Hyperacute reaction.

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.

Antibodies↗

PubMed1996

Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium.

The predominant early histological changes in irradiated tissues are edema and leukocyte infiltration. Cell adhesion molecules (CAMs) are required for the extravasation of leukocytes from the circulation. To study the role of CAMs in the pathogenesis of radiation-mediated inflammation, we quantified the expression of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 glycoproteins on the surface of irradiated human endothelial cells. We found that E-selectin and ICAM-1 expression increased after irradiation, whereas there was no increased expression of other cytokine-inducible adhesion molecules (P-selectin or vascular cell adhesion molecule-1). We found a dose- and time-dependent increase in radiation-induced expression of both E-selectin and ICAM-1. Furthermore, the threshold dose for E-selectin expression was 1 Gy, whereas the threshold dose for ICAM-1 synthesis was 5 Gy of X-rays. Northern blot analysis of RNA from irradiated endothelial cells demonstrated that ICAM-1 is expressed at 3-6 h following irradiation. No de novo protein synthesis was required for increased ICAM-1 mRNA expression. The 1.1-kb segment of the 5' untranslated region of the ICAM-1 gene was sufficient for X-ray induction of chloramphenicol acetyltransferase reporter gene expression. We measured whether ICAM-1 mediates adhesion of leukocyte to the irradiated endothelium and found that leukocyte adhesion occurred concurrently with ICAM-1 induction. Radiation-mediated leukocyte adhesion was prevented by anti-ICAM-1 blocking antibodies. These data indicate that ICAM-1 participates in the inflammatory response to ionizing radiation. Moreover, radiation induction of these CAMs occurs in the absence of tumor necrosis factor and interleukin 1 production.

Antibodies↗

PubMed1996

bFGF stimulates U937 cell adhesion to fibronectin and secretion of gelatinase B.

U937 cells are an immature monocytic cell line which has been used to study monocyte differentiation. For example, phorbol ester differentiation of U937 cells results in both an increase in adhesion to fibronectin through alpha 5 beta 1 integrin and the ability to degrade extracellular matrix (ECM) proteins through the secretion of gelatinase B (1, 2). The ability of monocytes to adhere to and degrade ECM molecules is fundamental to their localization at sites of inflammation and tissue damage. Here we find that bFGF treatment of U937 cells results in a six-fold increased adhesion to fibronectin. Further, monoclonal antibodies to alpha 5 or beta 1 integrin block the bFGF induced adhesion to fibronectin. bFGF also stimulated U937 cell secretion of a 92 kDa gelatinase which was identified by immunoblot to be gelatinase B. These data are the first to suggest a role for bFGF as an immunomodulatory factor during the early stages of inflammation.

Antibodies↗