Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality

Abstract

Background & Aims Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or GDF15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. Methods We collected data on survival of 618 participants diagnosed with CRC who provided pre-diagnosis blood specimens in 1990 (Nurses’ Health Study) and 1994 (Health Professionals’ Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by ELISA and then were categorized into quartiles based upon the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC-1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or COX2), measured in 245 tumor samples by immunohistochemistry. Results Compared to participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio (HR) for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval, 1.33–4.34; P for linear trend=.009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples (Pinteraction=.04). For individuals with PTGS2-positive tumors, the HR for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% CI, 0.99–4.58) compared to participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate HR=0.61; 95% CI, 0.13–2.93). Conclusions Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (GDF15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.

Identification of Nidogen 1 as a lung metastasis protein through secretome analysis

“…S3A,B). Consistent with the elevated levels of FN1 and NOV in the lung metastatic secretomes, both proteins have been associated previously with cell invasion and metastasis (Akiyama et al 1995;Benini et al 2005;Perbal 2006;Vallacchi et al 2008;Liu et al 2015;Mehta et al 2015) as well as higher risk of metastasis and poor prognosis in cancer patients (Glukhova et al 2001;Perbal et al 2008Perbal et al , 2009Malik et al 2010;Zhang et al 2013;Fernandez-Garcia et al 2014;Ueda et al 2015). These initial analyses Figure 1.…”

“…In support of this, several LMSS proteins have been reported previously as circulating biomarkers in cancer patients, correlating to presence of cancer or associating with poor clinical outcome. As such, serum CLIC4 levels were elevated in ovarian cancer patients compared with controls (Tang et al 2013), LCP1 was increased in the plasma of patients with kidney cancer (Tang et al 2013), and the plasma GDF15 levels were high in colorectal cancer patients and predicted poor survival (Wallin et al 2011;Mehta et al 2015).…”

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

“…In particular, PTGS, PTGER3 (prostaglandin E receptor 3), PTGFR (prostaglandin F receptor), and AKR1B1 (aldo-keto reductase family 1 member B) were found hyper-methylated in more than 40% of colorectal tumors 136 . A recent study on 618 participants diagnosed with CRC showed that CRC-specific mortality was higher in patients with PTGS2-positive tumors, when GDF15/MIC1 (growth differentiation factor 15) plasma levels were high preceding diagnosis 137 . When visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments were analyzed for metabolic and transcriptomic differences to elucidate a link between obesity and colorectal carcinogenesis, results showed that VAT compartments displayed elevated markers of inflammatory lipid metabolism, prostaglandin synthesis-related enzymes (PTGDS/PGS2S), PLA2G10 (phospholipase A2 group X), and free arachidonic acid.…”

Macrophage inhibitory cytokine‐1/growth differentiation factor‐15 as a predictor of colonic neoplasia

“…In colorectal cancer, the simultaneous elevation of local MIC‐1/GDF15 expression with changes in colonic mucosa and epithelial dysplasia also support its use as a biomarker . There are data to suggest that serum levels may increase progressively from normal intestinal mucosa, to adenomatous polyps and further in established malignancy .…”

“…There are data to suggest that serum levels may increase progressively from normal intestinal mucosa, to adenomatous polyps and further in established malignancy . Several studies also support the potential for serum MIC‐1/GDF15 levels to predict colon cancer and data are starting to emerge on its role in the diagnosis of colonic polyps. In serial sampling, a progressive rise in MIC‐1/GDF15 was associated with an increased relative risk of developing colorectal neoplasia .…”