Abstract
The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality in both sexes worldwide, with increasing incidence and mortality [1,2]
Endoglin (CD105) is a type I integral membrane-bound glycoprotein that serves as a co-receptor for members of the transforming growth factor-β (TGF-β) superfamily of proteins which has a crucial role in fibrogenesis and angiogenesis [24,68,69,70]
Most of the authors agree that the endoglin is an ideal instrument to study HCC microvessel density, i.e., it is better than the use of pan-endothelial endothelial cells (ECs) markers (e.g., CD31, CD34), as it visualises the ECs of newly formed tumour vasculature and correlates with Vascular Endothelial Growth Factor (VEGF) expression [14,15,16]
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality in both sexes worldwide, with increasing incidence and mortality [1,2]. Most works describing the role of factors stimulating the angiogenic process in human cancers (including HCC) were focused on VEGF [5,8,25]. This is understandable, as this protein appears to be the most critical angiogenic factor, and the blockade of VEGF-mediated pathways (by e.g., sorafenib) suppresses carcinogenesis and angiogenesis in HCC [5,7,8]. VEGF is the most well-studied angiogenic factor in the HCC, initiating several signalling pathways, resulting in proliferation, migration, and invasion of ECs [5] Another protein linked to the vascular endothelium was discovered in the 1990s. It is worth noting that increased endoglin expression can be observed in proliferating tumour ECs, with only small expression in resting ECs, which might be an advantage in the choice of anti-endoglin therapy
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