High levels of serum VEGF and TIMP-1 are correlated with colon cancer liver metastasis and intrahepatic recurrence after liver resection

Abstract

The purpose of this study was to develop predictive/prognostic markers for liver metastasis and recurrence following liver resection, investigating not only clinical parameters but also molecular markers that are known to be involved in the process of liver metastasis. Seventy colon cancer patients with either no distant metastasis (group A) or with resectable synchronous liver metastasis only (group B) were prospectively enrolled. All 70 patients received curative resection of the primary tumor. Group B patients underwent additional liver resection. Clinical parameters as well as serum levels of molecular markers [carcinoembryonic antigen (CEA), osteopontin, matrix metalloproteinase-7 (MMP-7), tissue inhibitor of metalloproteinase-1 (TIMP-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and E-selectin] from both tumor drainage (DV) and peripheral veins (PV) were analyzed. Results showed the clinical parameters were not significantly different between groups A and B. Nonetheless, the levels of VEGF and TIMP-1 from both DV and PV were significantly higher in group B compared to group A. In group A, 10 out of 33 (27.0%) patients developed metachronous liver metastasis. High levels of VEGF and TIMP-1 from DV were found to be significantly correlated with metachronous liver metastasis. In group B, 20 out of 33 (60.6%) patients had intrahepatic recurrence following resection of synchronous liver metastasis. The levels of VEGF from DV and the levels of TIMP-1 both from PV and DV were found to be significantly correlated with intrahepatic recurrence. Forty patients (7 from group A and 33 from group B) had liver resection and their 5-year disease-free survival rate was 15.9%. Univariate and multivariate analyses of prognostic factors revealed that the levels of VEGF and TIMP-1 from DV as well as the presence of lymph node metastasis from the primary tumor, synchronous metastasis and R1 resection were significantly associated with worse prognosis. The colon cancer patients with high levels of VEGF and TIMP-1 detected from the DV at the time of their initial surgery were found to have a high risk of metachronous liver metastasis and hepatic recurrence following the resection of synchronous liver metastasis. The high levels of VEGF and TIMP-1 were found to be significant predictive factors for poor prognosis following liver resection. These results require validation but pave the way for future transitional or clinical studies that may provide a greater understanding of colon cancer liver metastasis.

Figure 1

(A) Bar chart of serum levels of MMP-7, E-selectin and osteopontin. (B) Bar chart of serum levels of VEGF and HGF. (C) Bar chart of serum levels of CEA and TIMP-1. Numbers in rectangles are the P-values.

Figure 1

(A) Bar chart of serum levels of MMP-7, E-selectin and osteopontin. (B) Bar chart of serum levels of VEGF and HGF. (C) Bar chart of serum levels of CEA and TIMP-1. Numbers in rectangles are the P-values.

Figure 1

(A) Bar chart of serum levels of MMP-7, E-selectin and osteopontin. (B) Bar chart of serum levels of VEGF and HGF. (C) Bar chart of serum levels of CEA and TIMP-1. Numbers in rectangles are the P-values.

Figure 2

Disease-free survival curves according to the levels of (A) VEGF and (B) TIMP-1.

Figure 2

Disease-free survival curves according to the levels of (A) VEGF and (B) TIMP-1.