Matthias Eck

Publications of Matthias Eck

• Manifestation of an intra-abdominal angiosarcoma of the peritoneum 5 years after radiotherapy of an anal carcinoma.

  Authors: Bertram Illert, Marco Bueter, Matthias Eck

  International journal of colorectal disease. 09/2008;

• Colonization of experimental murine breast tumours by Escherichia coli K-12 significantly alters the tumour microenvironment.

  Authors: Stephanie Weibel, Jochen Stritzker, Matthias Eck, Werner Goebel, Aladar A Szalay

  Cellular microbiology. 07/2008; 10(6):1235-48.

  The successful application of live bacteria in cancer therapy requires a more detailed understanding of bacterial interaction with the tumour microenvironment. Here, we analysed the effect ofThe successful application of live bacteria in cancer therapy requires a more detailed understanding of bacterial interaction with the tumour microenvironment. Here, we analysed the effect of Escherichia coli K-12 colonization on the tumour microenvironment by immunohistochemistry and fluorescence microscopy in the murine 4T1 breast carcinoma model. We described the colonization of tumour-bearing mice, as well as the spatiotemporal distribution of E. coli K-12 in the 4T1 tumour tissue over a period of 14 days. The colonization resulted within 3 days in large avascular necrotic tissue, redistribution of hypoxic areas and an enhanced collagen IV deposition within the colonized tumour tissue, which changed the tumoral perfusion of systemically injected immunoglobulins. In addition, E. coli K-12 colonization led to the redistribution of tumour-associated macrophages, forming a granulation tissue around bacterial colonies, and also to an increase in TNFalpha and matrix metalloproteinase 9 expression. Colonization of 4T1 tumours by E. coli K-12 resulted in strong reduction of pulmonary metastatic events. These new insights will contribute to the general understanding of the tumour-microbe cross-talk and to the design of bacterial strains with enhanced anticancer efficiency.

• Immunostaining for p16INK4a used as a conjunctive tool improves interobserver agreement of the histologic diagnosis of cervical intraepithelial neoplasia.

  Authors: Lars-Christian Horn, Anja Reichert, Anne Oster, Sanne Frost Arndal, Marcus J Trunk, Ruediger Ridder, Ole Feldballe Rassmussen, Kaj Bjelkenkrantz, Pernille Christiansen, Matthias Eck, Thomas Lorey, Vibeke Ravn Skovlund, Thomas Ruediger, Volker Schneider, Dietmar Schmidt

  The American journal of surgical pathology. 05/2008; 32(4):502-12.

  The quality of cervical histopathology is critical to cervical cancer prevention, cancer treatment, and research programs. On the basis of the histology results further patient management isThe quality of cervical histopathology is critical to cervical cancer prevention, cancer treatment, and research programs. On the basis of the histology results further patient management is determined. However, the diagnostic interpretation of histologic hematoxylin-eosin (H&E)-stained slides is affected by substantial rates of discordance among pathologists. Overexpression of the cyclin-dependent kinase inhibitor p16INK4a, a cell cycle regulating protein, has been shown to be strongly correlated with dysplastic lesions of the cervix uteri. In this study, we assessed whether p16INK4a immunohistochemistry may increase the performance of pathologists in diagnosing squamous lesions in cervical punch and cone biopsies. When using a consecutive p16INK4a-stained slide in conjunction to the H&E-stained slide, interobserver agreement between 6 pathologists improved significantly for both cervical punch and cone biopsies (P < 0.001). For punch biopsies (n = 247), kappa value increased from 0.49 (moderate agreement) to 0.64 indicating substantial agreement, and interobserver agreement for cone biopsies (n = 249) improved from 0.63 (conventional H&E slide reading) to 0.70 when H&E-stained slides were read conjunctively with p16INK4a-stained slides. In comparison to a common consensus diagnosis established by 3 independent experts, 4 pathologists reached an improvement with the conjunctive p16INK4a test, 2 of them showing significantly better agreement (P < 0.001 and P = 0.002, respectively), p16INK4a immunohistochemistry as an adjunct to conventional H&E-stained specimens thus contributes to a more reproducible diagnosis of cervical intraepithelial neoplasia and may be a valuable aid for the interpretation of cervical histology.

• Overexpression of transketolase TKTL1 is associated with shorter survival in laryngeal squamous cell carcinomas.

  Authors: Hans-Ullrich Völker, Matthias Scheich, Bernd Schmausser, Ulrike Kämmerer, Matthias Eck

  European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 01/2008; 264(12):1431-6.

  Tumorigenesis involves energy production by aerobic glycolysis ("Warburg effect") in malignant tumors. One of the key enzymes is transketolase. Transketolase, transketolase-like-1 (TKTL1), andTumorigenesis involves energy production by aerobic glycolysis ("Warburg effect") in malignant tumors. One of the key enzymes is transketolase. Transketolase, transketolase-like-1 (TKTL1), and transketolase-like-2 are known. Antibodies against TKTL1 exist for immunohistochemical investigations. This study investigated the influence of TKTL1 on survival and metastasizing in 40 laryngeal squamous cell carcinomas (SCCs, T2-T4, 27 metastasized). Staining was assessed by an immunoreactive score (IRS) with values from 0 to 12 in primaries and their nodal metastases. The highest IRS was 8. Normal epithelium did not show an expression. Three SCCs were negative. Advanced SCCs had a higher IRS than lower stages. An IRS>4 was associated with a shorter disease specific survival, independent on the tumor stage in the multivariate analysis. Significant differences between metastasized and non-metastasized SCCs were absent, but poorly differentiated SCCs had a higher IRS in their metastases than moderate differentiated SCCs. TKTL1 overexpression is associated with a more aggressive behavior and shorter survival of laryngeal SCCs. These observations could lead to additional therapeutic options targeting a blocking of the enzyme activity.

• Nuclear localization and cytosolic overexpression of LASP-1 correlates with tumor size and nodal-positivity of human breast carcinoma.

  Authors: Thomas G P Grunewald, Ulrike Kammerer, Michaela Kapp, Matthias Eck, Johannes Dietl, Elke Butt, Arnd Honig

  BMC cancer. 02/2007; 7:198.

  BACKGROUND: LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to beBACKGROUND: LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to be overexpressed in 8-12 % of human breast cancers and thought to be exclusively located in cytoplasm. METHODS: In the present work we analyzed the cellular and histological expression pattern of LASP-1 and its involvement in biological behavior of human breast cancer through correlation with standard clinicopathological parameters and expression of c-erbB2 (HER-2/neu), estrogen- (ER) and progesterone-receptors (PR). For this purpose immunohistochemical staining intensity and percentage of stained cells were semi-quantitatively rated to define a LASP-1 immunoreactive score (LASP-1-IRS). LASP-1-IRS was determined in 83 cases of invasive ductal breast carcinomas, 25 ductal carcinomas in situ (DCIS) and 18 fibroadenomas. Cellular LASP-1 distribution and expression pattern was visualized by immunofluorescence and confocal microscopy and assessed through separate Western blots of nuclear and cytosol preparations of BT-20, MCF-7, MDA-MB231, and ZR-75/1 breast cancer cells. RESULTS: Statistical analysis revealed that the resulting LASP-1-IRS was significantly higher in invasive carcinomas compared to fibroadenomas (p = 0.0176). Strong cytoplasmatic expression of LASP-1 was detected in 55.4 % of the invasive carcinomas, which correlated significantly with nuclear LASP-1-positivity (p = 0.0014), increased tumor size (p = 0.0159) and rate of nodal-positivity (p = 0.0066). However, levels of LASP-1 expression did not correlate with average age at time point of diagnosis, histological tumor grading, c-erbB2-, ER- or PR-expression.Increased nuclear localization and cytosolic expression of LASP-1 was found in breast cancer with higher tumor stage as well as in rapidly proliferating epidermal basal cells. Confocal microscopy and separate Western blots of cytosolic and nuclear preparations confirmed nuclear localization of LASP-1. CONCLUSION: The current data provide evidence that LASP-1 is not exclusively a cytosolic protein, but is also detectable within the nucleus. Increased expression of LASP-1 in vivo is present in breast carcinomas with higher tumor stage and therefore may be related with worse prognosis concerning patients' overall survival.

• Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor--report of two cases with similar morphology.

  Authors: Hans-Ullrich Völker, Matthias Scheich, Sylvia Höller, Philipp Ströbel, Rudolf Hagen, Hans Konrad Müller-Hermelink, Matthias Eck

  Diagnostic pathology. 02/2007; 2:1.

  BACKGROUND: Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. CASE PRESENTATION: Case 1 is aBACKGROUND: Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. CASE PRESENTATION: Case 1 is a spindle cell carcinoma (SPC) in a 55 year-old male patient and case 2 an inflammatory myofibroblastic tumor (IMT) in a 34 year-old female patient. A comprehensive morphological and immunohistochemical analysis was done. Both tumors arose at the vocal folds. Magnified laryngoscopy showed polypoid tumors. After resection, conventional histological investigation revealed spindle cell lesions with similar morphology. We found ulceration, mild atypia, and myxoid stroma. Before immunohistochemistry, the dignity was uncertain. Immunohistochemical investigations led to diagnosis of two distinct tumors with different biological behaviour. Both expressed vimentin. Furthermore, the SPC was positive for pan-cytokeratin AE1/3, CK5/6, and smooth-muscle actin, whereas the IMT reacted with antibodies against ALK-1, and EMA. The proliferation (Ki67) was up to 80% in SPC and 10% in IMT. Other stainings with antibodies against p53, p21, Cyclin D1, or Rb did not result in additional information. After resection, the patient with SPC is free of disease for seven months. The IMT recurred three months after first surgery, but no relapses were found eight months after resurgery. CONCLUSION: Differential diagnosis can be difficult without immunohistochemistry. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from the assessment of proliferation) do not help.

• Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor – report of two cases with similar morphology

  Authors: Hans-Ullrich Völker, Matthias Scheich, Sylvia Höller, Philipp Ströbel, Rudolf Hagen, Hans Müller-Hermelink, Matthias Eck

  Diagnostic Pathology. 01/2007;

  Abstract Background Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. Case presentation CaseAbstract Background Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. Case presentation Case 1 is a spindle cell carcinoma (SPC) in a 55 year-old male patient and case 2 an inflammatory myofibroblastic tumor (IMT) in a 34 year-old female patient. A comprehensive morphological and immunohistochemical analysis was done. Both tumors arose at the vocal folds. Magnified laryngoscopy showed polypoid tumors. After resection, conventional histological investigation revealed spindle cell lesions with similar morphology. We found ulceration, mild atypia, and myxoid stroma. Before immunohistochemistry, the dignity was uncertain. Immunohistochemical investigations led to diagnosis of two distinct tumors with different biological behaviour. Both expressed vimentin. Furthermore, the SPC was positive for pan-cytokeratin AE1/3, CK5/6, and smooth-muscle actin, whereas the IMT reacted with antibodies against ALK-1, and EMA. The proliferation (Ki67) was up to 80% in SPC and 10% in IMT. Other stainings with antibodies against p53, p21, Cyclin D1, or Rb did not result in additional information. After resection, the patient with SPC is free of disease for seven months. The IMT recurred three months after first surgery, but no relapses were found eight months after resurgery. Conclusion Differential diagnosis can be difficult without immunohistochemistry. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from the assessment of proliferation) do not help.

• Nuclear localization and cytosolic overexpression of LASP-1 correlates with tumor size and nodal-positivity of human breast carcinoma

  Authors: Thomas Grunewald, Ulrike Kammerer, Michaela Kapp, Matthias Eck, Johannes Dietl, Elke Butt, Arnd Honig

  BMC Cancer. 01/2007;

  Abstract Background LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which wasAbstract Background LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to be overexpressed in 8–12 % of human breast cancers and thought to be exclusively located in cytoplasm. Methods In the present work we analyzed the cellular and histological expression pattern of LASP-1 and its involvement in biological behavior of human breast cancer through correlation with standard clinicopathological parameters and expression of c-erbB2 (HER-2/neu), estrogen- (ER) and progesterone-receptors (PR). For this purpose immunohistochemical staining intensity and percentage of stained cells were semi-quantitatively rated to define a LASP-1 immunoreactive score (LASP-1-IRS). LASP-1-IRS was determined in 83 cases of invasive ductal breast carcinomas, 25 ductal carcinomas in situ (DCIS) and 18 fibroadenomas. Cellular LASP-1 distribution and expression pattern was visualized by immunofluorescence and confocal microscopy and assessed through separate Western blots of nuclear and cytosol preparations of BT-20, MCF-7, MDA-MB231, and ZR-75/1 breast cancer cells. Results Statistical analysis revealed that the resulting LASP-1-IRS was significantly higher in invasive carcinomas compared to fibroadenomas (p = 0.0176). Strong cytoplasmatic expression of LASP-1 was detected in 55.4 % of the invasive carcinomas, which correlated significantly with nuclear LASP-1-positivity (p = 0.0014), increased tumor size (p = 0.0159) and rate of nodal-positivity (p = 0.0066). However, levels of LASP-1 expression did not correlate with average age at time point of diagnosis, histological tumor grading, c-erbB2-, ER- or PR-expression. Increased nuclear localization and cytosolic expression of LASP-1 was found in breast cancer with higher tumor stage as well as in rapidly proliferating epidermal basal cells. Confocal microscopy and separate Western blots of cytosolic and nuclear preparations confirmed nuclear localization of LASP-1. Conclusion The current data provide evidence that LASP-1 is not exclusively a cytosolic protein, but is also detectable within the nucleus. Increased expression of LASP-1 in vivo is present in breast carcinomas with higher tumor stage and therefore may be related with worse prognosis concerning patients' overall survival.

• Parathyroid-hormone-related-protein-associated hypercalcemia in a patient with CLL-type low-grade leukemic B-cell lymphoma.

  Authors: Björn Schöttker, Werner Heinz, Florian Weissinger, Korkut Sözener, Matthias Eck, Jochen Seufert

  Haematologica. 01/2007; 91(12 Suppl):ECR45.

  Humoral hypercalcemia of malignancy is a common metabolic disturbance associated with solid tumors, but it also occurs in lymphoma patients. Among these, low grade B-cell lymphoma accounts for onlyHumoral hypercalcemia of malignancy is a common metabolic disturbance associated with solid tumors, but it also occurs in lymphoma patients. Among these, low grade B-cell lymphoma accounts for only few cases, in which secretion of parathyroid hormone-related protein (PTHrP) remains even exceptional. We report the very rare case of a patient with a CLL type low grade leukemic B-cell lymphoma showing PTHrP-related hypercalcemia without evidence of bone lesions. Using immunohistochemistry, we demonstrate the cytoplasmic expression of PTHrP by the lymphoma cells in the bone marrow obtained at the onset of hypercalcemia. We postulate a pathogenetic role of leukemic cell production and secretion of PTHrP in hypercalcemia in low grade leukemic B-cell lymphoma.

• Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases.

  Authors: Jürgen Schauber, Daniel Rieger, Frank Weiler, Jan Wehkamp, Matthias Eck, Klaus Fellermann, Wolfgang Scheppach, Richard L Gallo, Eduard F Stange

  European journal of gastroenterology & hepatology. 07/2006; 18(6):615-21.

  BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by a breakdown of colon epithelial barrier function. Antimicrobial peptides like cathelicidins are molecules of the innate immuneBACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by a breakdown of colon epithelial barrier function. Antimicrobial peptides like cathelicidins are molecules of the innate immune system located at epithelial surfaces. Cathelicidins influence microbial growth and inflammation and may play a role in IBD. In this study, the expression of human cathelicidin hCAP18/LL-37 was investigated in the intestinal mucosa from patients suffering from ulcerative colitis or Crohn's disease. METHODS: Biopsy material from colon and ileal mucosa of a total of 89 patients (34 with Crohn's disease, 27 with ulcerative colitis, 28 control patients) was evaluated for cathelicidin expression by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. Colon epithelial cells were stimulated in vitro with various cytokines to evaluate mechanisms that influence cathelicidin production. RESULTS: Cathelicidin expression was significantly increased in inflamed and non-inflamed colon mucosa from ulcerative colitis patients compared to non-inflamed control mucosa. In patients with Crohn's disease cathelicidin expression was not changed in inflamed or non-inflamed colon or ileal mucosa independent of NOD2 status. Biopsies evaluated by immunohistochemistry showed epithelial cathelicidin expression in the upper crypt that was diffuse in controls and only basal in IBD patients. Inflammation mediators, alone or in combination with the known cathelicidin inducer butyrate, had no effect on cathelicidin expression in cultured colon cells. CONCLUSIONS: In IBD the colonic expression of human cathelicidin is altered: cathelicidin expression is increased in inflamed and non-inflamed mucosa in patients suffering from ulcerative colitis but not in Crohn's disease. This deficiency may further compromise the antimicrobial barrier in Crohn's disease.

• Metastasizing vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation: genetic evidence of clonal origin.

  Authors: Patrick Adam, Andreas Zettl, Ursula Zollner, Johannes Dietl, Hans Konrad Müller-Hermelink, Matthias Eck

  Human pathology. 11/2005; 36(10):1143-7.

  In this report, we present the first case of a vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation. Comparative genomic hybridization was used to analyzeIn this report, we present the first case of a vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation. Comparative genomic hybridization was used to analyze clonality of the two tumor components. A widely identical pattern of genetic imbalances in the comparative genomic hybridization analysis in both the carcinomatous and the sarcomatous tumor component strongly supported the concept of a bidirectionally differentiated neoplasm. In both tumor components and two lymph node metastases, an amplicon was detected on chromosome 11q12-q13, homing the cyclin D1 gene locus. In contrast, exclusively in the sarcomatoid component, a characteristic amplicon on 12q13-q14 was found. The cytogenetic profile of the lymph node metastases revealed an increase in imbalances compared with the primary tumor. In summary, we found strong indications for a clonal origin of the two tumor components in a vulvar carcinosarcoma and a good correlation of the histological morphology with the pattern of genetic imbalances.

• Placenta percreta with subsequent uterine rupture at 15 weeks of gestation after two previous cesarean sections.

  Authors: Arnd Honig, Lorenz Rieger, Florian Thanner, Matthias Eck, Marc Sutterlin, Johannes Dietl

  The journal of obstetrics and gynaecology research. 11/2005; 31(5):439-43.

  A 25-year-old gravida 3 para 2 woman was referred to our hospital at 15 weeks' gestation with an acute abdomen and free fluid in the peritoneal cavity. On admission she was somnolent. She had aA 25-year-old gravida 3 para 2 woman was referred to our hospital at 15 weeks' gestation with an acute abdomen and free fluid in the peritoneal cavity. On admission she was somnolent. She had a history of two cesarean sections. Fetal cardiac activity was detectable by ultrasound preoperatively. Intraoperatively, a lower uterine-segment rupture was identified in the area of the presumed prior uterine incision. The great blood loss with consecutive coagulopathy required an emergency hysterectomy and multiple blood transfusions. The placenta was located on the lower anterior uterine wall. Intervening decidual cells between placenta and maternal scar tissue were absent in the area of the prior uterine incision. Placental villous tissue deeply invaded and perforated the scar tissue. Histological examination revealed a placenta percreta. Placenta percreta with subsequent uterine rupture is a rare but dramatic complication after previous cesarean section. This should be kept in mind as the rate of elective cesarean sections is rising continuously. Our patient recovered completely.

• Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori.

  Authors: Bernd Schmausser, Mindaugas Andrulis, Simon Endrich, Hans Konrad Müller-Hermelink, Matthias Eck

  International journal of medical microbiology : IJMM. 07/2005; 295(3):179-85.

  In the human stomach Toll-like receptors (TLRs) expressed by the gastric epithelium interact with Helicobacter pylori and mediate production of proinflammatory cytokines and chemokines during H.In the human stomach Toll-like receptors (TLRs) expressed by the gastric epithelium interact with Helicobacter pylori and mediate production of proinflammatory cytokines and chemokines during H. pylori infection. This results in chronic active gastritis, the background from which gastric carcinoma arises via the epithelial precursor lesions, intestinal metaplasia and dysplasia. Therefore, the question is arising whether gastric carcinoma cells are also able to interact with H. pylori. In this study, TLR4, TLR5 and TLR9 expression was investigated on tumor cells of gastric carcinoma and on its precursor lesions, intestinal metaplasia and dysplasia, by immunohistochemistry. Gastric epithelium with intestinal metaplasia (n=10) and dysplasia (n=3) expressed TLR4 and TLR5. TLR4 was strongly expressed by tumor cells of 17 out of 22 and TLR5 by tumor cells of all 22 patients with gastric carcinoma. TLR9, however, was not detectable in intestinal metaplasia or dysplasia and only focally in 6 out of 22 gastric carcinomas. In contrast to H. pylori gastritis, epithelial TLR expression in intestinal metaplasia, dysplasia and gastric carcinoma was diffusely distributed without subcellular polarization as demonstrated by confocal microscopy. This is the first study describing TLR expression on tumor cells of gastric carcinoma and its precursor lesions. Expression of TLRs enables gastric carcinoma cells to interact with H. pylori. As H. pylori can induce gastric carcinoma-promoting factors, such as IL-8, via epithelial TLR expression, TLR expression by gastric carcinoma cells may have a dangerous potential.

• Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection?

  Authors: Bernd Schmausser, Christine Josenhans, Simon Endrich, Sebastian Suerbaum, Cassian Sitaru, Mindaugas Andrulis, Stephanie Brändlein, Peter Rieckmann, Hans Konrad Müller-Hermelink, Matthias Eck

  Infection and immunity. 01/2005; 72(12):6773-9.

  In Helicobacter pylori gastritis, neutrophil activation and migration, which play central roles in the pathogenesis of the disease, are regulated by the neutrophil attractant chemokines interleukin 8In Helicobacter pylori gastritis, neutrophil activation and migration, which play central roles in the pathogenesis of the disease, are regulated by the neutrophil attractant chemokines interleukin 8 (IL-8) and Groalpha, whose secretion is induced by H. pylori. However, the modulation of the corresponding chemokine receptors CXCR1 and CXCR2 on human neutrophils under the influence of H. pylori has not been investigated. Incubation of neutrophils with cag(+) and cag deletion H. pylori strains resulted in a complete downregulation of the CXCR1 and the CXCR2 receptors after 0.5 h, as tested by fluorescence-activated cell sorter analysis, independent of the cag status. Downregulation of CXCR1 and CXCR2 seems to occur via receptor internalization and rapid degradation, as shown by confocal microscopy and immunoblotting. Neither the proinflammatory cytokines IL-8 and tumor necrosis factor alpha produced by the neutrophils themselves nor H. pylori lipopolysaccharide, which are the known regulators of these two chemokine receptors, was responsible for the downregulation. Reverse transcription-PCR analysis showed that CXCR1 and CXCR2 mRNAs of neutrophils were reduced at a later time than the CXCR1 and CXCR2 proteins. Moreover, cag(+) H. pylori strains induced significantly stronger downregulation of CXCR1 and CXCR2 mRNAs than the cag deletion mutant. Therefore, receptor protein and mRNA downregulation seem to be mediated by two independent mechanisms. Data obtained by immunohistochemistry suggested that downmodulation of CXCR1 and CXCR2 on neutrophils may also occur in vivo in the human stomach during H. pylori infection. Downregulation of CXCR1 and CXCR2 expression on neutrophils in H. pylori infection by H. pylori itself may represent a new mechanism of modulating neutrophil migration and activation in the gastric mucosa.

• Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells.

  Authors: Jürgen Schauber, Konrad Iffland, Susanne Frisch, Theodor Kudlich, Bernd Schmausser, Matthias Eck, Thomas Menzel, Andrea Gostner, Hardi Lührs, Wolfgang Scheppach

  Molecular immunology. 08/2004; 41(9):847-54.

  Histone-deacetylase (HDAC) -inhibitors enhance acetylation of core proteins and this is linked to formation of transcriptionally active chromatin in various cells. In this study, the effect of HDACHistone-deacetylase (HDAC) -inhibitors enhance acetylation of core proteins and this is linked to formation of transcriptionally active chromatin in various cells. In this study, the effect of HDAC inhibitors (butyrate, trichostatin A (TSA)) on the expression of the cathelicidin LL-37 in colon, gastric and hepatocellular cells was investigated. METHODS: LL-37 expression was assessed in colon, gastric and hepatocellular cancer cells after treatment with HDAC-inhibitors. In parallel, histone H4 and HMGN2, a non-histone protein, acetylation was evaluated. In addition, the intracellular signalling pathway MEK-ERK was explored. RESULTS: In contrast to normal colon epithelial cells, gastrointestinal cancer cells lacked LL-37 expression. LL-37 was induced following treatment with HDAC-inhibitors in all investigated cell lines. This induction was time-dependent in butyrate-treated cells while TSA exerted a transient effect. Induction of LL-37 by butyrate was paralleled by acetylation of the histone H4 and the non-histone HMGN2. Again, TSA resulted in transient acetylation. Furthermore, inhibition of MEK-ERK blocked HDAC inhibitor-induced LL-37 expression in colonic and gastric cells. CONCLUSIONS: We have previously shown that butyrate induces LL-37 in colon epithelial cells. In the present study, we demonstrate that cathelicidin expression is modulated by HDAC-inhibitors in various gastrointestinal cells including gastric and hepatocellular cells. This is paralleled by changes in the acetylation of distinct core proteins suggesting a common regulatory mechanism of cathelicidin LL-37 regulation in these cells.

• PAM-1, a natural human IgM antibody as new tool for detection of breast and prostate precursors.

  Authors: Stephanie Brändlein, Matthias Eck, Philipp Ströbel, Ewa Wozniak, Hans Konrad Müller-Hermelink, Frank Hensel, H Peter Vollmers

  Human antibodies. 02/2004; 13(4):97-104.

  Early detection and differential analysis of premalignant lesions are very important for both prognosis and therapy of cancer patients. A good source of diagnostic tools is the natural antibody poolEarly detection and differential analysis of premalignant lesions are very important for both prognosis and therapy of cancer patients. A good source of diagnostic tools is the natural antibody pool of humans. Tumor-specific antibodies can be established by using hybridoma technology. The fully human germline-coded monoclonal IgM antibody PAM-1 was isolated from a patient with a stomach carcinoma. PAM-1 reacts with a post-transcriptionally modified isoform of membrane receptor CFR-1 which is overexpressed on almost all epithelial cancers of all types and origins.The expression of CFR-1/PAM-1 on precancerous stages of breast and prostate cancer was analyzed by immunohistochemistry and compared with normal breast and prostate tissue as well as adenocarcinomas of both. In addition FACS analysis was performed to detect receptor expression on benign and malign prostate cells. 73 different tissue samples of prostate and breast precancerous stages and prostate and breast carcinomas were analysed for CFR-1/PAM-1 expression immunohistochemically. The CFR-1/PAM-1 receptor was expressed on nearly all precancerous stages and carcinomas while normal breast and prostate tissue showed negative results. These results were confirmed by FACS analysis showing a CFR-1/PAM-1 expression only on prostate carcinoma cells but not on benign prostate hyperplasia cells. The unique expression of this new CFR-1/PAM-1 receptor makes the PAM-1 antibody an ideal diagnostic and even therapeutic tool for precancerous and cancerous epithelial lesions of the breast and the prostate.

• Cysteine-rich fibroblast growth factor receptor 1, a new marker for precancerous epithelial lesions defined by the human monoclonal antibody PAM-1.

  Authors: Stephanie Brändlein, Ines Beyer, Matthias Eck, Wolfgang Bernhardt, Frank Hensel, Hans Konrad Müller-Hermelink, H Peter Vollmers

  Cancer research. 06/2003; 63(9):2052-61.

  Precancerous epithelial lesions are sites of uncontrolled cellular proliferation, generated by irreversible genetic changes. Not all of these lesions progress to invasive cancer, some may evenPrecancerous epithelial lesions are sites of uncontrolled cellular proliferation, generated by irreversible genetic changes. Not all of these lesions progress to invasive cancer, some may even regress, but early detection of abnormal cells can be crucial for survival of the patient. Diagnosis is mainly performed by using morphological parameters. Proliferation markers can facilitate the analysis, if they show a consistent expression, and distinguish between healthy and malignant cells. The fully human monoclonal IgM antibody PAM-1 was isolated from a patient with stomach carcinoma and binds to a new variant of cysteine-rich fibroblast growth factor receptor 1 (CFR-1). This CFR-1/PAM-1 receptor is expressed on nearly all of the epithelial cancers of every type and origin, but not on healthy tissue. It is also present on precursor lesions found in: Helicobacter pylori-induced gastritis, intestinal metaplasia and dysplasia of the stomach, ulcerative colitis-related dysplasia and adenomas of the colon, Barrett's metaplasia and dysplasia of the esophagus, squamous cell metaplasia and dysplasia of the lung, and cervical intraepithelial neoplasia. The unique, growth-dependent expression of this new CFR-1 isoform makes the PAM-1 antibody an ideal diagnostic tool for the detection of precancerous and cancerous lesions.

• Disparity between mucosal and serum IgA and IgG in Helicobacter pylori infection.

  Authors: Bernd Schmausser, Matthias Eck, Axel Greiner, Hardy Lührs, Hans-Peter Vollmers, Hans Konrad Müller-Hermelink

  Virchows Archiv : an international journal of pathology. 09/2002; 441(2):143-7.

  Mucosal IgA and IgG are involved in the immune defense against Helicobacter pylori in infected patients. In contrast to IgG, IgA is transported into the gastric lumen and is responsible for theMucosal IgA and IgG are involved in the immune defense against Helicobacter pylori in infected patients. In contrast to IgG, IgA is transported into the gastric lumen and is responsible for the first-line defense. Therefore antigens recognized by mucosal IgA are possible candidates for vaccination. This study compared the IgA and IgG immune response to H. pylori in the gastric mucosa and that in the serum of 21 patients with H. pylori gastritis by the immunoblotting technique. In particular, mucosal IgA immune response against the urease antigen of H. pylori was studied in detail, as vaccination with this antigen was not curative in men. The results show that mucosal IgA was not represented by serum IgA and IgG, and that the H. pylori specific mucosal IgA and IgG immune responses differ in antigen-recognition pattern. This disparity may reflect the different transport ways and functions of these two immunoglobulin isotypes. Furthermore, mucosal IgA specific for urease was found inconsistently in patients with H. pylori gastritis. As vaccination antigens should induce an appropriate mucosal IgA immune response against H. pylori, our findings may have important implications for the selection of antigens for vaccination against H. pylori.

• Human monoclonal IgM antibodies with apoptotic activity isolated from cancer patients.

  Authors: Stephanie Brändlein, Judith Lorenz, Nele Ruoff, Frank Hensel, Ines Beyer, Justus Müller, Konrad Neukam, Bertram Illert, Matthias Eck, Hans Konrad Müller-Hermelink, H Peter Vollmers

  Human antibodies. 02/2002; 11(4):107-19.

  Monoclonal antibodies are accepted as ideal adjuvant therapeutic reagents for all kinds of diseases. Polyvalent (cross-linking) and low-mutated IgM antibodies (less immunogenic) are believed to beMonoclonal antibodies are accepted as ideal adjuvant therapeutic reagents for all kinds of diseases. Polyvalent (cross-linking) and low-mutated IgM antibodies (less immunogenic) are believed to be the most effective weapons against cancer. The best sources for these types of antibodies are the cancer patients themselves. Using conventional hybridoma technology, not only are fully human monoclonal IgM antibodies isolated, but also new tumor-related targets can be identified using the same experimental approach. The resulting antibodies can be used directly for therapeutic purposes without further modulation and manipulation. This report describes five newly established human monoclonal IgM antibodies; antibody LM-1 that was isolated from a patient with lung cancer, antibodies PM-1 und PM-2 that were isolated from a patient with pancreatic cancer, and antibodies CM-1 and CM-2 which were isolated from a patient with colon carcinoma. The mainly germ-line encoded antibodies are specific for malignant tissues and show only restricted reactivity with healthy cells. When tested for in vitro functional activity, all five antibodies inhibit tumor cell proliferation of carcinoma cells by inducing apoptosis.