High expression of endothelial progenitor cell‑induced angiogenic markers is associated with bile acid levels in HCC

Abstract

Endothelial progenitor cell (EPC)-induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and CD34, in patients with HCC. The expression levels of VEGFR-2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR-2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR-2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR-2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α-fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P= 0.009). Next, the expression levels of VEGFR-2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR-2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan-Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR-2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC-induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues.

Research Progress of Bile Acids in Cancer

“…In the late 19th century, some scholars have discovered the anti-angiogenic activity of UDCA and its derivatives, suggesting the potential of BAs for the treatment of diseases that are accompanied by uncontrolled angiogenesis, including tumors (39). In contrast, a subsequent study on liver cancer found that BAs levels were positively correlated with the expression levels of VEGFR-2 and CD34, that is, BAs promoted tumor angiogenesis in liver cancer (35). Coincidentally, another study showed that CDCA promotes esophageal cancer angiogenesis and tumor growth via the COX-2 pathway (36).…”

Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment

“…In addition, several chemical drugs (such as The FXR Agonist Obeticholic Acid and Bushen Jianpi) can inhibit liver tumor metastasis in orthotopic mouse xenograft model and reduce the recurrence and metastasis rate of HCC patients by interfering with BAs levels (Table 1) (56, 57). Although information is limited, BAs also play a role in promoting HCC angiogenesis to a certain extent, that provides good conditions for tumor metastasis (59). In summary, BAs drive the progression of liver tumor metastasis in an indirect way, and antagonizing excessive BAs may provide an effective means of treating liver cancer.…”

Bile Acids: Physiological Activity and Perspectives of Using in Clinical and Laboratory Diagnostics

“…The binding with membrane receptors promotes systemic effects of BAs, regulation of digestion and lipid metabolism, and differentiation of endothelial cells [49,50]. Moreover, there is evidence that the activation of BAs' membrane receptors promotes malignant transformation and cancer progression [51][52][53].…”