The United States and Canadian Academy of Pathology Lippincott Williams and Wilkins publishes Laboratory Investigation

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		SETTING THE PACE FOR GASTROINTESTINAL STROMAL TUMORS: There has been a burst of interest in the possible role of the Interstitial Cells of Cajal (ICC) as the cells of origin for gastrointestinal stromal tumors (GIST). The ICC form a complex cell network within the muscle wall of the gut and function as a muscular pacemaker system (Am J Physiol 1998;275:G1­7). The tyrosine kinase receptor kit, a proto-oncogene, is an established marker for ICC, although its expression is not limited to this cell type. Kit function is required for expression of the slow wave activity of ICC. In a recent report, a large series of GIST was found to exhibit strong immunoreactivity for both the kit receptor and for CD34, a sialylated transmembrane glycoprotein found in mesenchymal cells and often positive in GIST (Am J Pathol 1998;152:1259­1269). Immunoreactivity for both markers resided in a ramifying network of tumor cells, as would be expected for ICC. In a second report, several GIST were found to exhibit gain-of-function mutations of kit. The mutant kit tyrosine kinase receptors were constitutively activated in the absence of the kit ligand, stem cell factor, and stable transfection of the mutant kit cDNAs into murine lymphoid cells induced malignant transformation (Science 1998;279:577­580). The concept that GIST originate from the ICC lineage was thus advanced. In this month's issue of Laboratory Investigation, Vanderwinden and colleagues (Lab Invest 1999;79:59­66) clearly demonstrated, in confocal optical sections of normal intestinal muscle, that CD34 and kit immunoreactivity reside in closely adjacent, but not overlapping, cell populations. The CD34-positive cells expressed the fibroblast marker prolyl 4-hydroxylase, whereas kit-positive ICC did not. This finding corroborates electron microscopic observations that fibroblast-like cells are encountered close to ICC at all levels of the intestine and may be an integral part of ICC bundles. Although the current study was not undertaken to study the ontogeny of GIST, the striking finding of adjacent, rather than overlapping, immunoreactivity for fibroblast and ICC markers challenges the hypothesis of an ICC origin of GIST. Instead, this study opens the issue that somatic mutation of kit may represent part of the oncogenic process, rather than an indication of ICC origin per se. This position is supported by the recent finding that CD117, the c-kit proto-oncogene product, is in fact a more specific marker for GIST than is CD34 (Mod Pathol 1998;11:728­734). Although high-resolution confocal microscopy studies of GIST are now clearly called for, it is evident that our molecular understanding of these heretofore ill-defined tumors is undergoing a rapid and welcome evolution. CD34+ Cells in Human Intestine Are Fibroblasts Adjacent to, but Distinct from, Interstitial Cells of Cajal Jean-Marie Vanderwinden, Jüri J. Rumessen, Marc-Henri De Laet, Jean-Jacques Vanderhaeghen, and Serge N. Schiffmann GUT PERMEABILITY IN CROHN'S DISEASE: The pathogenesis of idiopathic inflammatory bowel disease is unclear, but is thought to involve an abnormal host inflammatory response to environmental antigens. Access of luminal antigens to the host immune system may occur via disruption of the integrity of mucosal epithelium. For years, it has been known that patients with Crohn's disease, and their unafflicted family members, can exhibit increased intestinal permeability to orally administered test substances. The hypothesis has thus been advanced that genetic defects in intestinal integrity may expose the gut immune system to abnormal levels of environmental antigens. In the current issue, Fries and coworkers (Lab Invest 1999;79:49­58) used a model of chemical-induced colitis to examine the effect of colonic inflammation on small intestinal tight junctional permeability. This was based on the hypothesis that tight junctional alterations, observed in patients with Crohn's disease (and their family members), are secondary to intestinal inflammation, rather than a primary defect. Trinitrobenzenesulphonic acid treatment of the distal colon in rats induced a distal colitis, and small intestinal permeability and ultrastructure were examined. There were marked alterations in duodenal and ileal paracellular permeability, but no ultrastructural changes in tight junctions could be documented. This study did not elucidate the basis for the changes in paracellular permeability, nor did it define how the distal colitis influences the function of proximal small intestine. However, the study clearly raised the possibility that the heretofore presumed genetic "susceptibility" to increased intestinal paracellular permeability in human patients and family members may in fact be an epiphenomenon of incipient or clinically-evident distal intestinal inflammation. Experimental Colitis Increases Small Intestine Permeability in the Rat Walter Fries, Emanuela Mazzon, Stefano Squarzoni, Alessandro Martin, Diego Martines, Antonio Micali, Giacomo Carlo Sturniolo, Sandra Citi, and Giuseppe Longo PROTEASE-INHIBITOR STOICHIOMETRY IN ASTHMA: Asthma, a disease characterized by hyper-reactivity and chronic inflammation of the airways, gives rise to subepithelial fibrosis of the airways characterized as thickening of the basement membrane zone by deposition of reticular collagen. This peribronchial fibrosis is thought to be a manifestation of a cytokine-mediated dysregulation of extracellular matrix remodeling. Specifically, the development of peribronchial fibrosis can be the result of increased synthesis of one or more extracellular matrix components (collagens, elastin, glycoproteins, proteoglycans, etc.), net decreased synthesis, and/or activities of extracellular matrix degrading proteases involved in extracellular matrix remodeling (matrix metalloproteinases). There is evidence suggesting that both extracellular matrix synthetic and degradative pathways are dysregulated in chronic asthma. In this issue of Laboratory Investigation, Mautino and colleagues (Lab Invest 1999;79:39-48) demonstrated a cytokine-mediated dysregulation of alveolar macrophage tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and its stoichiometry with matrix metalloproteinase-9 (MMP-9) in untreated asthmatics. These findings add to our growing appreciation of the importance of precise, continual, multilevel control of proteolysis during homeostasis and the consequences of its dysregulation in response to chronic inflammatory stimuli. The dynamic interactions (stoichiometries) of TIMPs with MMPs, as exemplified in this report, have also been shown to be pivotal in controlling several proteolytic events at the cell surface, including tethering and activation of MMP-2 by MT1-MMP and cleavage of adhesion receptors in addition to their importance in controlling extracellular matrix degradation. In light of this and other studies illustrating the importance of proteolytic balance in homeostasis and during disease development, the proposed use of synthetic inhibitors of MMPs in a variety of diseases should be re-examined for the possibility that these compounds may affect TIMP\NMMP levels, interactions, and stoichiometry. The generation and use of TIMP-1 and MMP transgenic and knock out mice has and will continue to facilitate our understanding of the roles these molecules play in a variety of normal and pathological processes. The future use of these and other genetically altered mice in experimental models of asthma has the potential of furthering our understanding of these important molecules in the pathogenesis of the fibrosis associated with asthma. Increased Expression of Tissue Inhibitor of Metalloproteinase-1 and Loss of Correlation with Matrix Metalloproteinase-9 by Macrophages in Asthma Gisèle Mautino, Corinne Henriquet, Claire Gougat, Alphonse Le Cam, Jean-Michel Dayer, Jean Bousquet, and Françoise Capony SERVICE AFTER RETIREMENT: >Marginal zone lymphoma (MZL) of the spleen is rare in both mice and man, and its pathogenesis is poorly understood. The careful study by Ward and co-workers, appearing in this issue (Lab Invest 1999;79:3­14), sheds light on the molecular pathogenesis of this type of lymphoma by demonstrating that loss of p53 function can be the rate limiting event for the causation of MZL in mice. New Zealand black mice, deficient in p53 function, were known to be prone to develop thymic lymphomas. By observing and studying retired breeder p53 deficient mice, Ward et al have observed a second type of lymphoproliferative disorder, namely splenic MZL, suggesting that lack of p53 function predisposes the marginal zone lymphocyte to transformation. The fact that this specific form of lymphoma is seen in colonies of retired breeder p53 deficient mice indicates that the cumulative genetic alterations, yet to be defined and leading to transformation of the marginal zone lymphocytes, require a prolonged life span. One can speculate that prolonged exposure to T independent antigens stimulates expansion of the marginal zone lymphocytes and causes expansion of clones of lymphocytes that are accumulating genetic alterations. It is not unexpected that a functional deficiency of the p53 gene, a "caretaker gene" would result in an increased rate of accumulation of mutations. The fact that NZB mice are prone to autoimmune disease could also be a factor in the pathogenesis of murine MZL. Splenic Marginal Zone B-Cell and Thymic T-Cell Lymphomas in p53-Deficient Mice Jerrold M. Ward, Lekidelu Tadesse-Heath, Susan N. Perkins, Sisir K. Chattopadhyay, Stephen D. Hursting, and Herbert C. Morse III