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Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas

Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas Abstract Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine that has been implicated in glioma invasion and angiogenesis. The SF/HGF receptor, MET, has been found to be expressed in neoplastic astrocytes as well as in endothelial cells of the tumor vasculature. Both SF/HGF and MET expression have also been described to correlate with the malignancy grade of human gliomas. However, most glioblastoma cell lines lack SF/HGF expression, raising the question of the cellular origin of SF/HGF in vivo. Using in situ hybridization, we analyzed glioblastomas, anaplastic astrocytomas, diffuse astrocytomas, pilocytic astrocytomas, and normal brain for the expression of SF/HGF mRNA. We detected strong SF/HGF expression by the majority of the tumor cells and by vascular endothelial cells in all glioblastoma specimens analyzed. Combined use of in situ hybridization with fluorescence immunohistochemistry confirmed the astrocytic origin of the SF/HGF-expressing cells. In contrast, CD68-immunoreactive microglia/macrophages, as well as vascular smooth muscle cells reactive to -smooth muscle actin, lacked SF/HGF expression. In anaplastic, diffuse, and pilocytic astrocytomas, SF/HGF expression was confined to a subset of tumor cells, and signals were less intense than in glioblasto mas. In addition, we detected SF/HGF mRNA in cortical neurons. SF/HGF expression was not up regulated around necroses or at tumor margins. MET immunoreactivity was observed in GFAP-expressing astrocytic tumor cells and endothelial cells as well as in a subset of microglia/macrophages. We conclude that in vivo, both autocrine and paracrine stimulation of tumor cells and endothelium through the SF/HGF-MET system are likely to contribute to tumor invasion and angiogenesis. Lack of SF/HGF expression by most cultured glioblastoma cells is not representative of the in vivo situation and most likely represents a culture artifact. References Abounader, R., Ranganathan, S., Lal, B., Fielding, K., Book, A., Dietz, H., Burger, P., and Laterra, J. ( 1999 ) Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J. Natl. Cancer Inst. 91 , 1548 -1556. Achim, C.L., Katyal, S., Wiley, C.A., Shiratori, M., Wang, G., Oshika, E., Petersen, B.E., Li, J.M., and Michalopoulos, G.K. ( 1997 ) Expression of HGF and cMet in the developing and adult brain. Brain Res. 102 , 299 -303. Badie, B., Schartner, J., Klaver, J., and Vorpahl, J. ( 1999 ) In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. Neurosurgery 44 , 1077 -1083. Di Renzo, M.F., Bertolotto, A., Olivero, M., Putzolu, D., Crepaldi, T., Schiffer, D., Pagni, C.A., and Comoglio, P.M. ( 1993 ) Selective expression of the met/HGF-receptor in human central nervous system microglia. Oncogene 8 , 219 -222. Ebens, A., Brose, K., Leonardo, E.D., Hanson, M.G., Jr., Bladt, F., Birchmeier, C., Barres, B.A., and Tessier-Lavigne, M. ( 1996 ) Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. Neuron 17 , 1157 -1172. Grant, D.S., Kleinman, H.K., Goldberg, I.D., Bhargava, M.M., Nickoloff, B.J., Kensella, J.L., Polverini, P., and Rosen, E.M. ( 1993 ) Scatter factor induces blood vessel formation in vivo. Proc. Natl. Acad. Sci. U.S.A. 90 , 1937 -1941. Hayashi, S., Morishita, R., Nakamura, S., Yamamoto, K., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Matsumoto, K., Nakamura, T., Higaki, J., and Ogihara, T. ( 1999 ) Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 100 (Suppl. 19), 301 -308. Hirose, Y., Kojima, M., Sagoh, M., Murakami, H., Yoshida, K., Shimazaki, K., and Kawase, T. ( 1998 ) Immunohistochemical examination of c-Met protein expression in astrocytic tumors. Acta Neuropathol. 95 , 345 -351. Jung, W., Castren, E., Odenthal, M., Vande Woude, G.F., Ishii, T., Dienes, H.P., Lindholm, D., and Schirmacher, P. ( 1994 ) Expression and functional interaction of hepatocyte growth factor-scatter factor and its receptor c-met in mammalian brain. J. Cell. Biol. 126 , 485 -494. Kleihues, P., and Cavenee, W.K. (Eds.) ( 2000 ) World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System . Lyon, France: IARC Press. Komminoth, P. ( 1996 ) Detection of mRNA in tissue sections using DIG-labeled RNA and oligonucleotide probes. In: Nonradioactive In Situ Hybridization Application Manual. 2nd ed. Mannheim, Germany: Boehringer-Mannheim. pp. 126 -135. Koochekpour, S., Jeffers, M., Rulong, S., Taylor, G., Klineberg, E., Hudson, E.A., Resau, J.H., and Vande Woude, G.F. ( 1997 ) Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 57 , 5391 -5398. Lamszus, K., Schmidt, N.O., Jin, L., Laterra, J., Zagzag, D., Way, D., Witte, M., Weinand, M., Goldberg, I.D., Westphal, M., and Rosen, E.M. ( 1998 ) Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells. Int. J. Cancer 75 , 19 -28. Lamszus, K., Laterra, J., Westphal, M., and Rosen, E.M. ( 1999 ) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int. J. Dev. Neurosci. 17 , 517 -530. Laterra, J., Nam, M., Rosen, E.M., Rao, J.S., Lamszus, K., Goldberg, I.D., and Johnston, P. ( 1997 ) Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab. Invest. 76 , 565 -577. Maina, F., Hilton, M.C., Poncetto, C., Davies, A.M., and Klein, R. ( 1997 ) Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 11 , 3341 -3350. Moore, S., and Thanos, S. ( 1996 ) The concept of microglia in relation to central nervous system disease and regeneration. Prog. Neurobiol. 48 , 441 -460. Phillips, H.S., Armani, M.P., Stavrou, D., Ferrara, N., and Westphal, M. ( 1993 ) Intense focal expression of vascular endothelial growth factor mRNA in human intracranial neoplasms: association with regions of necrosis. Int. J. Oncol. 2 , 913 -919. Plate, K.H., Breier, G., Weich, H.A., and Risau, W. ( 1992 ) Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 359 , 845 -848. Roggendorf, W., Strupp, S., and Paulus, W. ( 1996 ) Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol. 92 , 288 -293. Rosen, E.M., Nigam, S.K., and Goldberg, I.D. ( 1994 ) Scatter factor and the c-met receptor: A paradigm for mesenchymal/epithelial interaction. J. Cell Biol. 127 , 1783 -1787. Rosen, E.M., Laterra, J., Joseph, A., Jin, L., Fuchs, A., Way, D., Witte, M., Weinand, M., and Goldberg, I.D. ( 1996 ) Scatter factor expression and regulation in human glial tumors. Int. J. Cancer 67 , 248 -255. Schmidt, N.O., Westphal, M., Hagel, C., Ergün, S., Stavrou, D., Rosen, E.M., and Lamszus, K. ( 1999 ) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer 84 , 10 -18. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. ( 1992 ) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359 , 843 -845. Wong, V., Glass, D.J., Arriaga, R., Yancopoulos, G.D., Lindsay, R.M., and Conn, G. ( 1997 ) Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor. J. Biol. Chem. 272 , 5187 -5191. Yamada, T., Tsubouchi, H., Daikuhara, Y., Prat, M., Comoglio, P.M., McGeer, P.L., and McGeer, E.G. ( 1994 ) Immunohistochemistry with antibodies to hepatocyte growth factor and its receptor protein (c-MET) in human brain tissues. Brain Res. 637 , 308 -312. Yamamoto, Y., Livet, J., Pollock, R.A., Garces, A., Arce, V., de Lapeyriere, O., and Henderson, C.E. ( 1997 ) Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons. Development 124 , 2903 -2913. Yang, X.M., Toma, J.G., Bamji, S.X., Belliveau, D.J., Kohn, J., Park, M., and Miller, F.D. ( 1998 ) Autocrine hepatocyte growth factor provides a local mechanism for promoting axonal growth. J. Neurosci. 18 , 8369 -8381. Zarnegar, R., Muga, S., Rahija, R., and Michalopoulos, G. ( 1990 ) Tissue distribution of hepatopoietin-A: A heparin-binding polypeptide growth factor for hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 87 , 1252 -1256. Author notes Departments of Neurosurgery (P.K., S.M., R.F., M.W.) andNeuropathology (D.S., K.L.), University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; andInstitute of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany (P.S.) © 2001 by the Society for Neuro-Oncology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuro-Oncology Oxford University Press

Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas

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Publisher
Oxford University Press
Copyright
© 2001 by the Society for Neuro-Oncology
ISSN
1522-8517
eISSN
1523-5866
DOI
10.1093/neuonc/3.2.82
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11296484
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Abstract

Abstract Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine that has been implicated in glioma invasion and angiogenesis. The SF/HGF receptor, MET, has been found to be expressed in neoplastic astrocytes as well as in endothelial cells of the tumor vasculature. Both SF/HGF and MET expression have also been described to correlate with the malignancy grade of human gliomas. However, most glioblastoma cell lines lack SF/HGF expression, raising the question of the cellular origin of SF/HGF in vivo. Using in situ hybridization, we analyzed glioblastomas, anaplastic astrocytomas, diffuse astrocytomas, pilocytic astrocytomas, and normal brain for the expression of SF/HGF mRNA. We detected strong SF/HGF expression by the majority of the tumor cells and by vascular endothelial cells in all glioblastoma specimens analyzed. Combined use of in situ hybridization with fluorescence immunohistochemistry confirmed the astrocytic origin of the SF/HGF-expressing cells. In contrast, CD68-immunoreactive microglia/macrophages, as well as vascular smooth muscle cells reactive to -smooth muscle actin, lacked SF/HGF expression. In anaplastic, diffuse, and pilocytic astrocytomas, SF/HGF expression was confined to a subset of tumor cells, and signals were less intense than in glioblasto mas. In addition, we detected SF/HGF mRNA in cortical neurons. SF/HGF expression was not up regulated around necroses or at tumor margins. MET immunoreactivity was observed in GFAP-expressing astrocytic tumor cells and endothelial cells as well as in a subset of microglia/macrophages. We conclude that in vivo, both autocrine and paracrine stimulation of tumor cells and endothelium through the SF/HGF-MET system are likely to contribute to tumor invasion and angiogenesis. Lack of SF/HGF expression by most cultured glioblastoma cells is not representative of the in vivo situation and most likely represents a culture artifact. References Abounader, R., Ranganathan, S., Lal, B., Fielding, K., Book, A., Dietz, H., Burger, P., and Laterra, J. ( 1999 ) Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J. Natl. Cancer Inst. 91 , 1548 -1556. Achim, C.L., Katyal, S., Wiley, C.A., Shiratori, M., Wang, G., Oshika, E., Petersen, B.E., Li, J.M., and Michalopoulos, G.K. ( 1997 ) Expression of HGF and cMet in the developing and adult brain. Brain Res. 102 , 299 -303. Badie, B., Schartner, J., Klaver, J., and Vorpahl, J. ( 1999 ) In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. Neurosurgery 44 , 1077 -1083. Di Renzo, M.F., Bertolotto, A., Olivero, M., Putzolu, D., Crepaldi, T., Schiffer, D., Pagni, C.A., and Comoglio, P.M. ( 1993 ) Selective expression of the met/HGF-receptor in human central nervous system microglia. Oncogene 8 , 219 -222. Ebens, A., Brose, K., Leonardo, E.D., Hanson, M.G., Jr., Bladt, F., Birchmeier, C., Barres, B.A., and Tessier-Lavigne, M. ( 1996 ) Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. Neuron 17 , 1157 -1172. Grant, D.S., Kleinman, H.K., Goldberg, I.D., Bhargava, M.M., Nickoloff, B.J., Kensella, J.L., Polverini, P., and Rosen, E.M. ( 1993 ) Scatter factor induces blood vessel formation in vivo. Proc. Natl. Acad. Sci. U.S.A. 90 , 1937 -1941. Hayashi, S., Morishita, R., Nakamura, S., Yamamoto, K., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Matsumoto, K., Nakamura, T., Higaki, J., and Ogihara, T. ( 1999 ) Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 100 (Suppl. 19), 301 -308. Hirose, Y., Kojima, M., Sagoh, M., Murakami, H., Yoshida, K., Shimazaki, K., and Kawase, T. ( 1998 ) Immunohistochemical examination of c-Met protein expression in astrocytic tumors. Acta Neuropathol. 95 , 345 -351. Jung, W., Castren, E., Odenthal, M., Vande Woude, G.F., Ishii, T., Dienes, H.P., Lindholm, D., and Schirmacher, P. ( 1994 ) Expression and functional interaction of hepatocyte growth factor-scatter factor and its receptor c-met in mammalian brain. J. Cell. Biol. 126 , 485 -494. Kleihues, P., and Cavenee, W.K. (Eds.) ( 2000 ) World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System . Lyon, France: IARC Press. Komminoth, P. ( 1996 ) Detection of mRNA in tissue sections using DIG-labeled RNA and oligonucleotide probes. In: Nonradioactive In Situ Hybridization Application Manual. 2nd ed. Mannheim, Germany: Boehringer-Mannheim. pp. 126 -135. Koochekpour, S., Jeffers, M., Rulong, S., Taylor, G., Klineberg, E., Hudson, E.A., Resau, J.H., and Vande Woude, G.F. ( 1997 ) Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 57 , 5391 -5398. Lamszus, K., Schmidt, N.O., Jin, L., Laterra, J., Zagzag, D., Way, D., Witte, M., Weinand, M., Goldberg, I.D., Westphal, M., and Rosen, E.M. ( 1998 ) Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells. Int. J. Cancer 75 , 19 -28. Lamszus, K., Laterra, J., Westphal, M., and Rosen, E.M. ( 1999 ) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int. J. Dev. Neurosci. 17 , 517 -530. Laterra, J., Nam, M., Rosen, E.M., Rao, J.S., Lamszus, K., Goldberg, I.D., and Johnston, P. ( 1997 ) Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab. Invest. 76 , 565 -577. Maina, F., Hilton, M.C., Poncetto, C., Davies, A.M., and Klein, R. ( 1997 ) Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 11 , 3341 -3350. Moore, S., and Thanos, S. ( 1996 ) The concept of microglia in relation to central nervous system disease and regeneration. Prog. Neurobiol. 48 , 441 -460. Phillips, H.S., Armani, M.P., Stavrou, D., Ferrara, N., and Westphal, M. ( 1993 ) Intense focal expression of vascular endothelial growth factor mRNA in human intracranial neoplasms: association with regions of necrosis. Int. J. Oncol. 2 , 913 -919. Plate, K.H., Breier, G., Weich, H.A., and Risau, W. ( 1992 ) Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 359 , 845 -848. Roggendorf, W., Strupp, S., and Paulus, W. ( 1996 ) Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol. 92 , 288 -293. Rosen, E.M., Nigam, S.K., and Goldberg, I.D. ( 1994 ) Scatter factor and the c-met receptor: A paradigm for mesenchymal/epithelial interaction. J. Cell Biol. 127 , 1783 -1787. Rosen, E.M., Laterra, J., Joseph, A., Jin, L., Fuchs, A., Way, D., Witte, M., Weinand, M., and Goldberg, I.D. ( 1996 ) Scatter factor expression and regulation in human glial tumors. Int. J. Cancer 67 , 248 -255. Schmidt, N.O., Westphal, M., Hagel, C., Ergün, S., Stavrou, D., Rosen, E.M., and Lamszus, K. ( 1999 ) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer 84 , 10 -18. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. ( 1992 ) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359 , 843 -845. Wong, V., Glass, D.J., Arriaga, R., Yancopoulos, G.D., Lindsay, R.M., and Conn, G. ( 1997 ) Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor. J. Biol. Chem. 272 , 5187 -5191. Yamada, T., Tsubouchi, H., Daikuhara, Y., Prat, M., Comoglio, P.M., McGeer, P.L., and McGeer, E.G. ( 1994 ) Immunohistochemistry with antibodies to hepatocyte growth factor and its receptor protein (c-MET) in human brain tissues. Brain Res. 637 , 308 -312. Yamamoto, Y., Livet, J., Pollock, R.A., Garces, A., Arce, V., de Lapeyriere, O., and Henderson, C.E. ( 1997 ) Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons. Development 124 , 2903 -2913. Yang, X.M., Toma, J.G., Bamji, S.X., Belliveau, D.J., Kohn, J., Park, M., and Miller, F.D. ( 1998 ) Autocrine hepatocyte growth factor provides a local mechanism for promoting axonal growth. J. Neurosci. 18 , 8369 -8381. Zarnegar, R., Muga, S., Rahija, R., and Michalopoulos, G. ( 1990 ) Tissue distribution of hepatopoietin-A: A heparin-binding polypeptide growth factor for hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 87 , 1252 -1256. Author notes Departments of Neurosurgery (P.K., S.M., R.F., M.W.) andNeuropathology (D.S., K.L.), University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; andInstitute of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany (P.S.) © 2001 by the Society for Neuro-Oncology

Journal

Neuro-Oncology – Oxford University Press

Published: Apr 1, 2001

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