The results of predominantly retrospective series suggest that for certain persons (patients with SLE or closely related disorders) antiphospholipid antibodies may be important risk factors for thrombosis, neurologic disease, thrombocytopenia, and fetal loss. Standardized tests for lupus anticoagulant and anticardiolipin, as well as long-term, prospective clinical studies, are needed to determine the prognostic value of antiphospholipid antibodies.

No abstract

Endorepellin, the COOH-terminal domain of the heparan sulfate proteoglycan perlecan, inhibits several aspects of angiogenesis. We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen I, α2β1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and α2β1 integrin triggers a unique signaling pathway that causes an increase in the second messenger cAMP; activation of two proximal kinases, protein kinase A and focal adhesion kinase; transient activation of p38 mitogen-activated protein kinase and heat shock protein 27, followed by a rapid down-regulation of the latter two proteins; and ultimately disassembly of actin stress fibers and focal adhesions. The end result is a profound block of endothelial cell migration and angiogenesis. Because perlecan is present in both endothelial and smooth muscle cell basement membranes, proteolytic activity during the initial stages of angiogenesis could liberate antiangiogenic fragments from blood vessels' walls, including endorepellin.

Abstract. We have purified the platelet membrane glycoprotein Ia-IIa complex by detergent solubilization and sequential affinity chromatography on Concanavalin A-Sepharose and collagen-Sepharose. The complex, which is identical to the VLA-2 complex of lymphocytes and other cells and contains subunits of 160 and 130 kD on SDS-PAGE, was labeled with ~25I and incorporated into phosphatidyl choline liposomes. The liposomes, like intact platelets, adhered to collagenous substrates in an Mg~-dependent manner with a K'tM~ of 3.5 mM. Little adhesion of the liposomes to collagen occurred when Mg +÷ was replaced by Ca ++ or EDTA. Calcium ions inhibited the Mg +÷-dependent adhesion with a K'tca.+~ of 5.5 mM. Liposomes containing the Ia-IIa complex adhered to substrates cornposed of types I, II, III, and IV collagen, but did not effectively adhere to substrates composed of type V collagen or gelatin. Adhesion to collagen was specific. The liposomes did not adhere to fibronectin, vitronectin, laminin, thrombospondin, fibrinogen, or von WiUebrand factor substrates. The monoclonal antibody P1H5, which specifically immunoprecipitated the Ia-IIa complex, also specifically inhibited the Mg ++-dependent adhesion of both platelets and Ia-IIacontaining liposomes to collagen substrates. These findings provide additional evidence that the platelet membrane Ia-IIa complex is the mediator of Mg ++-dependent platelet adhesion to collagen and suggest that the VLA-2 complex may also function as an Mg++-dependent collagen receptor in other cells.

To assess the role of altered a2I18 integrin expression in breast cancer, we expressed the a2d31 integrin de novo in a poorly differentiated mammary carcinoma that expressed no detectable a2-integrin subunit. Expression of the a2131 integrin resulted in a dramatic phenotypic alteration from a fibroblastoid, spindle-shaped, non-contact-inhibited, motile, and invasive cell to an epithelioid, polygonal-shaped, contact-inhibited, less motile, and less invasive cell. Although expression of the a2 subunit did not alter adhesion to collagen, it profoundly altered cell spreading. Re-expression of the a2.1 integrin restored the ability to differentiate into gland-like structures in three-dimensional matrices and markedly reduced the in vivo tumorigenicity of the cells. These results indicate that the consequences of diminished a281-integrin expression in the development of breast cancer and, presumably, of other epithelial malignancies are increased tumorigenicity and loss of the differentiated epithelial phenotype.The role of the integrin family of heterodimeric transmembrane glycoproteins in mediating cell-cell or cell-extracellular matrix adhesion is now well established (1, 2). Viral or chemical oncogenic transformation of cells in culture results in altered morphologic phenotype and increased invasive activity accompanied by changes in integrin expression, suggesting that changes in integrin expression might contribute to changes in cell phenotype associated with malignant transformation (3, 4).The a23i integrin functions as a collagen receptor on platelets and fibroblasts and as both a collagen and laminin receptor on endothelial cells and most epithelial-cell types (5-7). In earlier immunohistochemical studies, we observed that the a231 integrin was expressed by the majority of epithelial cell types, including those of the skin, breast, lung, gastrointestinal system, and genitourinary tracts (8). The high level of a2f3i integrin expression by normal breast ducts and ductules was diminished in moderately differentiated carcinoma and markedly reduced or undetectable in poorly differentiated adenocarcinoma of the breast at both the protein and mRNA levels (9, 10). Others have confirmed that a21l-integrin expression is diminished or absent in adenocarcinoma of the breast and in other epithelial malignancies (11).To characterize the role of the a2131 integrin in breast epithelial morphogenesis and the contribution of lost a2131 expression to the malignant and invasive phenotype of mammary carcinoma cells, we re-expressed the a2131 integrin on poorly differentiated breast carcinoma cells lacking endogenous a2I31 integrin. Re-expression of the a211 integrin dramatically restored to the malignant and invasive carcinoma cells a phenotype typical of normal breast epithelial cells. We conclude that the loss of a23l-integrin expression in breast cancer directly contributes to enhanced tumorigenicity and loss of tumor-cell differentiation.