- Email: [email protected]
Importance of ECM remodeling clarified
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News & Comment
TRENDS in Cell Biology Vol.12 No.3 March 2002
Importance of ECM remodeling clarified Numerous papers in recent years have illustrated the importance of extracellular matrix remodeling for normal development. These remodeling events are carried out by matrix metalloproteases (MMPs) such as MMP-2 and MMP-9. The membrane-bound MT1-MMP appears to play a central role in the processing and activation of MMPs. One of the processes during embryogenesis that is dependent on the action of matrix metalloproteases is ‘The tumors derived from cells overexpressing RECK show reduced tumor vasculature sprouting...’
angiogenesis. Just as metalloproteases are required for growing tissues to establish vascular networks, the same proteases are needed when tumors establish a vasculature. Oh et al., in an elegant paper, identify RECK as a central regulator of matrix remodeling [1]. RECK is a GPIanchored membrane protein with serine
protease inhibitor activity, previously identified in an expression cloning strategy, which the authors have gone on to study by using gene targeting and tumor transplantation in mice. Inactivation of the RECK gene in mice leads to embryonic death at day 10.5. Analysis of the embryos reveals a smaller size, disarray of mesenchymal tissues and hemorrhage. Closer examination of blood vessels demonstrated defects in blood vessel maturation. In vitro studies of RECK function reveal that it inhibits the activity of MT1-MMP, thus indirectly also inhibiting other MMPs such as MMP-2 and MMP-9. Studies of cells from the RECK-deficient embryos intercrossed with MMP-2-deficient embryos support this mechanism of action as the lack of MMP-2 partly rescued the RECK phenotype. To analyze the importance of RECK for tumor angiogenesis, the fibrosarcoma cell line HT1080, with or without RECK, was transplanted into nude mice. The tumors derived from cells overexpressing RECK show reduced
tumor vasculature sprouting, resulting in massive tumor death. The paper by Oh et al. thus indicates that tightly regulated matrix turnover is needed for embryonic development and tumor angiogenesis. When an inhibitor of a central MMP activator is lacking, too much ECM is degraded, leading to dysregulated development. However, when too much of the MMP inhibitor RECK is expressed in tumor cells, vessel sprouting cannot occur. These very interesting results shed light on the molecular mechanism of RECK, which thus appears to be a central regulator of MMPs and angiogenesis. The authors’ findings warrant a fresh look at novel therapeutic strategies in tumor biology, and we will surely hear more about RECK in the years to come. 1 Oh, J. et al. (2001) The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789–800
Donald Gullberg [email protected]
In Brief
Cancer research charities fuse
The UK’s two prime cancer research charities – the Imperial Cancer Research Fund (ICRF) and the Cancer Research Campaign (CRC) – are merging into what will become the biggest independent cancer research organization in the world: Cancer Research UK (CRUK), effective February 2002. The new organization will combine CRC’s strong translational research programme with world-class basic cancer research at the ICRF. The joint forces mount up to 3000 researchers and doctors with a research budget of £130 million a year. Andrew Miller, a biophysicist and former principal and vice chancellor of the University of Stirling, has been appointed as Interim http://tcb.trends.com
Chief Executive and will mainly focus on the task of integrating the two organizations. Meanwhile, ICRF director general Paul Nurse acts as director of science at CRUK, and CRC director general Gordon McVie will be in charge of fundraising and communications. The funding model of the new charity will be styled after the US National Cancer Institute: about 50% will be spent in universities, and 50% in present labs. In an interview with BioMedNet, Miller said: ‘To have things all together in one building such as in Lincoln’s Inn Fields has huge benefits. Different people meet over coffee or in the canteen. It’s very powerful there, but we are ignoring a lot of people on the outside.’ The launch of CRUK coincided with the presentation of the Nobel Prize for Medicine to Paul Nurse for his pioneering work on the understanding of cell-cycle regulation. The 100th Nobel Prize was awarded jointly with Tim Hunt, also of the ICRF, and Leland Hartwell (of Fred Hutchinson Cancer Research Center Seattle, USA). Links: http://www.crc.org.uk; http://www.icnet.uk J.d.B. & D.S.
The ancient story of a key cell communication gene The first receptor tyrosine kinase (RTK) outside Metazoa, MBRTK1, has been discovered in the unicellular choanoflagellate Monosiga brevicollis [Proc. Natl. Acad. Sci. U. S. A. (2001) 98, 15032–15037]. Choanoflagellates are primitive microorganisms whose evolutionary roots can be traced to the era of the first metazoans, more than 600 million years ago. Identified by a team of scientists from the Howard Hughes Medical Institute at the University of Wisconsin (Madison, WI, USA), MBRTK1 has multiple extracellular ligand-binding domains, resembling the architecture of RTKs in sponges and humans. This similarity suggests that MBRTK1 might be able to receive and transduce signals. RTKs are molecular sensors involved in cell adhesion and signalling; single-cell organisms are therefore not expected to encode such proteins in their genomes. The discovery of MBRTK1 therefore implies that
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Cell Biology Vol.12 No.3 March 2002
Importance of ECM remodeling clarified Numerous papers in recent years have illustrated the importance of extracellular matrix remodeling for normal development. These remodeling events are carried out by matrix metalloproteases (MMPs) such as MMP-2 and MMP-9. The membrane-bound MT1-MMP appears to play a central role in the processing and activation of MMPs. One of the processes during embryogenesis that is dependent on the action of matrix metalloproteases is ‘The tumors derived from cells overexpressing RECK show reduced tumor vasculature sprouting...’
angiogenesis. Just as metalloproteases are required for growing tissues to establish vascular networks, the same proteases are needed when tumors establish a vasculature. Oh et al., in an elegant paper, identify RECK as a central regulator of matrix remodeling [1]. RECK is a GPIanchored membrane protein with serine
protease inhibitor activity, previously identified in an expression cloning strategy, which the authors have gone on to study by using gene targeting and tumor transplantation in mice. Inactivation of the RECK gene in mice leads to embryonic death at day 10.5. Analysis of the embryos reveals a smaller size, disarray of mesenchymal tissues and hemorrhage. Closer examination of blood vessels demonstrated defects in blood vessel maturation. In vitro studies of RECK function reveal that it inhibits the activity of MT1-MMP, thus indirectly also inhibiting other MMPs such as MMP-2 and MMP-9. Studies of cells from the RECK-deficient embryos intercrossed with MMP-2-deficient embryos support this mechanism of action as the lack of MMP-2 partly rescued the RECK phenotype. To analyze the importance of RECK for tumor angiogenesis, the fibrosarcoma cell line HT1080, with or without RECK, was transplanted into nude mice. The tumors derived from cells overexpressing RECK show reduced
tumor vasculature sprouting, resulting in massive tumor death. The paper by Oh et al. thus indicates that tightly regulated matrix turnover is needed for embryonic development and tumor angiogenesis. When an inhibitor of a central MMP activator is lacking, too much ECM is degraded, leading to dysregulated development. However, when too much of the MMP inhibitor RECK is expressed in tumor cells, vessel sprouting cannot occur. These very interesting results shed light on the molecular mechanism of RECK, which thus appears to be a central regulator of MMPs and angiogenesis. The authors’ findings warrant a fresh look at novel therapeutic strategies in tumor biology, and we will surely hear more about RECK in the years to come. 1 Oh, J. et al. (2001) The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789–800
Donald Gullberg [email protected]
In Brief
Cancer research charities fuse
The UK’s two prime cancer research charities – the Imperial Cancer Research Fund (ICRF) and the Cancer Research Campaign (CRC) – are merging into what will become the biggest independent cancer research organization in the world: Cancer Research UK (CRUK), effective February 2002. The new organization will combine CRC’s strong translational research programme with world-class basic cancer research at the ICRF. The joint forces mount up to 3000 researchers and doctors with a research budget of £130 million a year. Andrew Miller, a biophysicist and former principal and vice chancellor of the University of Stirling, has been appointed as Interim http://tcb.trends.com
Chief Executive and will mainly focus on the task of integrating the two organizations. Meanwhile, ICRF director general Paul Nurse acts as director of science at CRUK, and CRC director general Gordon McVie will be in charge of fundraising and communications. The funding model of the new charity will be styled after the US National Cancer Institute: about 50% will be spent in universities, and 50% in present labs. In an interview with BioMedNet, Miller said: ‘To have things all together in one building such as in Lincoln’s Inn Fields has huge benefits. Different people meet over coffee or in the canteen. It’s very powerful there, but we are ignoring a lot of people on the outside.’ The launch of CRUK coincided with the presentation of the Nobel Prize for Medicine to Paul Nurse for his pioneering work on the understanding of cell-cycle regulation. The 100th Nobel Prize was awarded jointly with Tim Hunt, also of the ICRF, and Leland Hartwell (of Fred Hutchinson Cancer Research Center Seattle, USA). Links: http://www.crc.org.uk; http://www.icnet.uk J.d.B. & D.S.
The ancient story of a key cell communication gene The first receptor tyrosine kinase (RTK) outside Metazoa, MBRTK1, has been discovered in the unicellular choanoflagellate Monosiga brevicollis [Proc. Natl. Acad. Sci. U. S. A. (2001) 98, 15032–15037]. Choanoflagellates are primitive microorganisms whose evolutionary roots can be traced to the era of the first metazoans, more than 600 million years ago. Identified by a team of scientists from the Howard Hughes Medical Institute at the University of Wisconsin (Madison, WI, USA), MBRTK1 has multiple extracellular ligand-binding domains, resembling the architecture of RTKs in sponges and humans. This similarity suggests that MBRTK1 might be able to receive and transduce signals. RTKs are molecular sensors involved in cell adhesion and signalling; single-cell organisms are therefore not expected to encode such proteins in their genomes. The discovery of MBRTK1 therefore implies that
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.