CD105 (Endoglin): A Potential Anticancer Therapeutic Inhibits Mitogenesis and Map Kinase Pathway Activation

Abstract

Background: CD105 is highly expressed on human activated endothelial cells (ECs), is an important component of the TGF-β1 receptor complex and is essential for angiogenesis. CD105 expression is up-regulated in activated ECs and is an important potential marker for cancer prognosis. Materials and Methods: In vitro rat myoblasts transfected with the L-CD105 and S-CD105 transfectants. The transfectants were treated with TGF-β1 for the angiogenesis study. Results: L-CD105 affects cell proliferation in the presence and absence of TGF-β1, and inhibits p-ERK1/2, p-MEK1/2 and p-c-Jun in L-CD105 transfectants compared to controls. The induction of phospho-ERK1/2 following treatment with TGF-β1 remained significantly lower in L-CD105 transfectants compared to controls. Conclusion: L-CD105 inhibits the phosphorylation of ERK1/2, MEK1/2, c-Jun1/2/3, and associated signalling intermediates. CD105 modulates cell growth and TGF-β1 induced cell signalling through ERK-c-Jun expression. CD105 (Endoglin) is a 180-kDa homodimeric integral transmembrane glycoprotein composed of disulphide-linked 90-95 kDa subunits and is a receptor component for TGF-β1 and TGF-β3 (1, 2). It is primarily found on activated angiogenic endothelial cells (ECs) of microvessels of cancer and numerous other angiogenic diseases (3-8). CD105 regulates a wide range of cellular and physiological responses, including embryonic development, homoeostasis, wound healing, chemotaxis, cell proliferation, differentiation, adhesion, migration, and apoptosis (4, 9-11). Overexpression of CD105 modulates TGF-β signalling by interacting with TGF-β receptor I (TGF-β RI) and/or TGFβ receptor II (TGF-β RII) on CD105 transfected L6E9 cells and human vascular smooth muscle cells through mitogenactivated protein kinases (MAPKs) (12, 13) and smallmothers-against-decapentaplegic (Smad) proteins (14, 15). Since CD105 overexpression was previously shown to be a marker of poor cancer outcome (16), and the phosphorylated ERK is a potential predictor of sensitivity to the treatment of carcinoma, as shown by various in vitro studies (17, 18), thus CD105 could be used as a potential therapy in cancer. Currently, CD105 is under phase 1 and phase 2 clinical trial in cancer patients (our and Seon et al.'s unpublished data). CD105 has two isoforms, long-form L-CD105 and shortform S-CD105 (19), both of which bind to TGF-β1 and TGF-β3. These two isoforms have contrasting roles in angiogenesis with L-CD105 being pro-angiogenic and S-CD105 inhibiting angiogenesis (20). Since L-CD105 is expressed at a markedly higher level than S-CD105 in ECs, the overall balance tends towards a pro-angiogenic phenotype in vivo (21). The expression of CD105 on ECs and other cells is upregulated by both TGF-β and hypoxia (22), but their additive effect is substantially greater than by themselves (23). Vascular lesions (telangiectasia and arteriovenous malformations) in CD105 haploinsufficient hereditary hemorrhagic telangiectasia type I (HHT1) patients are associated with a loss of the capillary network (1, 24). T...

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…This antibody, Carotuximab (TRC105), binds to the orphan domain of the extracellular domain of endoglin in proliferating endothelial cells, preventing BMP9 binding and Smad1/5/8 phosphorylation. Thus, it maintains quiescence and inhibits angiogenesis in vitro and in preclinical cancer models [140,142]. This involves BMP9 competitive inhibition as a mechanism of action of anti-endoglin antibodies [140].…”

“…This involves BMP9 competitive inhibition as a mechanism of action of anti-endoglin antibodies [140]. As well as competing with BMP-9, TRC105 induces the release of sEng via MMP-14, which can act as a ligand trap to inhibit angiogenesis [142].…”

“…In the clinic, the results obtained with TRC105 have been promising in different types of cancers, especially when combined with other antiangiogenic drugs. TRC105 has been tested in different clinical trials [142]. For example, it has been tested in phase I and II clinical trials for prostate cancer [144], hepatocarcinoma [145] and other types of solid tumors [146], and in phase III in patients with angiosarcoma, although so far no clinical benefits have been observed [147].…”