Editor's choice: Targeting cancer vasculature via endoglin/CD105: a novel antibody-based diagnostic and therapeutic strategy in solid tumours
Endoglin (CD105), a vascular target within the TGF-β receptor complex
CD105 is a homodimeric transmembrane protein that belongs to the TGF-β receptor complex and plays a key role in angiogenesis. Its expression is highly restricted to endothelial cells where its levels affect the response to TGF-β by modulating key cellular processes including proliferation, differentiation, and migration. Through its interactions with the TGF-β receptors type I and II, CD105 regulates their phosphorylation status and signalling ability. In endothelial cells, TGF-β activates two type I receptor pathways with opposite effects: ALK-5, which induces the phosphorylation of the intracellular mediators Smad 2/3, and ALK-1, which promotes the phosphorylation of Smad 1/5. CD105 binds TGF-β by associating with its type II signalling receptors: this tri-molecular complex activates endothelial cells via ALK-1 or inhibits their proliferation and migration via ALK-5.
Downstream signals include phosphorylation of Smads, which form heteromeric complexes with the common mediator Smad 4 and accumulate in the nucleus, acting as transcription factors regulating the expression of target genes. Based on its biological features and on its overexpression on highly proliferating tumor-associated endothelial cells, CD105 represents a powerful vascular target for cancer therapy. Along this line, anti-CD105 monoclonal antibodies are under investigation within phase I/II trials in metastatic cancer patients with promising evidence of clinical activity.
Abbreviations: TGF-β, transforming growth factor-β; ALK1, activin receptor-like kinases-1; ALK5, activin receptor-like kinases-5; ECs, endothelial cells; TβR-II, TGF-β receptor type II.
Schematic diagram of strategies for site-targeted imaging of stem/progenitor cells using contrast-enhanced ultrasound (CEU)
With the rapid progression of research into stem or progenitor cell therapy, there is a growing need to develop imaging modalities to track progenitor cells in vivo after their delivery. The ability to track delivered cells using contrast-enhanced ultrasound (CEU) has only been recently investigated. This schematic diagram shows the potential strategies for CEU-targeted imaging of stem/progenitor cells, such as endothelial progenitor cells (EPCs). One strategy involves alteration/transfection of EPCs to express a specific marker protein on the cell surface. Microbubbles (MB) targeted to engrafted EPCs could be constructed by the attachment of the ligand/antibody targeted against the specific cell surface marker protein on the microbubble surface (left panel, inset). When this EPC-targeted MB is administered intravenously, the MBs circulate to target sites where they can bind to EPCs that are engrafted within the vasculature and subsequently be imaged by CEU imaging techniques. The other described strategy involves manipulating EPCs to fully engulf MB prior to cell delivery. Once delivered and engrafted, ultrasonic imaging could then detect MBs present and retained within engrafted EPCs (right panel, inset). Future work will likely focus on 1) the refinement of these two strategies; 2) pre-clinical testing in relevant animal models of disease, and 3) the development of new techniques for progenitor cell-targeted CEU imaging.
Abbreviations: MB – microbubble; EPC – endothelial progenitor cell; PEG – polyethylene glycol; CEU – contrast-enhanced ultrasound
The relationship between glomerulus and epicardium has been postulated via pro-epicardial cells. Pro-epicardium gives rise to epicardial progenitor cells. Epicardium has an essential modulating role in the differentiation of the compact ventricular layer of the myocardium and the development of cardiac vessels. Moreover, the epicardial progenitor cells have been shown to differentiate into the pronephric external glomerulus (PEG), a structure composed of capillary networks, mesangial cells, and podocytes in vertebrates.