Human endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although endoglin is essential for angiogenesis and its expression is up-regulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in endoglin heterozygous mice (Eng^+/−) and their wild-type siblings Eng^+/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte transendothelial migration to peritoneum or lungs was significantly lower in Eng^+/− than in Eng^+/+ mice. Leukocyte transmigration through cell monolayers of endoglin transfectants was clearly enhanced in the presence of endoglin. Coating transwells with the RGD-containing extracellular domain of endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to endoglin-coated plates and to endoglin-expressing endothelial cells. This endoglin-dependent adhesion was abolished by soluble endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking.

Endoglin (ENG) is a transmembrane glycoprotein expressed on endothelial cells that functions as a co-receptor for several ligands of the transforming growth factor beta (TGF-β) family. ENG is also a recognized marker of angiogenesis and mutations in the endoglin gene are responsible for Hereditary Hemorrhagic Telangiectasia (HHT) type 1, a vascular disease characterized by defective angiogenesis, arteriovenous malformations, telangiectasia, and epistaxis. In addition to its involvement in the TGF-β family signaling pathways, several lines of evidence suggest that the extracellular domain of ENG has a role in integrin-mediated cell adhesion via its RGD motif. Indeed, we have described a role for endothelial ENG in leukocyte trafficking and extravasation via its binding to leukocyte integrins. We have also found that ENG is involved in vasculogenic properties of endothelial progenitor cells known as endothelial colony forming cells (ECFCs). Moreover, the binding of endothelial ENG to platelet integrins regulate the resistance to shear during platelet-endothelium interactions under inflammatory conditions. Because of the need for more effective treatments in HHT and the involvement of ENG in angiogenesis, current studies are aimed at identifying novel biological functions of ENG which could serve as a therapeutic target. This review focuses on the interaction between ENG and integrins with the aim to better understand the role of this protein in blood vessel formation driven by progenitor and mature endothelial cells.

Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders. Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-α (IFN-α) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified. Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.

Although the first description of salivary duct carcinoma (SDC) dates back to 1968,¹ the tumor was not officially recognized as a distinct entity by the World Health Organization until 1991.² Salivary duct carcinoma is characterized by peculiar clinical and pathologic features. Most patients are older than 40 years, with an approximate male to female ratio of 3:1. Ninety-five percent of lesions arise in the major salivary glands,³ especially the parotid,⁴ and only occasionally are the minor glands involved. The tumor can develop de novo or in a preexisting pleomorphic adenoma or polymorphous low-grade adenocarcinoma. Salivary duct carcinoma has an aggressive clinical behavior with a tendency for early facial nerve infiltration, extraparotid growth, and regional and distant spreading.⁴ The survival rate is poor, with more than 60% of patients dying of the tumor within 3 years despite aggressive treatment, generally consisting of surgical resection and radiotherapy.^4-6 The most peculiar histologic feature of this neoplasm is its resemblance to ductal carcinoma of the breast, with both intraductal (or in situ) and invasive components.