CD105: Key Insights on Endothelial and Tumor Dynamics

CD105, also known as endoglin, is a membrane glycoprotein primarily found on endothelial cells. It plays a crucial role in blood vessel formation and remodeling, making it significant in both normal physiology and disease. Beyond vascular biology, its expression influences tumor progression and metastasis.

Understanding CD105’s molecular interactions and functions provides insight into its potential as a biomarker and therapeutic target.

Molecular Structure And Binding Partners

CD105 is a homodimeric transmembrane glycoprotein composed of two identical subunits, each approximately 95 kDa. It belongs to the transforming growth factor-beta (TGF-β) receptor family and features a large extracellular domain, a single-pass transmembrane region, and a short cytoplasmic tail. The extracellular domain contains multiple glycosylation sites and a zona pellucida (ZP) domain, which contribute to structural stability and ligand binding.

As a co-receptor for TGF-β superfamily ligands, particularly TGF-β1 and TGF-β3, CD105 does not directly propagate intracellular signaling but regulates ligand availability and receptor complex formation. It preferentially associates with TGF-β type I receptors ALK1 and ALK5, influencing endothelial proliferation and migration. This selective interaction fine-tunes the balance between pro-angiogenic and anti-angiogenic signals.

CD105 also interacts with extracellular matrix proteins and integrins, reinforcing its role in cell adhesion and mechanotransduction. It binds to fibronectin and vitronectin, glycoproteins involved in extracellular matrix remodeling, contributing to endothelial adhesion dynamics under shear stress. Additionally, CD105 associates with β1 integrins, which are critical for cell-matrix interactions and cytoskeletal organization, enhancing endothelial responsiveness to mechanical forces.

Expression In Endothelial Cells

CD105 is predominantly expressed on endothelial cells, particularly in actively proliferating ones, underscoring its role in vascular remodeling. Immunohistochemical studies show enrichment in angiogenic tissues such as the placenta and embryonic development sites, marking it as a key indicator of endothelial activation.

Its expression varies across vascular beds, being more abundant in capillaries and venules than in arteries, reflecting its role in microvascular regulation. Endothelial cells from specialized niches, such as the bone marrow and tumor microenvironments, exhibit elevated CD105 levels, linking it to active vascular remodeling.

Shear stress from blood flow modulates CD105 expression, with higher levels under laminar flow, aiding endothelial adaptation to circulatory demands. Hypoxia is another key regulator, as demonstrated by studies in ischemic tissues. The hypoxia-inducible factor (HIF) pathway enhances CD105 transcription in low-oxygen environments.

Interaction With The TGF-Beta Pathway

CD105 modulates endothelial responses within the TGF-β signaling network. Rather than directly transmitting signals, it acts as a co-receptor, influencing ligand-receptor interactions. Its effects are particularly pronounced in endothelial cells, where it fine-tunes the balance between pro-angiogenic and growth-inhibitory signals.

By selectively associating with TGF-β type I receptors ALK1 and ALK5, CD105 influences endothelial behavior. The CD105-ALK1 interaction promotes endothelial proliferation and migration via Smad1/5/8 activation, while ALK5 activation induces Smad2/3 phosphorylation, suppressing proliferation and favoring vessel stabilization. CD105 skews signaling toward ALK1, promoting angiogenesis.

Beyond receptor binding, CD105 affects signal duration and intensity. Knockdown models reveal that CD105 loss prolongs ALK5-mediated Smad2/3 signaling, impairing vessel formation. Conversely, CD105 overexpression enhances Smad1/5/8 activation, accelerating angiogenic responses. This regulatory function is crucial for vascular homeostasis, as CD105 dysfunction is implicated in hereditary hemorrhagic telangiectasia (HHT), a disorder characterized by abnormal vessel formation.

Involvement In Angiogenesis

CD105 regulates endothelial behavior during blood vessel formation. Its expression increases in proliferating endothelial cells, particularly under hypoxic conditions driving neovascularization. Experimental models of wound healing and ischemic tissue repair show that CD105-deficient endothelial cells have impaired vessel elongation and branching.

By modulating TGF-β receptor activity, CD105 promotes endothelial proliferation while dampening inhibitory signals that restrict vascular growth. This regulation is crucial in embryonic development, where CD105 expression aligns with regions of intense vascular remodeling. In pathological conditions, CD105 levels are elevated in tumors, diabetic retinopathy, and inflammatory diseases, highlighting its role in aberrant angiogenesis.

Tumor-Associated CD105 Expression

CD105 is highly expressed in tumor vasculature, distinguishing neoplastic blood vessels from normal ones. Unlike quiescent endothelial cells with lower CD105 levels, tumor-associated endothelial cells exhibit pronounced upregulation, particularly in aggressive malignancies requiring rapid vascularization. Immunohistochemical analyses of various carcinomas, including breast, lung, and colorectal cancers, consistently show intense CD105 staining in tumor-associated blood vessels.

Some mesenchymal-origin tumors, such as sarcomas, also express CD105, suggesting a role beyond endothelial cells. CD105-positive tumor cells exhibit enhanced resistance to apoptosis and increased migration, promoting invasion and metastasis. High CD105 expression correlates with poor prognosis in several cancers, with patients showing reduced survival and higher recurrence rates.

Relevance In Diagnostics

CD105’s selective expression in proliferating endothelial cells and tumor vasculature makes it a valuable biomarker for cancer diagnostics and prognostics. Unlike traditional endothelial markers such as CD31 and von Willebrand factor, which are expressed in both normal and tumor-associated vessels, CD105 is preferentially upregulated in neoplastic blood vessels, allowing for precise tumor vascular mapping. Immunohistochemical staining for CD105 aids in assessing microvessel density (MVD) in tumor samples, with higher MVD values correlating with increased tumor aggressiveness and metastatic risk.

Beyond tissue analysis, CD105 is being explored as a circulating biomarker in liquid biopsies. Elevated levels of soluble CD105 in cancer patients’ plasma often correlate with disease stage and treatment response. This soluble form likely results from proteolytic shedding of membrane-bound CD105, reflecting tumor vascular remodeling. Monitoring CD105 levels in blood samples provides a non-invasive method for tracking tumor progression and evaluating anti-angiogenic therapies. Ongoing clinical studies are assessing its utility in predicting treatment outcomes, particularly in cancers reliant on angiogenesis-targeted therapies.