Gerhard Christofori

Universität Basel, Bâle, Basel-City, Switzerland

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Publications (124)1169.74 Total impact

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    ABSTRACT: De novo formation of blood vessels is a pivotal mechanism during cancer development. During the past few years, antiangiogenic drugs have been developed to target tumor vasculature. However, because of limitations and adverse effects observed with current therapies, there is a strong need for alternative antiangiogenic strategies. Using specific anti-junctional adhesion molecule (JAM)-B antibodies and Jam-b-deficient mice, we studied the role in antiangiogenesis of JAM-B. We found that antibodies against murine JAM-B, an endothelium-specific adhesion molecule, inhibited microvessel outgrowth from ex vivo aortic rings and in vitro endothelial network formation. In addition, anti-JAM-B antibodies blocked VEGF signaling, an essential pathway for angiogenesis. Moreover, increased aortic ring branching was observed in aortas isolated from Jam-b-deficient animals, suggesting that JAM-B negatively regulates proangiogenic pathways. In mice, JAM-B expression was detected in de novo-formed blood vessels of tumors, but anti-JAM-B antibodies unexpectedly did not reduce tumor growth. Accordingly, JAM-B deficiency in vivo had no impact on blood vessel formation, suggesting that targeting JAM-B in vivo may be offset by other proangiogenic mechanisms. In conclusion, despite the promising effects observed in vitro, targeting JAM-B during tumor progression seems to be inefficient as a stand-alone antiangiogenesis therapy.-Meguenani, M., Miljkovic-Licina, M., Fagiani, E., Ropraz, P., Hammel, P., Aurrand-Lions, M., Adams, R. H., Christofori, G., Imhof, B. A., Garrido-Urbani, S. Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling. © FASEB.
    The FASEB Journal 04/2015; DOI:10.1096/fj.15-270223 · 5.48 Impact Factor
  • Marco Archetti, Daniela A Ferraro, Gerhard Christofori
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    ABSTRACT: The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.
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    ABSTRACT: Epithelial to mesenchymal transition (EMT) is a program defined in epithelial cells and recognized as playing a critical role in cancer progression. Although melanoma is not a cancer of epithelial cells, hallmarks of EMT have been described to play a critical role in melanoma progression. Here we demonstrate that long term TGFβ exposure can induce a dedifferentiated EMT-like state resembling a previously described invasive phenotype (EMT-like). TGFβ-induced EMT-like is marked by the downregulation of melanocyte differentiation markers, such as MITF, and the upregulation of mesenchymal markers, such as N-cadherin, and an increase in melanoma cell migration and cell invasion. Pharmacological interference shows the dependency of TGFβ-induced EMT-like on the activation of the PDGF signaling pathway and the subsequent activation of PI3K in human melanoma cells. Together, the data provide novel insights into the transcriptional plasticity of melanoma cells that might contribute to tumor progression in patients and propose avenues to therapeutic interventions.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 11/2014; 24(1). DOI:10.1111/exd.12580 · 4.12 Impact Factor
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    ABSTRACT: The cellular changes during an epithelial-mesenchymal transition (EMT) largely rely on global changes in gene expression orchestrated by transcription factors. Tead transcription factors and their transcriptional co-activators Yap and Taz have been previously implicated in promoting an EMT, however, their direct transcriptional target genes and their functional role during EMT have remained widely elusive. We have uncovered a previously unanticipated role of the transcription factor Tead2 during EMT. During EMT in mammary gland epithelial cells and breast cancer cells, levels of Tead2 increase in the nucleus of cells, thereby directing a predominant nuclear localization of its co-factors Yap and Taz via the formation of Tead2/Yap/Taz complexes. Genome-wide chromatin immunoprecipitation/next generation sequencing in combination with gene expression profiling reveals the transcriptional targets of Tead2 during EMT. Among these, zyxin contributes to the migratory and invasive phenotype evoked by Tead2. The results demonstrate that Tead transcription factors are critical regulators of Yap/Taz cellular distribution and together they control the expression of genes critical for EMT and metastasis.
    Journal of Cell Science 02/2014; 127(7). DOI:10.1242/jcs.139865 · 5.33 Impact Factor
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    ABSTRACT: Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys40(Ahx-DTPA-natIn)NH2]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. Combination of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys40(Ahx-DTPA-111In)NH2]-exendin-4. The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.
    02/2014; 4(1):9. DOI:10.1186/2191-219X-4-9
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    ABSTRACT: An epithelial-mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue and disseminate to distant organs. EMT also enriches for cancer stem cells (CSCs) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the up-regulated expression of the pro-angiogenic factor vascular endothelial growth factor A (VEGF-A) and by increased tumor angiogenesis. Based on these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A-mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation.
    Cancer Research 01/2014; 74(5). DOI:10.1158/0008-5472.CAN-13-1641 · 9.28 Impact Factor
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    ABSTRACT: We have identified the zinc-finger transcription factor Kruppel-like factor 4 (Klf4) among the transcription factors that are significantly downregulated in their expression during epithelial-mesenchymal transition (EMT) in mammary epithelial cells and in breast cancer cells. Loss and gain of function experiments demonstrate that the down-regulation of Klf4 expression is required for the induction of EMT and for metastasis . In addition, reduced Klf4 expression correlates with shorter disease-free survival of subsets of breast cancer patients. Yet, reduced expression of Klf4 also induces apoptosis in cells undergoing TGFβ-induced EMT. Chromatin immunoprecipitation/deep-sequencing in combination with gene expression profiling reveals direct Klf4 target genes, including E-cadherin (), N-cadherin (), vimentin (), β-catenin (), VEGF-A (), endothelin-1 () and Jnk1 (). Thereby, Klf4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. Specifically, increased expression of Jnk1 () upon down-regulation of its transcriptional repressor Klf4 is required for EMT cell migration and for the induction of apoptosis. The data demonstrate a central role of Klf4 in the maintenance of epithelial cell differentiation and the prevention of EMT and metastasis.
    PLoS ONE 10/2013; 8(2):e57329. DOI:10.1371/journal.pone.0057329 · 3.53 Impact Factor
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    ABSTRACT: The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic β-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.
    Cell Reports 10/2013; DOI:10.1016/j.celrep.2013.09.014 · 7.21 Impact Factor
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    ABSTRACT: Gene expression profiling has uncovered the transcription factor Sox4 with upregulated activity during TGF-β-induced epithelial-mesenchymal transition (EMT) in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 (H3K27me3) for gene repression. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT in Sox4-deficient cells. Ezh2-mediated H3K27me3 marks associate with key EMT genes, representing an epigenetic EMT signature that predicts patient survival. Our results identify Sox4 as a master regulator of EMT by governing the expression of the epigenetic modifier Ezh2.
    Cancer cell 06/2013; 23(6):768-83. DOI:10.1016/j.ccr.2013.04.020 · 23.89 Impact Factor
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    ABSTRACT: The lymphatic system, the network of lymphatic vessels and lymphoid organs, maintains the body fluid balance and ensures the immunological surveillance of the body. In the adult organism, the de novo formation of lymphatic vessels is mainly observed in pathological conditions. In contrast to the molecular mechanisms governing the generation of the lymphatic vasculature during embryogenesis, the processes underlying pathological lymphangiogenesis are less well understood. A genome-wide screen comparing the transcriptome of tumor-derived lymphatic endothelial cells with that of blood vessel endothelial cells identified paralemmin-1 as a protein prominently expressed in lymphatic endothelial cells. Paralemmin-1 is a lipid-anchored membrane protein that in fibroblasts and neurons plays a role in the regulation of cell shape, plasma membrane dynamics and cell motility. Here, we show that paralemmin-1 is expressed in tumor-derived lymphatic endothelial cells as well as in lymphatic endothelial cells of normal, non-tumorigenic tissue. Paralemmin-1 represses cell migration and delays the formation of tube-like structures of lymphatic endothelial cells in vitro by modulating cell-substrate adhesion, filopodia formation and plasma membrane blebbing. While constitutive genetic ablation of paralemmin-1 expression in mice has no effect on the development and physiological function of the lymphatic system, the loss of paralemmin-1 impaired tumor-associated lymphangiogenesis. Together, these results newly identify paralemmin-1 as a protein highly expressed in lymphatic endothelial cells. Similar to its function in neurons, it may link the cytoskeleton to the plasma membrane and thereby modulate lymphatic endothelial cell adhesion, migration and lymphangiogenesis.
    Angiogenesis 05/2013; DOI:10.1007/s10456-013-9356-7 · 4.41 Impact Factor
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    ABSTRACT: The Hippo (Hpo) pathway is a novel signaling pathway that controls organ size in Drosophila and mammals and is deregulated in a variety of human cancers. It consists of a set of kinases that, through a number of phosphorylation events, inactivate YAP, a transcriptional co-activator that controls cellular proliferation and apoptosis. We have identified PTPN14 as a YAP-binding protein that negatively regulates YAP activity by controlling its localization. Mechanistically, we find that the interaction of ectopic YAP with PTPN14 can be mediated by the respective WW and PPxY motifs. However, the PTPN14 PPxY motif and phosphatase activity appear to be dispensable for the negative regulation of endogenous YAP, likely suggesting more complex mechanisms of interaction and modulation. Finally, we demonstrate that PTPN14 downregulation can phenocopy YAP activation in mammary epithelial cells and synergize with YAP to induce oncogenic transformation.
    PLoS ONE 04/2013; 8(4):e61916. DOI:10.1371/journal.pone.0061916 · 3.53 Impact Factor
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    ABSTRACT: The epithelial-mesenchymal transition (EMT), a prerequisite for cancer progression and metastasis formation, is regulated not only at the transcriptional but also at the post-transcriptional level, including at the level of alternative pre-mRNA splicing. Several recent studies have highlighted the involvement of splicing factors, including epithelial splicing regulatory proteins (Esrps) and RNA-binding Fox protein 2 (Rbfox2), in this process. Esrps regulate epithelial-specific splicing, and their expression is downregulated during EMT. By contrast, the role of Rbfox2 is controversial because Rbfox2 regulates epithelial as well as mesenchymal splicing events. Here, we have used several established cell culture models to investigate the functions of Rbfox2 during EMT. We demonstrate that induction of an EMT upregulates the expression of Rbfox2, which correlates with an increase in Rbfox2-regulated splicing events in the cortactin (Cttn), Pard3 and dynamin 2 (Dnm2) transcripts. At the same time, however, the epithelial-specific ability to splice the Enah, Slk and Tsc2 transcripts is either reduced or lost completely by Rbfox2, which might be due, in part, to downregulation of the expression of the Esrps cooperative factors. Depletion of Rbfox2 during EMT did not prevent the activation of transforming growth factor-β signaling, the upregulation of mesenchymal markers or changes in cell morphology toward a mesenchymal phenotype. In addition, this depletion did not influence cell migration. However, depletion of Rbfox2 in cells that have completed an EMT significantly reduced their invasive potential. Taken together, our results suggest that during an EMT, Rbfox2-regulated splicing shifts from epithelial-to mesenchymal-specific events, leading to a higher degree of tissue invasiveness.Oncogene advance online publication, 25 February 2013; doi:10.1038/onc.2013.50.
    Oncogene 02/2013; DOI:10.1038/onc.2013.50 · 8.56 Impact Factor
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    Meera Saxena, Gerhard Christofori
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    ABSTRACT: Most cancer deaths are due to the systemic dissemination of cancer cells and the formation of secondary tumors (metastasis) in distant organs. Recent years have brought impressive progress in metastasis research, yet we still lack sufficient insights into how cancer cells migrate out of primary tumors and invade into neighboring tissue, intravasate into the blood or the lymphatic circulation, survive in the blood stream, and target specific organs to initiate metastatic outgrowth. While a large number of cellular and animal models of cancer have been crucial in delineating the molecular mechanisms underlying tumor initiation and progression, experimental models that faithfully recapitulate the multiple stages of metastatic disease are still scarce. The advent of sophisticated genetic engineering in mice, in particular the ability to manipulate gene expression in specific tissue and at desired time points at will, have allowed to rebuild the metastatic process in mice. Here, we describe a selection of cellular experimental systems, tumor transplantation mouse models and genetically engineered mouse models that are used for monitoring specific processes involved in metastasis, such as cell migration and invasion, and for investigating the full metastatic process. Such models not only aid in deciphering the pathomechanisms of metastasis, but are also instrumental for the preclinical testing of anti-metastatic therapies and further refinement and generation of improved models.
    Molecular oncology 02/2013; 7(2). DOI:10.1016/j.molonc.2013.02.009 · 5.94 Impact Factor
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    ABSTRACT: An epithelial-mesenchymal transition (EMT) is a critical process during embryonic development and the progression of epithelial tumors to metastatic cancers. Gene expression profiling has uncovered the transcription factor LIM homeobox gene 2 (Lhx2) with up-regulated expression during TGFβ-induced EMT in normal and cancerous breast epithelial cells. Loss and gain of function experiments in transgenic mouse models of breast cancer and of insulinoma in vivo and in breast cancer cells in vitro indicate that Lhx2 plays a critical role in primary tumor growth and metastasis. Notably, the transgenic expression of Lhx2 during breast carcinogenesis promotes vessel maturation, primary tumor growth, tumor cell intravasation and metastasis by directly inducing the expression of platelet-derived growth factor (PDGF)-B in tumor cells and by indirectly increasing the expression of PDGF receptor-β (PDGFRβ) on tumor cells and pericytes. Pharmacological inhibition of PDGF-B/PDGFRβ signaling reduces vessel functionality and tumor growth and Lhx2-induced cell migration and cell invasion. The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRβ loop required for cell migration, invasion and metastatic dissemination and paracrine PDGF-B/PDGFRβ signaling to support blood vessel functionality and, thus, primary tumor growth.
    Molecular oncology 01/2013; 8(2). DOI:10.1016/j.molonc.2013.12.009 · 5.94 Impact Factor
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    ABSTRACT: Vascular integrity is fundamental to the formation of mature blood vessels and depends on a functional, quiescent endothelial monolayer. However, how endothelial cells enter and maintain quiescence in the presence of angiogenic factors is still poorly understood. Here we identify the fibroblast growth factor (FGF) antagonist Sprouty2 (Spry2) as a key player in mediating endothelial quiescence and barrier integrity in mouse aortic endothelial cells (MAECs): Spry2 knockout MAECs show spindle-like shapes and are incapable of forming a functional, impermeable endothelial monolayer in the presence of FGF2. Whereas dense wild type cells exhibit contact inhibition and stop to proliferate, Spry2 knockout MAECs remain responsive to FGF2 and continue to proliferate even at high cell densities. Importantly, the anti-proliferative effect of Spry2 is absent in sparsely plated cells. This cell density-dependent Spry2 function correlates with highly increased Spry2 expression in confluent wild type MAECs. Spry2 protein expression is barely detectable in single cells but steadily increases in cells growing to high cell densities, with hypoxia being one contributing factor. At confluence, Spry2 expression correlates with intact cell-cell contacts, whereas disruption of cell-cell contacts by EGTA, TNFα and thrombin decreases Spry2 protein expression. In confluent cells, high Spry2 levels correlate with decreased extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. In contrast, dense Spry2 knockout MAECs exhibit enhanced signaling by Erk1/2. Moreover, inhibiting Erk1/2 activity in Spry2 knockout cells restores wild type cobblestone monolayer morphology. This study thus reveals a novel Spry2 function, which mediates endothelial contact inhibition and barrier integrity.
    Angiogenesis 12/2012; 16(2). DOI:10.1007/s10456-012-9330-9 · 4.41 Impact Factor
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    ABSTRACT: INTRODUCTION: Increasing evidence supports a role of an epithelial to mesenchymal transition (EMT) process in endowing subsets of tumor cells with properties driving malignant tumor progression and resistance to cancer therapy. To advance our understanding of the underlying mechanisms, we sought to generate a transplantable cellular model system that allows defined experimental manipulation and analysis of EMT in vitro and at the same time recapitulates oncogenic EMT in vivo. METHODOLOGY/RESULTS: We have established a stable murine breast cancer cell line (Py2T) from a breast tumor of an MMTV-PyMT transgenic mouse. Py2T cells display a metastable epithelial phenotype characterized by concomitant expression of luminal and basal cytokeratins and sheet migration. Exposure of Py2T cells to transforming growth factor β (TGFβ) in vitro induces reversible EMT accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers, including EMT transcription factors, and a gain in single cell motility and invasiveness. Py2T cells give rise to tumors after orthotopic injection into syngeneic FVB/N mice. Notably, transplantation of epithelial Py2T cells results in the formation of invasive primary tumors with low to absent E-cadherin expression, indicating that the cells undergo EMT-like changes in vivo. This process appears to at least in part depend on TGFβ signaling, since tumors formed by Py2T cells expressing a dominant-negative version of TGFβ receptor widely maintain their epithelial differentiation status. CONCLUSIONS/SIGNIFICANCE: Together, the data demonstrate that the Py2T cell line represents a versatile model system to study the EMT process in vitro and in vivo. The observation that Py2T cells give rise to tumors and collectively undergo EMT-like changes in vivo highlights the suitability of the Py2T model system as a tool to study tumor-related EMT. In particular, Py2T cells may serve to corroborate recent findings relating EMT to cancer cell stemness, to therapy resistance and to tumor recurrence.
    PLoS ONE 11/2012; 7(11):e48651. DOI:10.1371/journal.pone.0048651 · 3.53 Impact Factor
  • Ernesta Fagiani, Gerhard Christofori
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    ABSTRACT: Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo-vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer.
    Cancer letters 08/2012; 328(1). DOI:10.1016/j.canlet.2012.08.018 · 5.02 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):5714-5714. DOI:10.1158/1538-7445.AM2012-5714 · 9.28 Impact Factor
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    Adrian Zumsteg, Gerhard Christofori
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    ABSTRACT: The lymphatic vascular system and the hematopoietic system are intimately connected in ontogeny and in physiology. During embryonic development, mammalian species derive a first lymphatic vascular plexus from the previously formed anterior cardinal vein, whereas birds and amphibians have a lymphatic vascular system of dual origin, composed of lymphatic endothelial cells (LECs) of venous origin combined with LECs derived from mesenchymal lymphangioblasts. The contribution of hematopoietic cells as building blocks of nascent lymphatic structures in mammals is still under debate. In contrast, the importance of myeloid cells to direct lymphatic vessel growth and function postnatally has been experimentally shown. For example, myeloid cells communicate with LECs via paracrine factors or cell-cell contacts, and they also can acquire lymphatic endothelial morphology and marker gene expression, a process reminiscent of developmental vasculogenesis. Here, we present an overview of the current understanding of how lymphatic vessels and the hematopoietic system, in particular myeloid cells, interact during embryonic development, in normal organ physiology, and in disease.
    Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a006494. DOI:10.1101/cshperspect.a006494 · 7.56 Impact Factor
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    ABSTRACT: NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic β-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared with Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-2, a high-affinity ligand for IGF1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials neither did affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, that is, the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-2 and of the IGF-2-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-2. The reduction of tumor invasion upon IGF1R blockade on the other hand indicates a critical function of IGF1R signaling for the acquisition of a malignant phenotype.
    Molecular Cancer Research 05/2012; 10(6):800-9. DOI:10.1158/1541-7786.MCR-11-0522 · 4.50 Impact Factor

Publication Stats

10k Citations
1,169.74 Total Impact Points

Institutions

  • 2003–2015
    • Universität Basel
      • • Department of Biomedicine
      • • Institut für Biochemie und Genetik
      Bâle, Basel-City, Switzerland
  • 2013
    • Swiss Institute of Bioinformatics
      Lausanne, Vaud, Switzerland
  • 2007
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 1997–2002
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 1999
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1994–1996
    • University of California, San Francisco
      • Department of Biochemistry and Biophysics
      San Francisco, CA, United States