Potentials of Plasma NGAL and MIC-1 as Biomarker(s) in the Diagnosis of Lethal Pancreatic Cancer

Abstract

Pancreatic cancer (PC) is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s) is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL) and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples from patients with pre-treatment PC patients (n = 91) and compared it with those in healthy control (HC) individuals (n = 24) and patients with chronic pancreatitis (CP, n = 23). The diagnostic performance of these two proteins was further compared with that of CA19-9, a tumor marker commonly used to follow PC progression. The levels of all three biomarkers were significantly higher in PC compared to HCs. The mean (± standard deviation, SD) plasma NGAL, CA19-9 and MIC-1 levels in PC patients was 111.1 ng/mL (2.2), 219.2 U/mL (7.8) and 4.5 ng/mL (4.1), respectively. In comparing resectable PC to healthy patients, all three biomarkers were found to have comparable sensitivities (between 64%-81%) but CA19-9 and NGAL had a higher specificity (92% and 88%, respectively). For distinguishing resectable PC from CP patients, CA19-9 and MIC-1 were most specific (74% and 78% respectively). CA19-9 at an optimal cut-off of 54.1 U/ml is highly specific in differentiating resectable (stage 1/2) pancreatic cancer patients from controls in comparison to its clinical cut-off (37.1 U/ml). Notably, the addition of MIC-1 to CA19-9 significantly improved the ability to distinguish resectable PC cases from CP (p = 0.029). Overall, MIC-1 in combination with CA19-9 improved the diagnostic accuracy of differentiating PC from CP and HCs.

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

“…We confirmed previous reports that LCN2 is elevated in sera from PDAC patients [19, 20]. LCN2 sera levels were compared among patients with normal pancreas, chronic pancreatitis (a benign inflammatory disease of the pancreas) and PDAC using ELISA.…”

“…Our results showed that serum levels of LCN2 are significantly higher in patients with PDAC (223.2 ng/ml): 1.9 fold increase when compared to those with normal pancreas (115.3 ng/ml) and 2.36 fold increase when compared to those with chronic pancreatitis (94.45 ng/ml). Plasma levels of LCN2 in patients with metastatic PDAC were also analyzed and found to be high (160.6 ng/ml) compared to a previous study which has shown LCN2 plasma levels to be around 111 ng/ml in PDAC patients compared to 67 ng/ml in healthy controls [20]. Furthermore, we analyzed mRNA levels of other members of the lipocalin family using microarray data from an earlier study [35] and found that LCN2 is the most up-regulated member of the lipocalin family in human PDAC compared to normal pancreas and pancreatitis tissue samples (Figure 1B).…”

Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

“…101,102 Some of these adipokines have been proposed as potential biomarkers for early detection of pancreatic ductal adenocarcinoma, and are also believed to have a role in tumour development. 102,103 One of these candidate markers, lipocalin 2 (LCN2; also known as neutrophil gelatinase associated lipocalin [NGAL]), has also been described in obesity associated with breast cancer. 104–106 LCN2 is elevated in the serum and visceral adipose tissue of obese individuals, and regulates adipose inflammation affecting glucose metabolism and insulin sensitivity.…”

Diagnostic value of selected markers and apoptotic pathways for pancreatic cancer

“…These results indicate that EUS-FNA is capable of non-operative detection of ZIP4, thus offering the potential for direct pre-operative detection and targeted therapy of PDAC. Acute phase proteins – neutrophil gelatinase-associated lipocalin (NGAL) and transforming growth factor-β (TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) – are proposed as the best potential biomarkers specifically elevated in the blood of pancreatic cancer patients [65]. MIC-1 in combination with CA19-9 improved the diagnostic accuracy of differentiating pancreatic cancer from chronic pancreatitis and healthy individuals.…”