Urokinase Receptor and Vascular Endothelial Growth Factor Are Synergistically Associated with the Liver Metastasis of Colorectal Cancer

Abstract

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.

Association of Interleukin-8 and Plasminogen Activator System in the Progression of Colorectal Cancer

“…This is the fi rst study to show quantitatively that IL-8 was correlated with PA system factors, uPA, uPAR, and PAI-1 in CRC. A positive correlation between VEGF overexpression and both uPAR expression and liver metastasis was demonstrated in our previous study [29] . In the present study, the VEGF level was quantitatively correlated with the levels of uPAR and PAI-1.…”

“…We previously reported the existence of a relationship between VEGF and the PA system, which promote angiogenesis synergistically in CRC [29] . In this context, we investigated the relationship of IL-8 with VEGF and PA system factors in CRC.…”

Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer

“…Increased uPA and uPAR expression in tumor cells is correlated with advanced disease, shorter survival time, and increased frequency of liver metastasis, thus supporting a role for the uPA system in tumor invasion [9][10][11][12][13][14][15]. The signaling mechanisms that regulate uPA and uPAR expression are not fully characterized but may involve the Ras/ERK, TGF-β, and Wnt signaling pathways [16][17][18][19].…”

A New Assay for Measurement of the Liberated Domain I of the Urokinase Receptor in Plasma Improves the Prediction of Survival in Colorectal Cancer

“…In both tumor tissue and blood, high uPAR concentrations have been shown to correlate with a poor prognosis in several types of cancer (8 ). The use of immunoassays that measure a combination of different uPAR forms has demonstrated that uPAR concentrations in extracts of tumor tissue samples from CRC patients are an independent prognostic factor for 5-year overall survival (9 ), and there are indications that uPAR concentrations correlate with liver metastasis (10 ). The plasma suPAR concentration has also been correlated with survival in CRC patients (11 ).…”