Importance of activated hepatic stellate cells and angiopoietin-1 in the pathogenesis of hepatocellular carcinoma

Abstract

Previous studies have determined that activated hepatic stellate cells (aHSCs) promote the progression of hepatocellular carcinoma (HCC) by increasing angiogenesis in cancerous tissues. In addition, angiopoietin 1 (Ang‑1) has been reported to be involved in tumor growth and metastasis via the promotion of angiogenesis. It remains unclear whether aHSCs and Ang‑1 are involved in the angiogenesis in HCC. A total of 25 HCC and tumor‑adjacent tissues, and 21 normal liver tissues were used in the present study. Immunohistochemistry (IHC) was used to detect the expression of Ang‑1 and α smooth muscle actin (α‑SMA). The expression of CD34 was also analyzed using IHC to evaluate the microvessel density (MVD). The protein expression levels of Ang‑1 were evaluated using western blot analysis. The association between aHSC, Ang‑1 and angiogenesis was determined using Spearman's rank correlation coefficient. The present study determined that the expression of α‑SMA, Ang‑1 and MVD (CD34) was significantly higher in the HCC tissues when compared with tumor‑adjacent tissues and normal liver tissues. Spearman's rank analysis identified a positive correlation between the expression of α‑SMA, Ang‑1 and CD34. This suggests that α‑SMA‑positive aHSCs promoted angiogenesis by expressing Ang‑1, resulting in the proliferation and metastasis of HCC.

Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma

“…1). Lin et al and Fang et al also detected α-SMA-positive cells in the cancer cell nest, hepatic blood sinus, and sporadic HCC cells [25, 26]. However, because CAFs lack specific protein markers, we can only observe the exact tissue distribution of some CAFs by immunohistochemistry; therefore, searching for more specific markers will be beneficial for improving our knowledge of the location of CAFs in the TME and increasing their accessibility.…”

The Angiopoietin/Tie2 Pathway in Hepatocellular Carcinoma

“…Lin et al also observed Ang-1 overexpression in HCC tissue. As previous studies had reported that HCC progression is promoted by activated hepatic stellate cell (HSC)-mediated microvessel formation, and the expression of Ang-1 was positively correlated with the MVD and α-smooth muscle actin (α-SMA) expression, the authors suggested that activated HSCs mediate angiogenesis through the upregulation of Ang-1 expression and, thereby, promote HCC growth and metastasis [44]. An obvious shortcoming of this study is the fact that the authors did not determine the intratumoral Ang-2 expression and, thus, had no insight into the quantitative balance between both Ang subtypes, and the resultant nature and magnitude of the Ang/Tie2 signal.…”

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

“…In response to the TME of HCC, HSCs undergo phenotypic transformation from quiescent to activated or transdifferentiated states, thus leading to morphological, behavioral, and biochemical changes. Generally, activated HSCs (a-HSCs) express pro-angiogenic factors, including VEGFA, PDGFB, and Angs, which promote angiogenesis by binding their cognate receptors on the surfaces of ECs 81 , 82 . Recently, several novel mechanisms associated with a-HSC-mediated angiogenesis have been reported.…”