National Center of Competence in Research - NCCR Molecular Oncology

Prof. Gerhard Christofori

Prof. Gerhard Christofori studied Biology at the University of Heidelberg, and obtained his PhD in 1988 in the laboratory of Walter Keller at the German Cancer Research Center in Heidelberg and at the Biocenter of the University Basel on the biochemistry of 3’ processing of eukaryotic messenger RNA. He did postdoctoral training with Douglas Hanahan at the University of California San Francisco, USA, where he began to study the molecular mechanisms of multistage tumor development. In 1994 he became a group leader at the Institute of Molecular Pathology (IMP) in Vienna, Austria. Since September 2001 he is Professor and Chair of Biochemistry and head of the Institute of Biochemistry and Genetics at the Department of Clinical-Biological Sciences of the University of Basel.

Department of Biomedicine
University of Basel
Center of Biomedicine

Unraveling the molecular regulation of tumor lymphangiogenesis and lymph node metastasis

Ninety-percent of cancer deaths are caused by metastasis – when the primary tumor turns malignant and part of it breaks away and spreads to other parts of the body. Understanding how this happens, and finding ways to stop it, is a major objective of our research. In addition to culturing tumor cells in Petri dishes, we employ transgenic mouse models of tumorigenesis to determine causal connections between the function of a particular gene product and tumor progression in a whole organism. Such molecular functions may offer effective targets for the development of cancer therapy.

Tumor angiogenesis

One major step in tumor outgrowth is the formation of new blood vessels to supply growing tumor cells with oxygen and nutrition, a process termed angiogenesis. While it is well know that angiogenesis is rate-limiting for tumor growth, the details of its regulation and its contribution to metastasis formation are still poorly understood. Moreover, faced by the upcoming possibilities to treat cancer patients with drugs that inhibit tumor angiogenesis, it is important to assess whether such treatments also prevent metastatic disease.

Tumor lymphangiogenesis

It is now well established that lymphatic vessels forming during carcinogenesis (tumor lymphangiogenesis) support the metastatic dissemination of tumor cells to lymph nodes, a first step in metastatic disease. We investigate how tumor lymphangiogenesis is regulated at the molecular level and how tumor cells intrude in the lymphatic system to form lymph node metastasis. Notably, we have recently demonstrated that bone marrow-derived cells of the myeloid lineage contribute to tumor lymphangiogenesis by differentiating into lymphatic endothelial cells and by incorporating into newly formed lymphatic vessels. The molecular processes underlying this differentiation process are one major focus in our laboratory.

Metastasis

Finally, we are studying the molecular mechanisms by which a benign tumour cell is triggered to become a malignant, invasive cell. One experimental approach is based on the rationale that when tumor cells leave their origin and start to migrate, they have to change their communication with the environment, which involves changes in adhesion molecules. We have found that these changes also activate signalling pathways which induce cell migration and the breaking down of the matrix that holds cells in place. As a result, tumor cells infiltrate the blood stream, disseminate through the blood circulation, and leave the blood vessels at a distant location to seed deadly metastases.

Figure 1. VEGF-D-mediated lymphangiogenesis during tumor progression in a mouse model of pancreatic beta cell carcinogenesis. Blood vessels (red) and lymphatic vessels (green) are visualized by immunofluorescent staining with antibodies aginst CD31 and LYVE-1, respectively. Note the presence of lymphatic vessels in the periphery and the body of the tumor and the morphological changes of blood vessels within the tumor.

List of publications

Zumsteg, A., Baeriswyl, V., Imaizumi, N., Schwendener, R., Rüegg, C., and Christofori, G. Myeloid cells contribute to tumor lymphangiogenesis. PLOS One (2009)

Francavilla, C., Cattaneo, P., Berezin, V., Bock, E., Ami, D., de Marco, A., Christofori, G., and Cavallaro, U. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J. Cell Biol., (2009)

Tremmel, M., Matzke, A., Albrecht, I, Laib, A., Olaku, V., Ballmer-Hofer, K., Christofori, G., Héroult, M., Augustin, H., Ponta, H., and Orian-Rousseau, V. CD44v6 peptides, potential angiogenesis inhibitors, show that CD44 regulates VEGFR-2 (2009)

Bergmann, A., Ahmad, S., Cudmore, M., Gruber, A.D., Wittschen, P., Lindenmaier, W., Christofori, G., Gross, V., da Costa Gonzalves, A.C., Gröne, H.J., Ahmed, A., Weich, H.A. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J. Cell Mol. Med. Jun 16. (2009)

Schomber, T., Zumsteg, A., Strittmatter, K., Crnic, I., Antoniadis, H., Littlewood-Evans, A., Wood, J., and Christofori, G. Differential effects of the VEGF receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol. Cancer Ther. 8, 55-63 (2009)

Lehembre, F., Yilmaz, M., Wicki, A., Schomber, T., Strittmatter, K., Ziegler, D., Kren, A., Went, P., Derksen, P., Berns, A., Jonkers, J., and Christofori, G. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J. 27, 2603-2615 (2008)

Andres, G., Leali, D., Mitola, S., Coltrini, D., Camozzi, M., Corsini, M., Belleri, M., Hirsch, E., Schwendener, R.A., Christofori, G., Alcami, A., and Presta, M. A pro-inflammatory signature mediates FGF-2-induced angiogenesis. J. Cell. Mol. Med. Jun 28. (2008)

Tammela, T., Zarkadi, G., Wallgard, E., Murtomäki, A., Suchting, S., Wirzenius, M., Waltari, M., Hellström, M., Schomber, T., Peltonen, R., Freitas, C., Duarte, A., Isonemi, H., Laakonen, P., Christofori, G., Ylä-Herttuala, S., Shibuya, M., Pytowski, B., Eichmann, A., Betsholtz, C., and Alitalo, K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656-660 (2008)

Sobczak, I., Galabova-Kovacs, G., Sadzak, I., Kren A., Christofori, G. and Baccarini, M. B-Raf is required for ERK activation and tumor progression in pancreatic b-cell carcinogenesis. Oncogene 27, 4779-4787 (2008)

Wicki, A., Wild, D., Storch, D., Seemayer, C., Béhé, M., Gotthardt, M., Kneifel, S., Mihatsch, M., Reubi, J.C., Mäcke, H.R., and Christofori, G. A new therapeutic approach to insulinoma: [(Lys40(Ahx-[111In-DTPA])]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 (GLP-1) receptor-targeted therapy. Clinical Cancer Res. 13, 3696-3705 (2007)

Schomber, T., Kopfstein, L., Djonov, V., Albrecht, I., Baeryiswyl, V., Strittmatter, K., and Christofori G. Placental growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during b cell carcinogenesis. Cancer Res. 67, 10840-10848 (2007)

Francavilla, C., Loeffler, S., Piccini, D., Kren, A., Christofori, G., and Cavallaro, U. Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor. J. Cell Sci. 120(Pt 24):4388-94 (2007)

Berx, G., Raspe, E., Christofori, G., Thiery, J.P., and Sleeman, J. Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 4, 587-97 (2007)

Kopfstein, L., Veikkola, T., Djonov, V.G., Baeriswyl, V., Schomber, T., Strittmatter, K., Stacker, S.A., Achen, M., Alitalo, K. and Christofori, G. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am. J. Pathol. 170(4):1348-61 (2007)

Wild, D., Béhé, M., Wicki, A., Storch, D., Waser, B., Gotthard, M., Christofori, G., Reubi, J.C., and Mäcke, H.R. [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma. J. Nuclear Med. 47(12):2025-33 (2006)

Herzig, M., Novatchkova, M., Savarese, F., Perl, A.-K., Wilgenbus, P., and Christofori, G. Tumor progression induced by the loss of E-cadherin independent of beta-catenin/Tcf-mediated Wnt-signaling. Oncogene. 26(16):2290-8 (2006)

Fiedler, U., Christian, S., Koidl, S., Kerjaschki, D., Emmett, M.S., Bates, D.O., Christofori, G., and Augustin, H.G. The sialomucin CD34 is a marker of tumor-associated lymphatic endothelial cells in tumors. Am. J. Pathol. 168, 1045-1053. (2006)

Eldor, R., Yeffet, A., Baum, K., Doviner, V., Amar, D., Ben-Neriah, Y., Christofori, G., Peled, A., Carel, J.C., Boitard, C., Klein, T., Serup, P., Eizirik, D.L., Melloul, D. Conditional and specific NF-{kappa}B blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci USA 103,5072-5077 (2006)

Wicki, A., Lehembre, F., Wick N., Hantusch B., Kerjaschki D., and Christofori, G. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the cytoskeleton. Cancer Cell 9, 261-272 (2006)

Schaffhauser, B., Strittmatter, K., Antoniadis, H., Veikkola, T., Alitalo, K., and Christofori, G. Moderate anti-angiogenic activity by local transgenic expression of endostatin in Rip1Tag2 transgenic mice. J. Leuk. Biol. 80, 669-676 (2006)

Grotegut, S., von Schweinitz, D., Christofori, G., and Lehembre, F. Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25, 3534–3545 (2006)

Cabrita, M., Jäggi, F., Widjaja, S., and Christofori, G. A functional interaction between Sprouty proteins and caveolin-1. J. Biol. Chem. 281, 29201-2912 (2006)

Reviews

Baeriswyl.V. and Christofori, G. The angiogenic switch in carcinogenesis. Sem. in Cancer Biol. May 29 (2009)

Yilmaz, M. and Christofori, G. EMT, the cytoskeleton, and cancer invasion. Cancer Metastasis Rev. 28, 15-33 (2009)

Zumsteg, A. and Christofori, G. Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr. Opin. Oncol. 21, 60-70 (2009)

Cabrita. M. and Christofori, G. Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11, 53-62 (2008)

Berx, G., Raspe, E., Christofori, G., Thiery, J.P., and Sleeman, J. Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Breast Cancer Metastasis 24, 587-597(2007)

Yilmaz, M., Christofori, G., and Lehembre, F. Distinct mechanisms of tumor invasion and metastasis. Trends Mol. Med. 13, 535-541 (2007)

Christofori, G. Division of labour (News and Views). Nature 446, 735-736 (2007)

Wicki, A. and Christofori, G. The potential role of podoplanin in tumour invasion. Br. J. Cancer. 96(1):1-5 (2007)

Fantozzi, A., Christofori, G., Mouse models of breast cancer metastasis, Breast Cancer Res., 8(4):212 (2006) full review [pdf]

Christofori, G., New signals from the invasive front, Nature, 441(7092):444-50 (2006)

Kopfstein, L. and Christofori, G., Metastasis: Cell autonomous versus stroma-contributed mechanisms, Cell. Mol. Life Sci., 63(4):449-68 (2006)

Book Chapter

Wicki, A. and Christofori, G. E-cadherin. In: Cancer Research, an Encyclopedic Reference, (2nd edition, ed. Schwab, M.) Springer Verlag, Heidelberg (2007)

Wicki, A. and Christofori, G. Podoplanin and cancer. In: Cancer Research, an Encyclopedic Reference, (2nd edition, ed. Schwab, M.) Springer Verlag, Heidelberg (2007)

Wicki, A. and Christofori, G. The molecular basis of the angiogenic switch In: Tumor Angiogenesis: Mechanisms and Cancer Therapy (eds. N. Fusenig and D. Marme) Springer Verlag, Heidelberg (2006)