Prognostic biomarkers in gastric cancer

Gastric cancer is a highly malignant disease and one of the leading causes of cancer-related mortality worldwide. The course of the disease can vary, making the accurate prediction of its progression difficult. New biomarkers could help us assess cancer aggressiveness and behavior, which would be of value when evaluating the prognosis of each individual patient with gastric cancer. Podocalyxin-like protein (PODXL) is a cell-adhesion glycoprotein associated with an aggressive tumor phenotype and a poor prognosis in several forms of cancer. Prospero homeobox protein 1 (PROX1) is a transcription factor involved in the development of various organs, and also plays an important role in colorectal cancer progression. Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) is a cysteine protease being a part of the protein homeostasis network, and is found both in healthy and in cancer tissue. Matrix metalloproteinase-8 (MMP-8) belongs to the collagenase subgroup of MMPs and is capable of degrading the extracellular matrix (ECM). MMP-8 participates in the proteolytic processing of inflammatory mediators in a wide variety of biological processes and is also associated with various diseases including cancer. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of MMPs and the extracellular environment. The aim of this study was to evaluate the expression and prognostic value of these potential biomarkers in gastric cancer. A total of 650 gastric cancer patients were included in this study. Two separate tissue microarray (TMA) series prepared from tumor tissue specimens from these patients were the material for immunohistochemical staining of studied antibodies. The expression of studied markers were evaluated and compared to clinicopathological variables and patient survival. From preoperative blood samples from 233 patients, serum levels of MMP-8 underwent determination with an immunofluorometric assay (IFMA) and TIMP-1 with enzyme-linked immunosorbent assay (ELISA). PODXL positivity indicated impaired gastric cancer-specific 5-year survival compared to that of patients with PODXL negativity. The result in multivariable analysis remained significant. Patients with high PROX1 expression had significantly better cancer-specific 5-year survival than did those with low expression, a result that remained significant in multivariable analysis. Patients with positive cytoplasmic UCHL5 tumor expression showed increased survival in the subgroups of small (131 ng/ml) serum MMP-8 level had an unfavorable prognosis compared to those with an intermediate (31-131 ng/ml) serum level. Those patients with high (≥170 ng/ml) serum TIMP-1 levels also had a poor prognosis, and the latter remained significant in multivariable analysis. The molar ratio of serum MMP-8 and TIMP-1 levels with low (0.30) molar ratios predicted a worse prognosis. The prognosis remained the same despite of MMP-8 tissue immunoreactivity. In gastric cancer tissue, positive PODXL expression is an independent marker of poor prognosis, high cytoplasmic PROX1 expression is an independent marker of better prognosis, and positive cytoplasmic UCHL5 is linked to better prognosis in certain subgroups. For prediction of prognosis in gastric cancer, serum MMP-8 and TIMP-1 are promising biomarkers.