Evaluation of serum midkine and carcinoembryonic antigen as diagnostic biomarkers for rectal cancer and synchronous metastasis

Abstract

Methods S-MK and CEA, related to cancer status, were measured in 106 patients and 30 controls by ELISAs. Diagnostic and Prognostic values of S-MK and CEA for rectal cancer were conducted by receiver operating characteristic (ROC) curves with the analysis of sensitivity, specificity, diagnostic accuracy, positive predictive value (PPV) and negative predictive value (NPV) for differential diagnosis. Results Pre-surgical S-MK was elevated in cancer patients than the normal and benign subjects. In term of phases, S-MK and CEA of T3/T4 were both significantly higher than those in T1/T2, with further up-regulation of S-MK. The diagnostic capability of S-MK was higher than CEA and increased in integrating S-MK with CEA when differentiated rectal cancer, benign rectal polyps and normal subjects. Moreover, when evaluating metastasis predictive efficacies, the combination of S-MK and CEA showed higher accuracy than any individual parameter. Conclusions Pre-surgical S-MK is a rectal cancer indicator which is superior to CEA. It can potentially be used to monitor the prognosis of rectal cancer, and predict synchronous metastases, providing assistance to clinicians.

Plasma protein changes reflect colorectal cancer development and associated inflammation

“…Of the elevated DEPs, dipeptidase 2 (DPEP2), hydroxyacylglutathione hydrolase (HAGH), and agouti-related neuropeptidase (AGRP) as well as downregulated DEPs as neutrophil cytosolic factor 2 (NCF2), epidermal growth factor-like protein 7 (EGFL7), and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5) were the DEPs with the most statistical difference. In line with previous studies which were carried out with different technologies for protein detection and quantification ( 17 , 23 – 28 ), high plasma levels of AGRP, FGF21, midkine (MDK), C-C motif chemokine ligand 20 (CCL20), IL6, and CSF3 as well as reduced ribonucleotide reductase regulatory TP53 inducible subunit M2B (RRM2B) on plasma level of CRC patients were also identified in our study. Importantly, we found novel protein changes including high levels of oncogenic proteins such as R-Spondin 3 (RSPO3) and secernin 1 (SCRN1) as well as low levels of tumor suppressors such as Ret proto-oncogene (RET) and Rho guanine nucleotide exchange factor 12 (ARHGEF12) in CRC patients.…”

“…Of the elevated DEPs, dipeptidase 2 (DPEP2), hydroxyacylglutathione hydrolase (HAGH), and agouti-related neuropeptidase (AGRP) as well as downregulated DEPs as neutrophil cytosolic factor 2 (NCF2), epidermal growth factor-like protein 7 (EGFL7), and ectonucleotide pyrophosphatase/ phosphodiesterase family member 5 (ENPP5) were the DEPs with the most statistical difference. In line with previous studies which were carried out with different technologies for protein detection and quantification (17,(23)(24)(25)(26)(27)(28), high plasma levels of AGRP, FGF21, midkine (MDK), C-C motif chemokine ligand 20 (CCL20), IL6, and CSF3 as well as reduced ribonucleotide reductase regulatory TP53…”

“…Next, to distinguish which of the protein changes were a consequence of an altered secretion from a certain type of cells and which were a result of destructed tissues or cells released during CRC tumorigenesis, from the 202 DEPs, 50 proteins were identified in the human blood secretome from Human Protein Atlas, including cytokines that modulate the immune responses within the TME, such as IFNG, IL6, IL15, CCL20, CXCL9, and CCL23 ( Supplementary Table 6 ). Some of these cytokines were previously found with high plasma levels in CRC such as pro-inflammatory cytokine IL6 which is also required for Th17 differentiation ( 26 ), the pro-inflammatory MDK involved in multiple biological processes ( 17 ), and the chemoattractant of B- and T-cells CCL20 ( 25 ), whereas the detected IFNG is a well-recognized pro-inflammatory and antitumorigenic protein ( 31 ). Interestingly, the elevated plasma levels of the chemoattractants CXCL9 and CCL23 in CRC patients were reported for the first time in our study.…”

“…CEA is expressed in the embryonic endodermal epithelium, colorectal cancer, and other malignancies, such as inflammatory bowel disease (IBD), peptic ulcer, and pancreatitis ( 13 ). CEA is a promising plasma biomarker for the detection of CRC with high specificity and sensitivity ( 12 , 14 ), however, due to the limited organ specificity ( 15 ), it is not the best sole biomarker for population-based screening, yet it might be useful in CRC recurrence monitoring ( 16 ) and metastasis ( 17 ). Currently, the trend in biomarkers discovery is to focus on the biomarker panels rather than on a single-target protein as the broader spectrum of the analysis may help to address the cancer prognosis and detection more precisely.…”