Prof. Curzio Rüegg - Impact of antiangiogenic treatments on tumor evolution and tumor microenvironment
Prof. Curzio Rüegg
Multidisciplinary Oncology Center (CePO)
Prof. Curzio Rüegg received his M.D. and Doctorate in Medicine from the University of Basel in 1985. He attended the Postgraduate Course in Experimental Medicine and Biology at the University of Zürich. He did post-doctoral research at the Department of Inflammation and Allergy at CIBA-GEIGY in Basel and with Dr. R. Pytela and Dr. D. Sheppard at University of California at San Francisco (CA). In 1993 he joined the Centre Pluridisciplinaire d’Oncologie (CePO) with a SCORE fellowship from the Swiss National Science Foundation to head the CePO laboratory at ISREC. From 2006 to 2010 he was director and Médecin Chef of the Division of Experimental Oncology of CePO-CHUV-UNIL. He is cofounder of Diagnoplex, a Health Science start-up company active in early detection and monitoring of cancer. His current main research interest is the study of the role of the tumor microenvironment and its therapeutic modulation in controlling tumor invasion and metastasis. Since 2010 he became affiliated as a Full Professor at the University of Fribourg. University of Fribourg
CH-1700 Fribourg, Switzerland
Impact of antiangiogenic treatments on the tumor microenvironment and on tumor evolution
Cancer cells establish complex heterotypic multicellular interactions with the healthy neighboring tissue. Hence the concept of tumor microenvironment as an integrated and essential part of the cancer tissue. The tumor microenvironment contains many distinct cell types, including endothelial cells forming blood and lymphatic vessels, fibroblasts forming a fibrotic tissue and inflammatory and bone marrow-derived cells sustaining a ‘tumor-associated’ inflammatory reaction and provides essential cues to tumor cell survival, growth, motility and invasion, and eventually metastasis formation (Fig. 1). Furthermore, tumors experience chronic hypoxia owing to increased metabolism and insufficient oxygen delivery within poorly perused tumor regions. Hypoxia elicits a stress reaction in tumor cells orchestrated by hypoxia-inducible factor (HIF), a transcription factor that activates programs regulating cellular metabolism, cell survival, angiogenesis and invasion.
In recent years the tumor microenvironment has received much attention as possible therapeutic target to control tumor grow. Inhibition of the formation of tumor-associated vessels, an event also known as tumor angiogenesis, was shown to result in decreased tumor growth. Several anti-angiogenic compounds have been approved for human use (such as the anti-VEGF antibody Avastin®, of the VEGFR-kinase inhibitors Sutent® and Nexavar®) based on their ability to provide survival benefits to patients with advanced cancers.
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Figure 1. Tumor cells orchestrate the modification of the microenvironment by attracting or activating many non-tumoral cells, including blood and lymphatic endothelial cells, fibroblast, bone marrow-derived cells, immune and inflammatory cells. Tumor cells can also deposit or modify the extracellular matrix. In turn, the tumor microenvironment promotes tumor progression by stimulating tumor growth and survival, and facilitating invasion and metastasis. Mild to severe hypoxia is chronically present in the tumor microenvironment. Hypoxia induces programs promoting cell survival, invasion, angiogenesis and resistance to therapy though the activation of the transcription factor HIF. Although antiangiogenic therapy initially suppressed tumor growth, it appears that tumor adapt and escape. It is therefore important to characterize microenvironmental modifications induced by antiangiogenic therapy and hoe tumors adapt to it. |
The proposed project is aimed at characterizing the effects of antiangiogenic treatments on the tumor microenvironment and on tumor cells using in vivo experimental models of tumor progression, in vitro cellular, biochemical and molecular approaches and ex vivo cellular and correlative studies using material obtained from patients undergoing antiangiogenesis treatments. Specifically, the questions addressed include
How do tumor cells adapt to antiangiogenic therapy ?
While it has been traditionally assumed that antiangiogenic treatments will not face the problem of resistance as observed with classical chemotherapy, emerging evidence indicates that indeed tumors can escape angiogenic blockade. We will transiently treat tumor-bearing mice with antiangiogenic drugs using various models established in the laboratory in combination with tumor re-transplantation studies, cell biology, biochemical and gene expression experiments, to unravel the molecular basis of evasive resistance an identify putative therapeutic targets to prevent it.
How does antiangiogenic therapy modify bone marrow derived cell (BMDC) mobilization and recruitment to the tumor microenvironment ?
Cells recruited to the tumor microenvironment, in particular BMDC and monocytes, actively contribute to tumor progression. BMDC and monocytes are important sensors of tissue hypoxia and necrosis and it is not clear how these cells will react in response to antiangiogenic treatments. We will characterize phenotypical, molecular and functional changes in BMDC in the in the circulation and tumor stroma of tumor-bearing mice during ad after antiangiogenic treatments.
Do chemo and antiangiogenic therapies modify circulating and tumor-recruited BMDC in cancer patients, and how do these changes relate to response/resistance to therapy ?
To date there are no validate surrogate markers of angiogenesis or anti-angiogenic activity. Tumor growth and therapy was shown to modulate circulating BMDC and inflammatory cells in experimental models. In cancer patients some of these BMDC and leukocyte cell population appear to correlate with the tumor burden. The impact of therapy of these cells and their implication in promoting resistance and/or tumor progression remain largely elusive. We propose to monitor the presence of specific BMDC and leukocyte subsets in patients with non-metastatic cancers before, during and after treatment with the purpose to identify changes associated with response, resistance to therapy and/or tumor progression.
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Figure 2. Microenvironmental changes, including therapy-induced, can favor the selection of tumor cells escaping the primary tumor and forming metastases through the lymphatic system or via blood vessels. Bone marrow-derived and inflammatory cells mobilized by the tumor and recruited at the primary or metastatic sites are essential promoters of tumor growth and metastatic seeding. One main aim of this project is to understand how antiangiogenic and chemotherapy modify the tumor microenvironment including bone marrow-derived cells, and identify novel target to prevent tumor escape and metastasis formation. |
List of publications
Bieler, G., Hasmim, M., Monnier, Y., Imaizumi, N., Ameyar, M., Bamat, J., Ponsonnet, L., Chouaib, S., Grell, M., Goodman, S.L., Lejeune, F., Ruegg, C. Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival. Oncogene. Mar 19; [Epub ahead of print] (2007)
Hasmim, M., Bieler G., and Rüegg, C. Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways. J. Thromb. Hemost. 5(1):166-73 (2007)
Lejeune, F.J., Monnier, Y., Ruegg, C. Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase-2 inhibitor, Melanoma Res., 16(3):263-5 (2006)
Zaman, K., Driscoll, R., Hahn, D., Werffeli, P., Goodman, S.L., Bauer, J., Leyvraz, S., Lejeune, F., Stupp, R., Ruegg, C. Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy. International Journal of Cancer, 118(3):755-64 (2006)
Hasmim, M., Vassalli, G., Ponsonnet, l., Vassalli, G., Bamat, J., Bieler, C., Paroz, J., Oguey, D., and Rüegg, C. Endothelial cell death induced by expression of isolated integrin b1 subunit cytoplasmic domain in vitro and in vivo is secondary to cell detachment Thromb. Haemost., 94: 1060-1070 (2005)
Foletti, A., Alghisi, GC., Ponsonnet L., Ruegg C. Isolated integrin beta3 subunit cytoplasmic domains require membrane anchorage and the NPXY motif to recruit to adhesion complexes but do not discriminate between beta1- and beta3-positive complexes. Thrombosis and Haemostasis, 94,155-66 (2005)
Broillet A., Hantson, J., Ruegg, C., Messager, T., Schneider, M. Assessment of microvascular perfusion changes in a rat breast tumor model using SonoVue to monitor the effects of different anti-angiogenic therapies.
Academic Radiology, 12, S28-33 (2005)
Monnier, Y., Zaric, J., Ruegg, C. Inhibition of Angiogenesis by Non-Steroidal Anti-Inflammatory Drugs: From the Bench to the Bedside and Back. Curr Drug Targets Inflamm Allergy. 4, 31-38 (2005)
Zaric, J., Ruegg, C. Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation. Journal of Biological Chemistry 280, 1077-1085 (2005)
Bezzi, M., Hasmim, M., Bieler, G., Dormond, O., Rüegg, C. Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death, evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. Journal of Biological Chemistry 278, 43603-14 (2003)
Dormond, O., Rüegg, C. Regulation of endothelial cell integrin function and angiogenisis by COX-2, cAMP and Protein Kinase A. Thrombosis and Haemostasis 90, 577-855 (2003)
Rüegg, C., Zaric, J., Stupp, R. Non steroidal anti-inflammatory drugs and COX-2 inhibitors as anti-cancer therapeutics, hypes, hopes and reality. Annals of Medecine 35, 476-87 (2003)
Stupp, R., Rüegg, C. New drugs and combinations for malignant glioma. FORUM Trends Clinical and Experimental Medicine 13, 61-75 (2003)
Reviews
C. Rüegg and Solange Peters. Thalidomide in small cell lung cancer: wrong drug or wrong disease? J. Natl Cancer Inst, 101(15):1034-5 (2009)
C. Sessa, A. Guybal, GL Del Conte and C. Rüegg. Biomarkers of angiogenesis in the development of antiangiogenic therapies in oncology: tools or decorations? Nature Clin. Pract. Oncol., 5:378-91 (2008)
G. Lorusso and C. Rüegg. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem. Cell Biol., 130:1091-103 (2008)
C. Rüegg, J.D. Tissot, P. Farmer and A. Mariotti. The omics revolution meets hypothesis-driven research: partnership for innovative discoveries in vascular biology and angiogenesis. Thromb. Haemost. 100:738-46 (2008)
N. Mutter and C. Rüegg. Anti-angiogenic therapies in cancer: achievements and open questions. Bull. Cancer, 94:753-62 (2007)
Stupp, R. and Rüegg, C. Integrin inhibitors reach the clinic (editorial). J. Clin Oncol. 25(13):1637-8 (2007)
Mariotti, A., Perotti, A., Sessa, C., and Rüegg, C. N-cadherin as a therapeutic target in cancer. Expert Opinion on Investigational Drugs 16(4):451-65 (2007)
Lejeune, F.J., and Rüegg, C. Recombinant human tumor necrosis factor: an efficient agent for cancer treatment. Bull Cancer 93, E90-100. (2006)
Alghisi, G.C. and Ruegg, C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets, Endothelium, 13(2):113-35 (2006)
Ruegg, C. Leukocytes, inflammation, and angiogenesis in cancer: fatal attractions, J Leukoc Biol. 80(4):682-4 (2006)
Lejeune, F.J., Lienard, D., Matter, M., Ruegg, C. Efficiency of recombinant human TNF in human cancer therapy, Cancer Immun., 6:6 (2006)
Monnier, Y., Zaric, J. and Rüegg, C. Inhibition of Angiogenesis by Non-Steroidal Anti-Inflammatory Drugs: From the bench to the bedside and back. Curr Drug Targets, 4, 33-40 (2005)
Rüegg, C., Hasmim, M., Lejeune, F. and Alghisi G.C., Anti-angiogenic peptides and proteins: from experimental tools to clinical drugs, Biochim Biophys Acta., 1765(2):155-77 (2005)
Rüegg, C., Dormond, O., Mariotti, A. Endothelial cell integrins and COX-2, Mediators and therapeutic targets of tumor angiogenisis. Biochimica et Biophysica Acta (BBA). - Reviews on Cancer 1654, 51-67 (2004)
Rüegg, C., Driscoll, R., Werffely-George, P., Meuwly, J., Khalil, Z., Stupp, R. The quest for surrogate markers of angiogenisis, a paradigm for translational research in tumor angiogenisis and anti-angiogenesis trials. Current Molecular Medicine 3, 673-691 (2003)
Rüegg, C., Driscoll R., Werffely-George P., Stupp R. Translational research in tumor angiogenesis, from bench to bedside and back to the bench. Bulletin Suisse du Cancer 23, 3 (2003)
Rüegg, C. Targeting the tumor vasculature as an anti-cancer therapy, emerging paradigms and open questions. Swiss Medical Forum 14, 317-323 (2002)
Book Chapter
C. Rüegg and G.C. Alghisi. Integrins in angiogenesis and angiogenesis inhibition. In Recent Results in cancer Research. Editors: Berdel, Kessel, Liersch, Springer Verlag (2009)
C. Rüegg (2009). New answers to old questions in metastasis research. In Interdisziplinäres Zürcher Symposium, Edition 2009. Editor. C.A. Redaelli, Zürich (2009)
Lejeune, F.J., Liénard, D., and Rüegg, C. Recombinant human TNF in human cancer therapy (book chapter), 1906-2006 - Cent ans d'innovations diagnostiques et thérapeutiques en cancérologie (Ed Jacques Robert et al.) John Libbey (2006)