Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma

Abstract

BackgroundMacrophage inhibitory cytokine 1 (MIC-1/GDF15) has been identified as a potential novel biomarker for detection of pancreatic cancer (PCa). However, the diagnostic value of serum MIC-1 for pancreatic ductal adenocarcinoma (PDAC), particularly for those at the early stage, and the value for treatment response monitoring have not yet been investigated.MethodsMIC-1 expression in tumor tissue was analyzed by RT-PCR from 64 patients with PDAC. Serum MIC-1 levels were detected by ELISA in 1472 participants including PDAC, benign pancreas tumor, chronic pancreatitis and normal controls. The diagnostic performance of MIC-1 was assessed and compared with CA19.9, CEA and CA242, and the value of it as a predictive indicator for therapeutic response and tumor recurrence was also evaluated.ResultsMIC-1 levels were significantly elevated in PDAC tissues as well as serum samples. The sensitivity of serum MIC-1 for PDAC diagnosis was much higher than that of CA19.9 (65.8% vs. 53.3%) with similar specificities. Furthermore, serum MIC-1 detected 238 out of 377 (63.1%) CA19.9-negative PDAC. Moreover, receiver operating characteristic (ROC) curve analysis also showed that serum MIC-1 had a better performance compared with CA19.9 in distinguishing early-stage PDAC from normal serum with a higher sensitivity (62.5% vs. 25.0% respectively). Notably, serum MIC-1 level was significantly decreased in patients with PDAC after curative resection and returned to elevated levels when tumor relapse occurred.ConclusionsSerum MIC-1 is significantly elevated in most PDAC, including those with negative CA19.9 and early stage disease, and thus may serve as a novel diagnostic marker in early diagnosis and postoperative monitoring of PDAC.

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

“…Having shown the tumor-promoting potential of GDF-15 in Ras-MEF cells, we next sought to validate our observations using a tumor model that better recapitulated human disease. A recently published study involving several types of cancers showed that circulating levels of GDF-15 are elevated in patients with pancreatic ductal adenocarcinoma (PDAC) (12). This finding was confirmed by measuring plasma GDF-15 levels from patients with PDAC compared with control subjects whose tissue was obtained from our own institutional pancreatic cancer tissue bank (Supplemental Figure 2A).…”

“…Patients utilized as cona dense stroma with infiltration of innate immune cells (35,36). In addition, GDF-15 is highly expressed in PDAC compared with other cancers (12). However, interest in this cytokine has been mostly restricted to its role as a potential biomarker, and therefore no mechanism has been proposed for how this cytokine might function during the development of PDAC.…”

Plasma Inflammatory Markers and Risk of Advanced Colorectal Adenoma in Women

“…(9-25) Studies examining the association of other inflammatory cytokines, such as interleukin-6 (IL-6) (10, 22-24, 26) and tumor necrosis factor (TNF)-α,(23, 26, 27) with CRC are limited and inconsistent. Recently, macrophage inhibitory cytokine-1 (MIC-1, also known as growth differentiation factor 15, GDF15), a divergent member of the human transforming growth factor (TGF)-β superfamily and a mediator of the systemic inflammatory response,(28) has been related to development of cancers in various organs,(29-32) including CRC. (33) We recently showed that elevated levels of plasma MIC-1 were associated with higher risk of incident CRC.…”

Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics

“…This data has been validated using RTPCR to confirm upregulation of mir146a and G-CSF as well as downregulation of BMP-7 in sfRON expressing cells (Supplementary Figure S8). We have previously shown that RON P5P6 isoform is oncogenic, TNFRSF6B (DcR3 protein) prevents TRAIL induced apoptosis [32] and GDF15 (MIC-1 protein) is being investigated as a highly specific marker of pancreatic cancer [33]. GAS1 is a tumor suppressor involved in hedgehog signaling and RUNX3 is a transcription factor that is lost in pancreatic cancer and modulates metastatic potential [34, 35].…”