Mesothelioma TreatmentOther Sources
Fifth Meeting of the International Mesothelioma Interest Group (IMIG) - October 6, 1999
IMIG report
Summary
October 6, 1999
October 7, 1999
October 8, 1999
The first day of the meeting had combined IMIG/PAX sessions with concurrent sessions on the following two days. Wednesday morning commenced with Dr. Steven Mutsaers (conference organizer, IMIG), Dr. Marjan Versnel (IMIG President) and Mr. Jeremy Thomson (conference organizer, PAX) giving their welcoming addresses. The first scientific session entitled "Inflammation and Fibrin Regulation" was chaired by Mr. Jeremy Thompson (London, UK) and Professor Jack Gauldie (Hamilton, Canada). Professor Steven Idell (Tyler, USA) commenced the session by presenting some of his studies on post-translational regulation of the urokinase receptor by mesothelial and mesothelioma cells. Urokinase-type plasminogen activator (uPA) has been implicated in the pathogenesis of neoplastic growth and studies have shown that various factors implicated in pleural injury and neoplasia upregulate and stabilise the message for the uPA receptor (uPAR). Professor Idell described studies where he identified a 50 kDa uPAR binding protein that binds a fragment of uPAR mRNA that is involved in posttranslational regulation of uPAR mRNA. Overexpression of the uPAR mRNA binding protein binding region doubled uPAR expression at the cell surface that increased cell proliferation and invasiveness. These data demonstrate that posttranslational regulation of the fibrinolytic system can modify the role of mesothelial cells in mesothelial and mesothelioma cells in pleural remodelling after injury or in pleural neoplasia.
Professor Lena Holmdahl (Gteburg, Sweden) followed describing some of her studies characterizing protease's that participate in the breakdown of extracellular matrix, particularly in the peritoneal cavity. Changes in local expression of plasmin may play a role in the establishment of post-operative adhesions either directly or through the regulation of other proteases such as members of the matrix metalloproteinase family (MMPs) or through proteolytic activation of latent growth factors. It was proposed that variability in the expression of plasmin may explain differences in adhesion severity.
The late morning session was chaired by Professors Steven Idell and Lena Holmdahl and continued the theme of inflammation and fibrin regulation. Dr. Teake Kooistra (Rotterdam, Netherlands) presented a study designed to determine the temporal expression of fibrinolytic effector proteins during the development of peritoneal adhesions in a rat model. Analyses of fibrinolytic parameters in peritoneal lavage and biopsy samples were conducted to elucidate how differential expression of fibrinolysins, mainly tPA, and plasminogen activator inhibitors interact to influence adhesion formation. Dr. Kooistra's interpretation of the data was that the findings suggested that determinants of increased fibrin formation rather than decreased local fibrinolytic activity were chiefly responsible for increased extravascular fibrin deposition and adhesion formation in the model. Expression of fibrinolytic parameters was next studied in an in vitro model system using human mesothelial cells. It was proposed that interventions designed to up-regulate fibrinolytic activity of these cells could potentially be exploited to increase endogenous fibrinolytic capacity after operative peritoneal injury and thereby limit adhesion formation.
Dr. Geoff Bellingan (London, UK) then presented a descriptive analysis of macrophage-mesothelial cell adhesive interactions that occur in models of acute versus more chronic peritoneal injury. Inflammatory cells were harvested from acute or chronic injury, labeled with a fluorescent dye and analyzed for their ability to adhere to monolayers of MeT5A mesothelial cells. While the peak of macrophage adhesion to the MeT5A cells differed between cells harvested from the two models, the authors concluded that, in both cases, peak adhesion was found when resolution of the inflammatory response began. This study confirms that myeloid-mesothelial cell interactions may regulate inflammatory cell traffic during the course of peritoneal inflammation.
The next two presentations dealt with different aspects of the regulation of mediator expression in the context of peritoneal injury. Mr. Tom Wilkinson (Cardiff, UK) presented work designed to use transgenic animals to elucidate the role of interleukin-6 (IL-6) in the control of inflammatory cell traffic in a model of peritoneal injury. Mice with a homozygous deficiency of IL-6 were used. The preliminary data demonstrated that neutrophil influx into the peritoneal exudate was increased in mice deficient in IL-6, an effect that was associated with increased levels of MIP-2. The data suggest that IL-6, possibly derived from the mesothelium, is a key determinant of neutrophil traffic in inflammatory peritonitis induced by cell-free supernatants of cultures of Staph. Epidermidis.
Dr. Cathy Hoff (McGaw park, USA) concluded the session and presented work in which rat mesothelial cells were genetically engineered to overexpress rat interleukin-10 (IL-10) to inhibit mediator expression by macrophages. The genetically modified cells were able to inhibit cytokine expression by rat NR8383 macrophages, an effect that was attributable to rIL-10 based upon antibody neutralisation studies. The stable transfectants could be transplanted into the peritoneum of rats, providing a potential avenue to influence the course of macrophage-derived mediator expression in peritoneal injury.
The afternoon session, co-chaired by Professor Geoffrey Laurent (London, UK) and Dr. Simon Whawell (London, UK), was focused on "Serosal Repair". Professor Elizabeth Hay (Boston, UK) opened the session by describing her studies on epithelial-mesenchymal transformations (EMT). She carefully described these events as part of normal embryogenesis and in the development of mesothelium from primitive streak mesenchyme. Of particular interest were studies describing the dramatic EMT of primary corneal fibroblasts following transfection with E-cadherin, where cells changed morphology to resemble stratified epithelium and expressed tight junctions and desmosomes. This has particular relevance to tumotumorogy as current studies indicate that tumour cells can convert to a less invasive phenotype by E-cadherin transfection. The involvement of c-src in EMT was also discussed.
Professor Jack Gauldie (Hamilton, Canada) described the effects of transient overexpression of TGFb1 on the peritoneal membrane. It is thought that fibrosis of the peritoneum may result as a complication of dialysis in patients with renal disease. In general, adenovirus mediated transfections into mesothelial lined spaces was thought to be a very effective system of gene delivery. TGF1 transfection in lung, liver and rectum resulted in submesothelial fibrosis but only in the peritoneum did such events lead to adhesion formation.
The final lecture of the session was delivered by Dr. Wolfgang Sendt (Freiburg, Germany) and described co-culture experiments of mesothelial and endothelial cells as a model to study the physiology of the peritoneal membrane. Endothelial cells were grown on the bottom of a collagen coated 3 mm pore size culture insert, with mesothelial cells on the top. Careful immunohistochemical studies were performed to confirm the identity of the cells and the model was used to study transmigration of stimulated polymorphonuclear neutrophils from the lower to the upper compartment.
Following afternoon tea, the theme of serosal repair continued, chaired by Professor Agnes Kane (Providence, USA) and Mr. David Scott-Coombes (London, UK), with the emphasis of identifying the origin of the regenerating mesothelial cell. Mesothelium, unlike other epithelial-like surfaces, does not heal solely by centripetal migration of cells from the edge of the wound towards the wound center. This is evident as both small and large mesothelial lesions heal in exactly the same time. Mr. Andrew Raftery (Sheffield, UK) described some of his and others early studies on mesothelial healing and presented evidence to suggest that the regenerating mesothelium originates from subserosal fibroblast-like cells. Three papers followed showing evidence to suggest that the healing mesothelium may not originate in the subserosa but from cells in the surrounding mesothelium which divide, float in the serosal fluid and settle on the injured serosa to repopulate the wound. Dr. Steven Mutsaers (London, UK) presented kinetics data showing that in an experimental model, replenishment of the mesothelium was well under way even before submesothelal cells at the ccenterof the lesion had begun to divide. Mr. Talib Al Mishlab (London, UK) described an immunohistochemical study where he was unable to demonstrate differentiation of subserosal cells into cells with mesothelial characteristics at any stage of serosal healing. This study contradicted a previous study that suggested submesothelial differentiation on the basis of immunohistochemical studies. Mr. Adam Foley-Comer (London, UK) then presented data showing that application of fluorescently llabeledcultured mesothelial cells to injured serosa resulted in attachment and incorporation of these cells into the healing mesothelium. He also presented preliminary data suggesting that free-floating cells may be derived from a precursor/stem cell population in the mesothelial monolayer.
