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

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		PINK AND GRANULAR COMES IN TWO FLAVORS. WHAT DOES CGH SEE THAT WE DON`T? A characteristic oncocytic appearance is a striking phenotypic feature of some epithelial tumor types. The causes and significance of the appearance are still poorly understood. Is it a feature with little significance or is it an essential characteristic of the tumor cell that tells us something important about the origin and life history of the tumor? Studying oncocytomas from a variety of angles can perhaps assemble a body of data upon which we can build a clever hypothesis, one that, when pursued, will yield a construct that will illuminate the pathogenesis of oncocytomas. In this issue (Lab Invest 1999;79:547-556) Tallini et al apply comparative genome hybridization to the study of both benign and malignant thyroid oncocytic neoplasms. Their observations are of interest. First, there is no clear difference in the genomic unbalance profile between benign and malignant thyroid oncocytic tumors. Second, based on CGH abnormalities, there are two distinct groups of lesions but clinically and pathologically they appear indistinguishable. Clearly CGH detects a difference that remains to be confirmed and calls for a hypothesis. The easiest explanation is that the difference(s) resides in the pathway of progression. Two independent pathways lead to an identical clinicopathological picture. Why bother with the pathways? There are at least two good reasons to identify distinct routes of independent tumor progression. The first is that some of the steps may constitute realistic targets for therapeutic intervention, and if the steps are early enough, they may be of interest for prevention. The second is that the choice of pathway may not be random but dictated by the etiology of the tumor. It would indeed be of interest if epidemiologists found two clearly distinguishable sets of risk factors for the two distinct CGH categories. Strengthening the thought that "pink and granular is special" is the fact that mutations in the Ki-ras gene, frequent in thyroid cancer, appear to be unusual in oncocytic tumors. Frequent Chromosomal DNA Unbalance in Thyroid Oncocytic (Hürthle Cell) Neoplasms Detected by Comparative Genomic Hybridization Giovanni Tallini, Aileen Hsueh, Steven Liu, Ginesa Garcia-Rostan, Michael R. Speicher, and David C. Ward MORPHOGEN NOT MOTOGEN: TFF2 REVEALED: Ulceration of the gastrointestinal track, whether by infection, physical or chemical agent, or inflammatory condition, presents an ominous and unique challenge to the barrier function of the gut and the health of the organism. With ulceration, a complex cascade of cellular regeneration, differentiation, and migration is activated that involves all constituents of the gut wall. Understanding this process at the molecular level remains a central challenge. While many growth factors participate, a group of factors less studied but likely to play a central role in mediating mucosal repair are the trefoil factors. The trefoil factors are a group of small (50 to 100 residue) secreted proteins first recognized for their appearance in epithelial tumors and gastrointestinal ulcers and now named for the unique 38 or 39 amino acid "trefoil" disulphide loop structure that they share. Three variants are recognized: TFF1 (pS2); TFF2 (human spasmolytic polypeptide, hSP); and TFF3 (intestinal trefoil factor). Constitutively expressed in most epithelial tissues, they are particularly prominent in the gastrointestinal tract where they associate with the mucin layer. Their role has long been somewhat of a mystery, although it is clear that these peptides are up-regulated in ulcers and appear to be necessary for proper healing of ulcerations in the gastrointestinal track. Although TFF1 knock-out mice do develop intestinal tumors with increased frequency, the more direct role of TFF1 appears to be to stimulate cellular spreading and motility. TFF3 also possesses motogenic activity, but perhaps more importantly it down-regulates the expression of the tumor suppressor genes APC (adenomatous polyposis coli) and beta-catenin, thereby linking its expression to a loss of tumor suppression. In this issue, Gordon Stamp and his colleagues present evidence for a specific role for TFF2 (Lab Invest 1999;79:537-546). Using the cultured breast cell line MCF-7, they find that even low concentrations of TFF2, when applied in the presence of TFF1, induce the formation of complex branched tubular like structures. Coincident with this remarkable morphogenic effect, TFF2 suppressed apoptosis by 30%. This novel action of TFF2, when considered with the motogenic actions of TFF1 and the growth stimulating action of TFF3, is thus a large step in building a comprehensible view of how the mucin associated trefoil factors act to maintain the epithelial barrier of gastrointestinal track and other glandular tissues. Trefoil Factor-2, Human Spasmolytic Polypeptide, Promotes Branching Morphogenesis in MCF-7 Cells El Nasir Lalani, Ross Williams, Yogi Jayaram, Chris Gilbert, Khurram S. Chaudhary, Lai-San Siu, Anna Koumarianou, Ray Playford, and Gordon W.H. Stamp PLEOMORPHIC ADENOMA ONCOGENES Pleomorphic salivary gland adenomas are the most common salivary tumors and have characteristic karyotypic abnormalities. The most common rearrangement, t(3:8)(p21;q12), affects PLAG1 (pleomorphic adenoma gene 1; 8q12), which encodes a zinc finger-containing transcription factor, and CTNNB1 gene, which encodes [beta]-catenin. The translocation results in a "promoter swap" that places PLAG1 coding sequences under CTNNB1 control, and vice versa. A second, less frequent translocation partner for PLAG1 is the leukemia inhibitory factor receptor (LIFR; 5p13). A final set of translocations, involving 12q13-15, affects the high mobility group protein gene HMGIC. Since both [beta]-catenin and transcription factors are common targets for oncogenic mutations, the 3:8 translocation might logically work by activating either one or both of the affected genes. Circumstantial evidence indicates that the PLAG1 alteration is preeminent. The majority (60%) of 8q12 alterations involve translocation partners other than CTNNB1, so the common feature is alteration of PLAG1. Adenomas with either 3:8 or 5:8 translocations show elevated transcription of PLAG1 coding exons but reduced or extinguished expression of the translocation partner. Queimado and colleagues have now analyzed PLAG1 expression in cells from benign and malignant salivary gland tumors (Lab Invest 1999;79:583-590). Surprisingly, PLAG1 mRNA was present in all material derived from salivary gland tumors, regardless of the presence of 8q12 rearrangements, but it was not expressed in normal salivary tissue. This means that there may be a variety of mechanisms that promote expression of PLAG1 in salivary adenomas and implies that selection of overexpression is important in etiology of these tumors. This is an exciting juncture in the genetic elucidation of salivary neoplasms, with at least four candidate oncogenes identified. However, major issues remain to be resolved, including, for PLAG1, the means for transcriptional activation in translocation negative tumors, the nature of the target genes, and the significance of multiple spliced forms. Characterization of any of the pleomorphic adenoma oncogenes at the level of protein abundance and regulation is a critical next step. Pleomorphic Adenoma Gene 1 is Expressed in Cultured Benign and Malignant Salivary Gland Tumor Cells Lurdes Queimado, Carla Lopes, Fenghe Du, Carmo Martins, Anne M. Bowcock, Jorge Soares, and Michael Lovett ARE GRO AND IL-8 FUNCTIONALLY REDUNDANT? The chemokine (chemotactic cytokine) family was originally described as a group of structurally homologous small protein mediators of leukocyte recruitment into inflammatory reactions. Chemokines have recently been identified as participants in cell migration during embryogenesis. One of the oldest known chemokines is Gro-[alpha], a close structural relative of the neutrophil recruiting chemokine IL-8. Whereas IL-8 was initially identified as a neutrophil-selective inflammatory mediator, Gro was originally discovered as a mitogen for melanoma cells. However it quickly became apparent that Gro could replace IL-8 as a neutrophil chemotaxin in vitro, binding to one of the two known IL-8 receptors. On the other hand, to date Gro has not been significantly implicated in inflammatory processes in vivo. In the present issue of the journal, Matsukawa and colleagues fill in this gap (Lab Invest 1999;79:591-600). Using new reagents that can clearly distinguish between Gro and IL-8 in rabbits, these investigators demonstrate that not only is Gro expressed in an LPS-arthritis model, but that inhibition of Gro is every bit as effective as inhibition of IL-8 as an anti-inflammatory therapy. Why are both molecules made? The usual explanation for multiple chemokines being synthesized in a pathological process is that different chemokines act on overlapping but distinct cell types. There is as yet no evidence that this is true for Gro and IL-8, although it is formally possible that each chemokine recruited different subsets of neutrophils for which there are as yet no distinguishing markers. It also remains to be determined whether these two chemokines are truly interchangeable in other settings, ie, whether Gro will be involved in all of the disease models and processes currently thought to depend primarily on IL-8. The present study makes an additional point: even when two chemokines appear functionally redundant, two agents may be better than one because neutralization of either chemokine was less effective than neutralization of both chemokines together. Finally, the fact that even double neutralization did not completely inhibit neutrophil recruitment raises the specter of yet additional chemokines contributing to neutrophil recruitment. Involvement of Growth-Related Protein in Lipopolysaccharide-Induced Rabbit Arthritis: Cooperation between Growth-Related Protein and IL-8, and Interrelated Regulation among TNF[alpha], IL-1, IL-1 Receptor Antagonist, IL-8, and Growth-Related Protein Akihiro Matsukawa, Teizo Yoshimura, Kazunori Fujiwara, Takako Maeda, Susumu Ohkawara, and Masaru Yoshinaga