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

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		REPORTS FROM THE BATTLEFIELD: Clonal evolution is regarded as the best model by which to understand the mechanism underlying tumor progression. Each novel clone has the potential to contribute a heretofore unexpressed capacity that will confer a selective advantage to the tumor cell that expresses it. The driving force for this process is thought to be genetic instability. By constantly generating variants, instability provides the diversity that constitutes the raw material for selection. A still unanswered question is whether changes in the balance existing between the tumor and its host contribute to progression. In this issue, three papers describe different aspects of tumor-host interaction that contribute to the definition of the continual-escalation characteristic of tumor progression. Sawaoka et al (Lab Invest 1999;79:1469-N1478) present experimental data that strongly support the hypothesis that attributes to cyclooxygenase a central role in cancer growth via angiogenesis. The obvious importance of this finding is that it explains how COX inhibitors (NSAIDS) exert their antineoplastic effect. These studies show that administration of COX inhibitors lowered the expression of angiogenic factors, and inhibited the growth of COX-overexpressing xenografts in a dose-dependent manner. Tumor growth fueled by oxygen requires expansion and therefore invasion of the adjacent tissues. Thus a war for volume and territory follows the battle for oxygen. Here the escalation appears to take place between matrix constituents and the tumor cell enzymes capable of their degradation. Haroon and coworkers (Lab Invest 1999;79:1679-N1686) explore the role of tissue transglutaminase (TG) in protecting the host from tumor growth. TG is a calcium-dependent enzyme capable of cross-linking the major proteins found in the extracellular matrix, rendering them more resistant to proteolytic and mechanical damage. Their studies show that TG is synthesized by the host endothelial cells and macrophages, and that increased amounts of collagen are found in TG-treated tumors. They conclude that TG is a distinct component of the host-response mechanism against the tumor and that it acts as an inhibitor of tumor growth. An interesting question to ponder is whether TG may be one of the forces selecting for clones capable of enhanced expression of proteolytic enzymes. Confrontation between the tumor and the host is in part mediated through the immune system. Here, Gerharz and colleagues (Lab Invest 1999;79:1521-N1534) describe how renal cell carcinoma evades immune attack and how the armor deployed to stymie immune surveillance may generate resistance to cancer drugs. The data presented suggest that resistance to CD95-activated apoptosis is a key characteristic of the tumor cells in several of the histological subtypes of renal cell carcinoma. Thus rather than selecting for cells that express low levels of receptor, or synthesize soluble ligand capable of locally deleting tumor-reactive T cell clones, the cells of renal cell cancers are selected because of their nonresponsiveness to the engagement of the CD95 receptor. This resistance may not only allow the tumor cells to be insensitive to immune attack but may also explain the resistance of renal cell carcinoma to standard chemotherapeutic regimes. It is interesting to consider escalation at the host-tumor interface as a contributing factor to progression, because by gaining insight in to it, and by learning how to manipulate it, we may well reverse the outcome of the battle! Cyclooxygenase Inhibitors Suppress Angiogenesis and Reduce Tumor Growth In Vivo Hitoshi Sawaoka, Shingo Tsuji, Masahiko Tsujii, Edhi S. Gunawan, Yutaka Sasaki, Sunao Kawano, and Masatsugu Hori Tissue Transglutaminase Is Expressed as a Host Response to Tumor Invasion and Inhibits Tumor Growth Zishan A. Haroon, Thung-Shenq Lai, Joann M. Hettasch, Robert A. Lindberg, Mark W. Dewhirst, and Charles S. Greenberg Resistance to CD95 (APO-1/Fas)-Mediated Apoptosis in Human Renal Cell Carcinomas: An Important Factor for Evasion from Negative Growth Control Claus D. Gerharz, Uwe Ramp, Marion Déjosez, Csaba Mahotka, Beate Czarnotta, Ute Bretschneider, Ingrid Lorenz, Martina Müller, Peter H. Krammer, and Helmut E. Gabbert CADHERIN EXPRESSION IN CELIAC DISEASE: Inflammatory insult is a central feature of many intestinal pathologies. One condition whose etiology is now reasonably well understood is gluten enteropathy, also known as celiac disease or in older nomenclature, nontropical sprue. In susceptible patients, dietary gluten crossing the intestinal barrier incites a chronic T-cell mediated inflammatory response. The impact on the intestinal mucosa is profound, with villous atrophy, crypt hyperplasia, premature enterocyte apoptosis, and a loss of intercellular cohesion and the mucosal permeability barrier. Relevant mechanistic factors include the release by infiltrating lymphocytes of pro-inflammatory cytokines including tumor necrosis factor alpha, IL-1, interferon gamma, and TGF-beta. However, despite these understandings, the way such agents actually alter epithelial cell function remains a mystery. In this issue Perry and colleagues (Lab Invest 1999;79:1489-N1500) offer new and important observations that bear on this question. Reasoning from the premise that components of the cadherin adhesion cascade are well established as important morphoregulators of epithelial differentiation and phenotype, they examined the appearance and distribution E-cadherin and beta catenin in the small bowel biopsies of such patients. In all cases of active disease, marked reductions in the levels of these two proteins were found. With treatment, or in controls, levels were normal. These same findings could be reproduced in model systems using cultured human intestinal cells by treatment of such cultures with the cytokines TNF-alpha, IL-1, or IFN-gamma. For TNF-alpha, this effect was readily reversible, and was shown to act the level of transcription of the E-cadherin gene. Collectively, these data provide a clear mechanistic link between the inflammatory events that initiate a well defined pathologic process and the effector systems that mediate the phenotypic changes recognized as the pathologic process. These results are also interesting in a more general sense, because changes in tumor cell metastatic behavior have also been mechanistically linked with the loss of E-cadherin or alpha or beta catenin display. In the future, it will be interesting to explore whether the complex cytokine and immunologic responses that accompany many tumors may unexpectedly themselves play a role (via pathways outlined above) in mediating the aggressiveness of such tumors. Reduced Cadherin/Catenin Complex Expression in Celiac Disease Can Be Reproduced In Vitro by Cytokine Stimulation Ian Perry, Chris Tselepis, Judith Hoyland, Tariq H. Iqbal, D. Scott A. Sanders, Brian T. Cooper, and Janusz A. Z. Jankowski LAMININ-2/MEROSIN AND [ALPHA]7[BETA]1 INTEGRIN: DYNAMIC PLAYERS AT THE MYOTENDINOUS JUNCTION: Our ability to move depends upon efficient force transmission and the capability of skeletal muscle to repair and regenerate. Two critical aspects of the machinery responsible for efficient force transmission are the maintenance of mechanical stability of the myotendinous junction and the ability of newly regenerated myocytes to survive and become incorporated in the existing tissue. Over the past several years we have developed an increasingly sophisticated appreciation for the importance and complexity of the dystrophin-glycoprotein complex and selected integrins ([alpha]7[beta]1) as modulators of mechanical stability of the myotendinous junction (MTJ) and as potential signaling complexes, affecting extracellular matrix (ECM) protein synthesis and organization. Parallel to our appreciation of the importance of these two adhesion/signaling complexes, we have become cognizant of the importance of selected extracellular matrix components in maintaining structure and function of the MTJ. In this issue Miosge et al (Lab Invest 1999;79:1591-N1600) and Kuang et al (Lab Invest 1999;79:1601-N1614) demonstrate the importance of a particular integrin ([alpha]7[beta]1) and Laminin [alpha] chain ([alpha]2) expression in the biology of the MTJ and their importance in our understanding of muscular dystrophies and future molecular-based therapies. Miosge and colleagues couple knockout technology with an immuno-morphological approach to investigate the role of [alpha]7[beta]1 integrin in the MTJ. Their findings of altered organization of MTJ interdigitations, retracted myofilaments from the sarcolemmal membranes, and loss of Laminin-2/merosin from the MTJ are consistent with the concept that [alpha]7[beta]1 is a major receptor connecting muscle cells to tendons and functions as a stabilizer of the MTJ. In addition it raises the possibility that, as a potential organizer of Laminin-2/merosin, loss of [alpha]7[beta]1 could influence the organization of the ECM, which could affect several aspects of skeletal muscle behavior. The notion that ECM components/organization are modulators of cellular behavior is well-founded and Kuang et al explore this possibility utilizing homozygous and heterozygous Laminin-2 mutant mice and the lacZ gene as a reporter for the lama2 gene. In their studies they find that the absence of Laminin [alpha]2 chain has no apparent effects in the perinatal period, however homozygous mice develop muscular dystrophy at 2-N3 weeks of age and express high b-galactosidase activity in contrast to heterozygous mice, which display no such activity. In addition, following induction of injury, both homozygous and heterozygous mice exhibit intense expression of [beta]-galactosidase-positive cells, however, only the heterozygous mice exhibit tissue repair and a decline of [beta]-galactosidase activity. Homozygous mice were found to exhibit poor repair due to excessive cell death of the newly-regenerated myofibers. Interestingly, injured homozygous mice expressing a human Lama2 gene exhibit efficient muscle repair. These studies illustrate a survival/maintenance role for Laminin-2/merosin as satellite cells are induced to develop into new myocytes. Thus, these two reports illustrate the dynamic, complex interactions between integrins and ECM components as modulators of cellular behavior in general and at the MTJ in particular and potentially may aid in the future development of molecular-based therapies for the muscular dystrophies and related diseases. Organization of the Myotendinous Junction is Dependent on the Presence of [alpha]7[beta]1 Integrin Nicolai Miosge, Christina Klenczar, Rainer Herken, Michael Willem, and Ulrike Mayer Activation of the lama2 Gene in Muscle Regeneration: Abortive Regeneration in Laminin [alpha]2-Deficiency Wen Kuang, Hong Xu, Jean-Thomas Vilquin, and Eva Engvall S19 DIMERS LINK APOPTOSIS TO IMMUNITY: Cells undergoing apoptosis form covalently cross-linked dimers of ribosomal subunit protein S19. Remarkably, S19 dimers, but not monomers, bind to the leukocyte receptor for the C5a fragment of the complement system, activating monocyte chemotaxis but inexplicably inhibiting neutrophil chemotaxis. What can monocytes do that neutrophils cannot? One answer is that they can present new antigens to the immune system. In this issue (Lab Invest 1999;79:1629-N1642), Shrestha and colleagues show that apoptotic human HL-60 cells, but not necrotic HL-60 cells, can recruit monocytes into the skin of guinea pigs or rabbits where these monocytes phagocytose the apoptotic cells and, via lymphatics, transport them to draining lymph nodes where an immune response, measured by specific IgM antibody against HL-60 cell antigens, ensues. Monocyte recruitment to the skin and all of the subsequent events were blocked by a neutralizing antibody to S19 dimers formed by the apoptotic HL-60 cells. One can speculate that the apoptotic human cells behave the same way that host cells, induced to undergo apoptosis in response to microbial infection, would behave, providing a mechanism for the immune system to recognize microbial antigens that are clever enough to avoid infecting professional antigen presenting cells, such as dendritic cells or monocytes. This phenomenon, which immunologists have called "cross-priming," allows the immune system to recognize pathogens that do not cause inflammation. The work of Shrestha and colleagues is perhaps the most detailed in vivo visualization of cross-priming to date. Acquired Immune Response as a Consequence of the Macrophage-Dependent Apoptotic Cell Clearance and Role of the Monocyte Chemotactic S19 Ribosomal Protein Dimer in This Connection Arjun Shrestha, Kei Horino, Hiroshi Nishiura, and Tetsuro Yamamoto