Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer

Abstract

BackgroundTissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions.MethodsPlasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters.ResultsTIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed.ConclusionThis retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients

“…Protein network analysis indicated that these proteins were interconnected with known PDAC pathways and oncogenes, including KRAS (GTPase KRas), SMAD4 (Mothers against decapentaplegic homolog 4), CDKN2A (Cyclin-dependent kinase inhibitor 2A), MYC (Myc proto-oncogene protein), TP53 (Cellular tumor antigen p53), TNF (Tumor necrosis factor), TGFB1 (Transforming growth factor beta-1 proprotein) and EGF (epidermal growth factor) ( Figure S3). It is noteworthy that despite the relatively low blood concentration of TIMP1 (at low ng/mL level), this protein was included for further testing in this study, as its blood concentration has been previously associated with PDAC in multiple studies [8,12,13,23].…”

“…(Transforming growth factor beta-1 proprotein) and EGF (epidermal growth factor) ( Figure S3). It is noteworthy that despite the relatively low blood concentration of TIMP1 (at low ng/mL level), this protein was included for further testing in this study, as its blood concentration has been previously associated with PDAC in multiple studies [8,12,13,23].…”

Metalloproteinases and their roles in human cancer

“…Similarly, addition of TIMP‐1 to CA19‐9, the currently used clinical marker for PDAC, may significantly improve PDAC detection (Capello et al, ). However, a few recent studies report that serum or plasma TIMP‐1 levels may be an indicator of PDAC‐associated cachexia or obstructive jaundice rather than a candidate marker for PDAC lesions (Jenkinson et al, ; Prokopchuk et al, ).…”

Analytically validated protein biomarkers of chronic pancreatitis and pancreatic cancer for potential clinical diagnosis with mass spectrometry

“…Mroczko et al reported that the tissue inhibitor of metalloproteinase 1(TIMP‐1) is a potential marker of PC with AUC of 0.923, which is superior to CA 19‐9 (0.862), CEA (0.894) and matrix metalloproteinase‐9 (MMP‐9) (0.711). TIMP‐1 has also been found with elevated level in serum orplasma in PC pateints compared with healthy subjects and CP patients in other studies and is superior to MMP‐9 in the diagnosis of PC…”

“…Mroczko et al 38 reported that the tissue inhibitor of metalloproteinase 1(TIMP-1) is a potential marker of PC with AUC of 0.923, which is superior to CA 19-9 (0.862), CEA (0.894) and matrix metalloproteinase-9 (MMP-9) (0.711). TIMP-1 has also been found with elevated level in serum orplasma in PC pateints compared with healthy subjects and CP patients in other studies 39,40,42,48 and is superior to MMP-9 in the diagnosis of PC. 41 Urinary urokinase-type plasminogen activator receptor (uPAR)/ creatinine values are also reported as an accurate marker for PC diagnosis with 53.2% sensitivity and 93.6% specificity, which is significantly increased in patients with PC but is not correlated with the severity.…”