Plasminogen activator system, vascular endothelial growth factor, and colorectal cancer progression

Abstract

Aims: To plasminogen activator system (PAS) consists of the plasminogen activators (urokinase (uPA) and tissue-type (tPA) plasminogen activators), the uPA receptor (uPAR), and the plasminogen activator inhibitors (PAI-1 and PAI-2). Plasminogen activators activate plasminogen to plasmin, which can break down extracellular matrix (ECM) components. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is involved in angiogenesis. VEGF has been shown to upregulate uPA and this may facilitate tumour angiogenesis further.

Methods: PAS components and VEGF were determined by enzyme linked immunosorbent assay (ELISA) in paired colorectal tumour and normal tissue (n = 50) and correlated with pathological staging.

Results: uPA, uPAR, PAI-1, and VEGF values were significantly higher in tumour tissue (for example, tumour uPA: median, 2.3 (range, 0.1-6.7) ng/mg protein v normal uPA: median, 0.2 (range, 0-2.6) ng/mg protein). tPA was significantly higher in normal mucosa and there was no difference in PAI-2. uPA, uPAR, PAI-1, and VEGF values significantly correlated with each other and with Dukes's staging (uPA in adenomas: median, 0.42 (range, 0.1-1.2) ng/mg protein; upA in Dukes's B tumours: median, 2.1 (range, 0.4-4.3) ng/mg protein; and uPA in Dukes's D tumours: median, 4.0 (range, 3.7-4.2) ng/mg protein) and lymphatic invasion. In addition PAI-1 also correlated with tumour size and differentiation.

Conclusion: The involvement of the PAS and VEGF in colorectal cancer appears to be complex. uPA, uPAR, PAI-1, and VEGF were upregulated in tumour tissue and this correlated with Dukes's staging and lymphatic invasion.

Figure 1

Box plots showing the positive correlation between (A) urokinase plasminogen activator (uPA), (B) the uPA receptor (uPAR), (C) plasminogen activator inhibitor 1 (PAI-1), and (D) vascular endothelial growth factor (VEGF) values with the Dukes's stage of the tumour (median and interquartile range) in colorectal cancer tissue (*p < 0.05, Spearman's correlation). The line within the box plot corresponds to the median value.

Figure 2

Box plots showing the positive correlations between (A) urokinase plasminogen activator (uPA), (B) the uPA receptor (uPAR), (C) plasminogen activator inhibitor 1 (PAI-1), and (D) vascular endothelial growth factor (VEGF) values and lymphatic invasion (median and interquartile range). Expression was significantly greater in tumours that had undergone lymphatic invasion (*p < 0.05, Spearman's correlation). The line within the box plot corresponds to the median value.

Figure 3

Box plots showing the positive correlation between plasminogen activator inhibitor 1 (PAI-1) values and (A) tumour differentiation and (B) tumour size (median and interquartile range). * p < 0.05 Spearman's correlation. The line within the box plot corresponds to the median value.