Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer

Abstract

Summary Despite the advances in pre-, peri-and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni-and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.

Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

“…Furthermore, uPA and uPAR expression were more intensive and more frequent in Dukes C/B than in Dukes A tumors [13,17], indicating that the proteins were associated with tumor progression. A positive association was found between survival of patients with Dukes B or C colorectal cancer and epithelial uPA or uPAR staining [18,19]. The uPA and uPAR appear to be strong prognostic markers for patients with CRC and their value to predict metastasis (liver metastasis), disease recurrence and overall survival has been documented [5,10,14].…”

ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer

“…As reported in the scientific literature, the increased levels of tissue and circulating PAI-1 would not significantly inhibit plasminogen activators activity in primary tumors, so that the balance will favor proteolysis, and PAI-1 serum and tissue levels negatively influence prognosis and overall and disease-free survival in breast, bladder, ovarian, lung, gastric, and colorectal cancer patients (Sakakibara et al 2006;Beyer et al 2006;Offersen et al 2007;Speleman et al 2007). In colorectal cancer patients, even several plasminogen activation parameters in normal colorectal mucosa are of prognostic relevance for the overall survival of the patients (Ganesh et al 1997).…”

The role of cysteine and serine proteases in colorectal carcinoma

“…Some of the studies discussed above also showed that cathepsins or some PAs also have a prognostic significance for patients with CRC; 23,24,30 however, to our knowledge, cysteine and serine proteases have not been evaluated in the same experimental setting, and the prognostic relevance of cathepsins in CRC has not been compared with that of UPA, TPA, and PAI-1. Therefore, the objective of the current study was to measure the tissue antigen concentrations of cysteine proteases (CATB and CATL), serine proteases (UPA and TPA), and their inhibitor (PAI-1) in the same patients, in CRC tissue (CANCER), and in its normal counterpart (NORMAL) obtained from a tumor free area and, then, to evaluate any correlation between these parameters and the major histomorphologic and prognostic parameters of CRC.…”

“…16 -20 In the specific case of colorectal carcinoma (CRC), several studies have been also published on tissue cathepsins 21,22 and the PA system. [23][24][25][26] Immunohistochemical studies have shown intensive staining with antibodies against CATB, UPA, and PAI-1 in CRC, particularly at sites of invasive growth. [27][28][29][30][31] The correlations between cysteine and serine proteases and tumor invasion and metastases also have been confirmed by several in vitro studies, which demonstrated that increased protease levels correlate with the invasive and metastatic potential of malignant tumors.…”