Tobias Ehnis

The Extracellular Matrix in Cellular Proliferation and Differentiationa

Originally, the extracellular matrix (ECM) had been defined as a supramolecular assembly of the structural molecules of connective tissues, comprising collagens, noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and elastin.’ In a broader but biologically meaningful sense, it is now justified to include in this definition molecules that are biochemically or functionally associated with the ECM, such as growth factors, matrix degrading proteases and their inhibitors, and matrix receptors.24 Furthermore, the majority of structural molecules of the ECM do not simply serve as a mechanical scaffold but also provide the adherent cells with clues indispensable for the complex genetic programs necessary for migration, growth, and differentiation (FIG. 1). These matrix signals lead to restructuring of the cytoskeleton and, as recognized most recently, elicit classical signal transduction pathways, with matrix receptors serving as “environmental sensor~’’.~-~ In addition, certain growth factors and cytokines may be localized and their activities modulated by their ability to bind to molecules of the ECM.”’ Taken together, the ECM may be considered a key player in pattern formation and intercellular signal transduction, both hallmarks of multicellular organisms (FIG. 2). Consequently, tumor growth and metastasis do not simply depend on the tumor cell’s potential to proliferate in response to autocrine or paracrine stimuli and to escape the host’s immune defense, but also require the ability to ignore the constraints that are usually imposed by the signals of the adjacent ECM or of cell-cell contacts. These matrix signals are three-dimensional for fibroblasts/smooth muscle cells or two-dimensional for endothelial/epithelial cells. Disruption of the normal environment triggers a wounding reaction with cell migration, matrix degradation, ECM-bound growth-factor release, cell proliferation, angiogenesis, and matrix synthesis that are aimed at repair, that is, restitution of the original tissue architecture. From a still unorthodox viewpoint, tumor cells may sense a continuous state of wounding due to their unresponsiveness to matrix signals that usually induce differentiation and quiescence. Restitution of such responsiveness, for example, by matrix receptor transfection, or by the offering of matrix signals by interactive matrix peptides, has already been shown to convert tumor cells to a benign phenotype, leading to novel strategies of pharmacological intervention in neoplasia and regeneration.

Identification of the Autoantigen of Celiac Disease

ABSTRACT: Tissue transglutaminase is demonstrated to be the unknown endomysial autoantigen by means of immunoprecipitations from a fibrosarcoma cell culture. A novel hypothesis for the pathogenesis of celiac disease is formulated: The mainly intracellular tissue transglutaminase is released from cells during wound healing where it aids in stabilizing the wound area by cross‐linking a small set of extracellular matrix components.