Mechanisms by which CXCR4/CXCL12 cause metastatic behavior in pancreatic cancer

Abstract

C-X-C motif chemokine receptor (CXCR) 4/CXCL12 is associated with tumor invasion and metastasis in pancreatic cancer. The present study aimed to investigate the possible mechanisms behind this process by studying the association between the expression of CXCR4 and numerous molecular markers. A total of 60 patients with pancreatic cancer who had been treated with radical surgery between July 2012 and February 2016 were included in the present study. The expression of CXCR4/CXCL12 in primary pancreatic cancer lesions, tissues adjacent to cancerous tissue, non-cancerous pancreatic tissues and in the surrounding lymph nodes was evaluated by immunohistochemistry. Expression levels of four candidate biomarkers [vascular endothelial growth factor-C (VEGF-C), Ki-67, matrix metalloproteinase 2 (MMP-2) and β-catenin] were also evaluated. The correlation between CXCR4 and these four biomarkers was assessed. CXCR4 (CXCL12) expression levels were higher in pancreatic cancer 56.7% (86.7%), paracancerous tissue 50.0% (85.0%) and surrounding lymph nodes 53.3% (80.0%), compared with in normal tissues 18.3% (45.0%). CXCR4 expression was significantly associated with the lymph node metastasis of tumors (P=0.001), pathological type (P=0.037) and tumor-node-metastasis stage (P=0.031). CXCR4 expression exhibited a positive correlation with VEGF-C (r=0.417; P=0.001), Ki-67 (r=0.316; P=0.014), MMP-2 (r=0.284; P=0.028) and β-catenin (r=0.368; P=0.04). Furthermore, logistic regression analysis revealed VEGF-C (β=1.722; P=0.005) and Ki-67 (β=1.196; P=0.047) to be two biomarkers that cause metastasis via CXCR4. CXCR4/CXCL12 is closely associated with tumor grade and lymphatic metastasis. VEGF-C and Ki-67 are two important biomarkers, through which CXCR4 initiates metastatic behavior in pancreatic cancer. Therefore, angiogenesis inhibitors will continue to be effective agents in treating pancreatic cancer.

Keywords: CXCR4/CXCL12; biomarkers; mechanism; pancreatic cancer.

Figure 1.

Immunohistochemical staining of pancreatic cancer tissue using hematoxylin and eosin staining. (A) CXCR4 positive expression, magnification ×100; (B) CXCL12 positive expression, magnification ×100; (C) Ki-67 positive expression, magnification ×200; (D) MMP-2 positive expression, magnification ×100; (E) β-catenin positive expression, magnification ×200; (F) VEGF-C positive expression, magnification ×200. CXCR, C-X-C motif chemokine receptor; CXCR, C-X-C motif chemokine ligand; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.