Ectopic expression of neutrophil gelatinase‐associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin 2, is a 25-kDa lipocalin initially purified from neutrophil granules. It is thought to play a role in regulating cellular growth since its expression is highly upregulated in a variety of proliferative cells such as cancer cells. However, experimental evidence showing a clear causal relationship between NGAL expression and the proliferation of tumor cells is lacking. Here, we found NGAL expression in highly and poorly metastatic colon cancer cell lines of the same genetic origin correlated inversely with the metastatic potential of these cells, which suggests NGAL participates in the metastatic process. To explore the role NGAL plays in tumor growth and metastasis, the KM12SM human colon cancer cell line, which is highly metastatic while showing decreased NGAL expression, was genetically manipulated to overexpress NGAL. The effects of this on tumor growth and liver metastasis were then analyzed using experimental animal models established by injecting BALB/c nude mice with tumor cells subcutaneously or intrasplenically. Ectopic expression of NGAL in the colon cancer cells had little effect on the growth and viability of the tumor cells both in vitro and in vivo. However, NGAL expression not only suppressed the ability of the colon carcinoma cells to invade Matrigel in vitro, it also substantially inhibited liver metastasis in an experimental animal model. Collectively, these results indicate that NGAL may be a candidate metastasis suppressor in colon cancer cells. ' 2005 Wiley-Liss, Inc.

Serum levels of matrix metalloproteinase-2 and -9 and conventional tumor markers (CEA and CA 19-9) in patients with colorectal and gastric cancers

“…(24). Experimental data suggest that increased lipocalin-2 expression results in either significant stimulation of tumor growth (26) or lipocalin-2 may be a suppressor of colon cancer metastasis (27). However, we did not find any significant relationship between serum 130-kDa and histological grade and clinical stage in patients with colorectal or gastric cancer.…”

NGAL decreases E-cadherin-mediated cell–cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells

“…It is also likely that different experimental conditions (cellular environment) may account for the differences. Recently, Lee et al 54 reported that a C-terminal-tagged form of NGAL expressed in lentivirus inhibited the invasion of KM12SM cells, a metastatic clone of the KM12C cell line used in our study. Differences in the extracellular matrix environment used in their study may also be a cause of difference in the results.…”

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

“…Surprisingly, a link between circulating level of this biomarker and metastasis and prognostic outcome of CRC has not been reported. Particularly surprising is that even the results of in vitro studies appear to be inconsistent; one study showed that overexpression of lipocalin 2 aggravated metastatic colon cancer cells [24], while another showed an opposite pattern [20]. In this study we investigated whether increased circulating level of lipocalin 2 may be a useful biomarker by which to predict metastasis and clinical outcome of CRC after surgical intervention.…”

“…In addition, experimental data have shown that lipocalin 2 plays an important role in regulating cell growth since its expression is highly upregulated in a variety of proliferative cells such as cancer cells [20,21]. Increased lipocalin 2 expression has been reported in various cancers including ovarian, pancreatic, lung and breast cancers, indicating there is a strong association between this biomarker and the malignance of cancer cells and metastasis [20][21][22][23].…”

“…Increased lipocalin 2 expression has been reported in various cancers including ovarian, pancreatic, lung and breast cancers, indicating there is a strong association between this biomarker and the malignance of cancer cells and metastasis [20][21][22][23]. Surprisingly, a link between circulating level of this biomarker and metastasis and prognostic outcome of CRC has not been reported.…”