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25 key publications

In the following, a listing of the 25 most important publications of principle investigators (PIs) of the Cluster Translational Oncology is provided.
(bold underlined: PI of the Cluster; bold: Heidelberg/Mannheim - investigators/group member; italics: brief description of the main aspects of the publication)


1. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG (2006)
Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.
Nat Med
12, 235-239.
Constitutive signalling between the paracrine acting secreted ligand Angiopoietin-1 with its cognate endothelial receptor Tie2 controls the quiescent phenotype of the blood vascular system. Loss of the quiescent endothelial cell phenotype is a critical commonality in many diseases with vascular involvement including atherosclerosis and cancer. The study identifies Angiopoietin-2 as a hierarchically high autocrine-acting (i.e. endothelial cell produced) antagonistic Tie2 ligand that destabilizes the vascular endothelium and thereby facilitates its responsiveness to exogenous cytokines.
link to PubMed


2. Muller-Decker K, Furstenberger G, Annan N, Kucher D, Pohl-Arnold A, Steinbauer B, Esposito I, Chiblak S, Friess H, Schirmacher P, Berger I (2006)

Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice. Gastroenterology 130, 2165-2178. Cyclooxygenase (COX-2) is overexpressed in about 75% of human cancers and inhibition of the prostaglandin pathway represents one of the promising therapeutic targets in tumors of the digestive tract. The manuscript is one of several of the group on the protumorigenic role of COX-2 and its functional dissection and shows for the first time that its overexpression in a few ductal cells is sufficient to establish preinvasive precursor lesions of pancreatic cancer. link to PubMed  


3. Mertens D, Wolf S, Tschuch C, Mund C, Kienle D, Ohl S, Schroeter P, Lyko F, Dohner H, Stilgenbauer S, Lichter P (2006)

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism. Proc Natl Acad Sci U S A 103, 7741-7746. In many human malignancies, in particular in chronic lymphocytic leukemia (CLL), there is a common deletion within chromosome band 13q14.3 harboring a tumor-suppressor pathomechanism. While none of the genes residing in this commonly deleted region are mutated in tumors, several candidate genes are down-regulated suggesting an epigenetic pathomechanism. The model from these data proposes epigenetic silencing of one copy of candidate genes marked by replication timing and deletion of the single active copy of the candidate gene in the situation of the tumor, i.e. an interaction of genetic lesions and epigenetic silencing as pathomechanism in CLL. link to PubMed  


4. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, Hehlmann R (2006)

Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet.Blood 108, 1809-1820.

The introduction of imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia (CML). On the initiative of the European LeukemiaNet a panel of 19 international experts therefore reviewed treatment of CML since 1998. Their detailed recommendations are the sound and internationally accepted basis for current CML management.

link to PubMed 


5. Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S (2006)
Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway.Blood 107, 3221-3228. Depending on the type of tumor, alternatively activated macrophages differentiating in a tumor-conditioned cytokine environment also express stabilin-1. Stabilin-1 exerts a dual role as a multiligand scavenger receptor and as an intracellular cargo carrier. This study shows that stabilin-1, as an intracellular cargo carrier, mediates intracellular sorting of newly synthesized stabilin-1-interacting chitinase-like protein (SI-CLP) into the lysosomal secretory pathway.

link to PubMed 


6. Yuan X, Zhou Y, Casanova E, Chai M, Kiss E, Grone HJ, Schutz G, Grummt I (2005)
Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis.Mol Cell 19, 77-87.

P53 is one of the key regulatory proteins of the cell and is inactivated in more than 50% of human cancers. This study shows that genetic inactivation of the transcription factor TIF-IA abrogates Pol I transcription, leads to disintegration of the nucleolus, blocks cell cycle progression, and triggers p53-dependent apoptosis. RNAi-induced loss of p53 overcomes proliferation arrest and apoptosis in response to TIF-IA ablation. The striking correlation between perturbation of nucleolar function, elevated levels of p53 and induction of cell suicide supports the view that the nucleolus is a stress sensor that regulates p53 activity.
link to PubMed


7. Gehring NH, Kunz JB, Neu-Yilik G, Breit S, Viegas MH, Hentze MW, Kulozik AE (2005)
Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements.Mol Cell 20, 65-75.

Messenger RNA stability plays a major role in the regulation of gene expression and recent data suggest its relevance in certain types of neoplasias. Messenger RNAs (mRNAs) bearing premature translation termination codons (PTCs) are degraded by nonsense-mediated mRNA decay (NMD). The paper identifies the relevant proteins, which are essential for NMD, provides insights into the formation of complexes, that classify alternative NMD pathways, and develops a nonlinear model for mammalian NMD involving alternative routes of entry that converge at a central function of the factor UPF1.

link to PubMed 


8. Bermejo JL, Eng C, Hemminki K (2005)
Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer.Gastroenterology 129, 1889-1899.

The Swedish Family Cancer Database is one of the outstanding sources for epidemiological cancer studies. In this study it is exploited for the analysis of hereditary nonpolyposis colorectal cancer (HNPCC) especially to determine the extent to which tumors in classified families are HNPCC-related. Families that fulfilled the Bethesda criteria showed increased risks of cancer not only in the colorectum and endometrium but also of the small bowel, ovary, stomach, bile ducts, renal pelvis, and ureter while the risks of lung and cervical cancers were decreased. The data of this study were of great help to define surveillance strategies for members of families that fulfill the criteria for HNPCC testing.

link to PubMed 


9. Vinokurova S, Wentzensen N, Einenkel J, Klaes R, Ziegert C, Melsheimer P, Sartor H, Horn LC, Hockel M, von Knebel Doeberitz M (2005)
Clonal history of papillomavirus-induced dysplasia in the female lower genital tract.
J Natl Cancer Inst 97, 1816-1821.

The molecular characterization of integration sites of human papillomavirus (HPV) genomes allowed to track the clonal origin of multifocal and metachronic dysplastic lesions of the vagina and vulva. As shown in this study, most HPV-induced dysplastic lesions in the female lower genital tract arise from cell clones that originated from the epithelium of the transformation zone of the cervix uteri. The results of the study demonstrate that HPV-mediated 'de novo' transformation of cells in the vagina or vulva is rare. Most vaginal or vulval precancers and cancers arise from HPV transformed cells that originate at the transformation zone of the cervix.
link to PubMed


10. Brueckner B, Boy RG, Siedlecki P, Musch T, Kliem HC, Zielenkiewicz P, Suhai S, Wiessler M, Lyko F (2005)
Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases.Cancer Res  65, 6305-6311.

This paper describes the identification, synthesis and preclinical characterization of the first rationally designed DNA methyltransferase inhibitor. The results suggest that the compound effectively reverses epigenetic mutations in human cancer cell lines, in the absence of detectable cytotoxic side effects.
link to PubMed


11. Schmidt K, Hoffend J, Altmann A, Strauss LG, Dimitrakopoulou-Strauss A, Engelhardt B, Koczan D, Peter J, Vorwald S, Eskerski H, Eisenhut M, Metz J, Kinscherf R, Haberkorn U (2005)
Transfer of the sFLT-1 gene in Morris hepatoma results in decreased growth and perfusion and induction of genes associated with stress response.Clin Cancer Res 11, 2132-2140.

Monitoring with functional imaging and histomorphometrical analyses is crucial to evaluate the biological effects caused by antiangiogenic treatment. Using the Morris hepatoma model and employing detailled in vivo monitoring by H(2)(15)O positron emission tomography the paper demonstrates that sFLT inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes, while at the same time tumor defense reactions are activated.

link to PubMed 


12. Eichhorst ST, Krueger A, Muerkoster S, Fas SC, Golks A, Gruetzner U, Schubert L, Opelz C, Bilzer M, Gerbes AL, Krammer PH (2004)
Suramin inhibits death receptor-induced apoptosis in vitro and fulminant apoptotic liver damage in mice. Nat Med 10, 602-609.

The paper shows that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells. It also inhibits the proapoptotic effect of chemotherapeutic drugs. The antiapoptotic mechanism is specific to cell type and is caused by reduced activation, but not altered composition, of the death-inducing signaling complex (DISC), and by inhibition of the initiator caspases 8, 9 and 10, Thus, the antiapoptotic property of suramin may be therapeutically exploited
link to PubMed 


13. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Buchler MW (2004)
A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med 350, 1200-1210.

Multicenter randomized controlled trial using a two-by-two factorial design comparing chemoradiotherapy alone, chemoradiotherapy and chemotherapy, chemotherapy alone, and no adjuvant treatment in patients with resected pancreatic ductal adenocarcinoma. The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy. The benefit of chemotherapy persisted after adjustment for major prognostic factors. The trial confirmed that adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer and was the first study to demonstrate a positive non-surgical treatment effect in pancreatic cancer at all.
link to PubMed


14. Abdollahi A, Hahnfeldt P, Maercker C, Grone HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE (2004)
Endostatin's antiangiogenic signaling network.
Mol Cell 13, 649-663.

This study demonstrated that gene expression underlying the angiogenic balance in tissues can be molecularly reset en masse by the endogenous angiogenesis inhibitor endostatin, which downregulates many signaling pathways in human microvascular endothelium associated with proangiogenic activity and at the same time upregulates many antiangiogenic genes. The result is a complex interpathway communication in an intricate signaling network that provided novel insights into the nature of genetic networking from the cell biologic and therapeutic perspectives.
link to PubMed


15. Wagner W, Ansorge A, Wirkner U, Eckstein V, Schwager C, Blake J, Miesala K, Selig J, Saffrich R, Ansorge W, Ho AD (2004)
Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis.Blood 104, 675-686.

The manuscript is one of the key papers on the molecular mechanisms that regulate asymmetric divisions of hematopoietic progenitor cells (HPCs). It focused on the slow-dividing fraction (SDF) of HPCs  and provided molecular evidence that the SDF is associated with primitive function.
link to PubMed


16. Schmidt M, Carbonaro DA, Speckmann C, Wissler M, Bohnsack J, Elder M, Aronow BJ, Nolta JA, Kohn DB, von Kalle C (2003)
Clonality analysis after retroviral-mediated gene transfer to CD34+ cells from the cord blood of ADA-deficient SCID neonates.Nat Med 9, 463-468.

In this paper, linear amplification-mediated PCR (LAM-PCR) was used to characterize the in vivo clonal composition and insertion locus sequences of vector-marked progeny cells from two ADA-deficient SCID patients in a retroviral gene transfer trial. In one patient, a single vector integrant was predominant in T lymphocytes at a stable level over most of the eight-year time span analyzed and was also detected in some myeloid samples. T-cell clones with the predominant integrant showed multiple patterns of T-cell receptor (TCR) gene rearrangement, indicating that a single pre-thymic stem or progenitor cell served as the source of the majority of the gene-marked cells over an extended period of time.

link to PubMed 


17. Hacein-Bey-Abina S, von Kalle C (shared first coauthorship), Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M (2003)
LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.Science 302, 415-419.

The paper reports the development of an uncontrolled clonal proliferation of mature T lymphocytes in two children with X-linked severe combined immunodeficiency (SCID-X1) after retroviral-mediated gene transfer. The results indicate that retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
link to PubMed  


18. Mahnke K, Qian Y, Knop J, Enk AH (2003)
Dendritic cells, engineered to secrete a T-cell receptor mimic peptide, induce antigen-specific immunosuppression in vivo.
Nat Biotechnol 21, 903-908.

This study reports on the clinical use of genetically engineered DC. DC were transfected with an adeno virus encoding for a T cell receptor mimick peptide that blocks T cell function. When transduced DC try to stimulate specific T cells, the secreted peptide shuts off T cell effector functions. This leads to the antigen-specific blockade of T cells therapeutically useful in autoimmune disease and cancer.
link to PubMed


19. Iben S, Tschochner H, Bier M, Hoogstraten D, Hozak P, Egly JM, Grummt I (2002)
TFIIH plays an essential role in RNA polymerase I transcription.Cell 109, 297-306.

This study showed for the first time that TFIIH, besides its well-established role in transcription of protein coding genes and DNA repair, is also required for rRNA synthesis. It demonstrated an important function of TFIIH on cellular metabolic activity and explained several of the clinical features that are associated with inherited TFIIH defects.
link to PubMed


20. Ostareck DH, Ostareck-Lederer A, Shatsky IN, Hentze MW (2001)
Lipoxygenase mRNA silencing in erythroid differentiation: The 3'UTR regulatory complex controls 60S ribosomal subunit joining.
Cell 104, 281-290

Translational silencing is an important posttranscriptional regulatory mechanism of gene expression. The paper uses 15-lipoxygenase (LOX) expression as a model to study translational silencing and demonstrates that the 40S ribosomal subunit can be recruited and scan to the translation initiation codon even when the silencing complex is bound to the 3'UTR. It identifies the critical step at which LOX mRNA translation is controlled.
link to PubMed


21. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Buchler MW (2001)
Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.
Lancet 358(9293), 1576-1585.

Multicenter randomized controlled trial of adjuvant therapy in pancreatic cancer. Patients were randomised into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). Median follow-up was 10 months. This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy in pancreatic cancer.

link to PubMed  


22. Gerlich D, Beaudouin J, Gebhard M, Ellenberg J, Eils R (2001) Four-dimensional imaging and quantitative reconstruction to analyse complex spatiotemporal processes in live cells.Nat Cell Biol 3, 852-855.

The paper presents a computational approach for reconstruction of spatio-temporally resolved processes based on light microscopic data from living cells. It allows the quantitative analysis of complex biological processes in living cells and paves the way for quantitative computational modeling of these processes. The method is exemplified on the study of nuclear envelope reassembly in mitosis.
link to PubMed


23. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001)
Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193, 1285-1294.

This study represents the initial identification and functional characterization of human naturally occurring Tregs. Their function, surface markers and mechanism of action are described.

link to PubMed 


24. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000)
Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343, 78-85.

The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. This large and exemplary study uses the combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. It shows that inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms and indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

link to PubMed 


25. Sido B, Braunstein J, Breitkreutz R, Herfarth C, Meuer SC (2000) Thiol-mediated redox regulation of intestinal lamina propria T lymphocytes.
J Exp Med 192, 907-912.

Inflammatory bowel disease (IBD) is a definite premalignant condition for colonic cancer. Intestinal lamina propria T lymphocytes (LP-Ts) have a markedly low proliferative potential both in vivo and in vitro. The study demonstrates that the capacity of antigen-presenting cells to release cysteine upon receptor-ligand interactions represents a critical parameter for proliferation of LP-Ts. Thus the local recruitment of blood monocytes represents an important parameter underlying hyperresponsiveness of T cells, an essential component of the pathogenesis of IBD.

link to PubMed