover, NGAL overexpression reduced focal adhesion kinase (FAK) tyrosine-397 phosphorylation in PaCa cells. Furthermore, NGAL overexpression potently decreased angiogenesis in vitro partly through reduced vascular endothelial growth factor (VEGF) production and vice versa. Stable NGAL overexpression or underexpression had no effect on PaCa cell survival, viability, and response to chemotherapeutic drugs. Finally, MIAPaCa-2 cells overexpressing NGAL reduced tumor volume (P = 0.012), local and distant metastasis (P = 0.002), and angiogenesis (P = 0.05) with no effect on K-67 proliferation index (P > 0.1) in an orthotopic nude mouse PaCa model. Collectively, our results suggest that NGAL reduces adhesion/invasion partly by suppressing FAK activation and inhibits angiogenesis partly by blocking VEGF production in PaCa cells. Thus, NGAL is a potential suppressor of invasion and angiogenesis in advanced PaCa. [Cancer Res 2008;68(15):6100-8]

Lipocalin 2 Level Predicts Prognostic Outcome in Patients with Colorectal Cancer Undergoing Surgical Intervention

“…However our results are supported by one previous experimental study [20] that found that higher levels of lipocalin 2 suppressed the invasion and metastasis of colon cancer cells to the liver. We are uncertain why there is discrepancy between our and previous findings [21,22,26,27,31]. Perhaps different cancer cells (i.e., CRC vs. lung, ovarian, breast and pancreas cancer cells) have divergent responses to stimulation by different lipocalin 2 concentrations in invasion and mobilization, and distal organ metastasis.…”

“…Our findings thus provide evidence that lipocalin 2 is a useful biomarker for monitoring the long-term clinical status of CRC patients following surgical/pharmacological therapies. An extremely surprising finding was that in comparison with our result, previous studies have demonstrated that higher rather than lower levels of lipocalin 2 are significantly predictive of distal metastasis in lung, pancreas, ovarian and breast cancer settings [21][22][23]26,27,31]. However our results are supported by one previous experimental study [20] that found that higher levels of lipocalin 2 suppressed the invasion and metastasis of colon cancer cells to the liver.…”

“…Surprisingly, despite the association between lipocalin 2 level and inflammatory colon disease and distal organ metastasis from lung, pancreas, ovarian and breast cancers being the subject of extensive investigation [25][26][27][28][29][30], the link between the circulating level of this biomarker and the prognostic outcomes in CRC patients has not been reported. To the best of our knowledge, this is the first study to investigate the impact of circulating level of lipocalin 2 on the long-term prognostic outcome in CRC patients undergoing surgical intervention.…”

Neutrophil Gelatinase Associated Lipocalin: Structure, Function and Role in Human Pathogenesis

“…Pancreatic cancer (PC) is the most lethal of all malignant solid tumors in humans . Several groups including ours have now shown that while NGAL is either completely absent or weakly expressed in the normal pancreatic ducts, a strong expression of NGAL is seen in the malignant cells (Moniaux et al, 2008;Furutani et al, 1998;Tong et al, 2008;Tong et al, 2011). We also observed that the expression of NGAL first appears in pre-malignant lesions (termed as Pancreatic intraepithelial neoplasia or PanINs), with a progressive increase from low to high grade dysplasia.…”

PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

“…Transforming growth factor-b is upregulated (Friess et al, 1993) and induces the expression of connective tissue growth factor, a metastasis factor known to interact with integrin receptors (Grotendorst et al, 1996;Gao and Brigstock, 2005;Bennewith et al, 2009). In another study, overexpression of neutrophil gelatinaseassociated lipocalin reduces tumor volume and distant metastasis by blocking cell adhesion and invasion (Tong et al, 2008).…”