The Role of Endoglin in Hepatocellular Carcinoma

Abstract

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-β (TGF-β) ligands. The endoglin/TGF-β signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.

Keywords: angiogenesis; endoglin; hepatocellular carcinoma.

Figure 1

Endoglin and transforming growth factor-β (TGF-β) signaling in hepatocellular carcinoma (HCC). Endoglin binds to TGF-β1 by linking with TGF-β type II receptor activin receptor-like kinase 1 (ALK1). This leads to downstream SMAD family member 1/5 (SMAD1/5) phosphorylation with SMAD4, increasing EC proliferation, migration, and angiogenesis. This process results in HCC progression, invasion, and metastasis. In addition, endoglin-mediated fibronectin/α5β1 integrin demonstrates crosstalk with the TGF-β pathway to facilitate capillary stabilization and increase angiogenesis. Conversely, endoglin binds to TGF-β1/3 by associating with TGF-β type II receptor (ALK5). This behavior activates SMAD2/3 phosphorylation with SMAD to promote extracellular matrix (ECM) synthesis.

Figure 2

A schematic of endoglin structure. The soluble endoglin (sol-endoglin), short isoform endoglin (S-endoglin) and long isoform endoglin (L-endoglin). Relevant domains such as the extracellular domain (ECD), transmembrane domain (TM), cellular domain (CD) and phosphorylation sites by TGF-βII and ALK1 are indicated.