Proliferation and invasion: plasticity in tumor cells.
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Journal: 2005/December - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.
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Proc Natl Acad Sci U S A 102(30): 10528-10533
PMID: 16024725

Proliferation and invasion: Plasticity in tumor cells

Laboratory of Molecular Oncology, Laboratory of Germline Modification, Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503; and Fred Hutchinson Cancer Research Center, 1212 Aloha Street, Seattle, WA 98109
To whom correspondence should be addressed. E-mail: gro.iav@eduowednav.egroeg.
Contributed by George F. Vande Woude, May 31, 2005
Contributed by George F. Vande Woude, May 31, 2005
Copyright © 2005, The National Academy of Sciences

Abstract

Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.

Keywords: glioblastoma multiforme, hepatocyte growth factor/scatter factor, Met
Abstract

The development and growth of tumor metastasis require that neoplastic cells must either have the potential to shift genetically or epigenetically between proliferative and invasive phenotypes or simply express both phenotypes simultaneously. Thus, many questions about the process of malignant progression remain unanswered, e.g., whether cells in the primary tumor possess malignant properties (1, 2), whether micrometastases are obligatory precursors to frank metastases, and how the heterogeneity of tumor phenotypes contributes to malignant disease (3, 4).

Hepatocyte growth factor/scatter factor (HGF/SF) is the ligand for the Met receptor tyrosine kinase (5). In response to HGF/SF, cells expressing Met trigger several signaling cascades that, depending on cell type, mediate a multitude of biological events such as proliferation (6), scattering and migration (7, 8), angiogenesis (9-11), branching morphogenesis (12), and/or growth in soft agar (13). HGF/SF-induced signals and cellular responses are required for the development of the placenta, liver, tongue, diaphragm, limb muscles, and axons during normal embryogenesis (14-17) and for wound healing (18) and organ regeneration (19). Like other tyrosine kinase receptors, but for many more types, Met signaling has been implicated in the etiology and malignant progression of most types of human cancer (5) (www.vai.org/vari/metandcancer). Discovered independently as a mitogen for hepatocytes and as a motility factor for canine kidney cells, in many tumor cell lines, HGF/SF induces both proliferative and invasive responses (20-22). It is not certain whether fixed subpopulations exist within a cell line that are either invasive or proliferative or whether some cells proliferate and invade. Here, we have established in vitro methods to select tumor cells with highly invasive or proliferative phenotypes to allow characterization of the cells and the molecular pathways responsible for each phenotype. We chose to study a Met-expressing human glioblastoma multiforme tumor cell line, because of its unique, highly invasive phenotype in response to HGF/SF. From these cells, we isolated highly proliferative subclones and cells with both proliferative and invasive phenotypes. We have examined these cells in vitro for proliferation, migration, branching morphogenesis (23), and anchorage-independent growth (13), and in vivo tumorigenesis assays in immune-compromised mice. We show that segregation of the proliferative and invasive phenotypes correlate with the selection of signaling pathways activated by HGF/SF. The invasive cells signal through mitogen-activated protein kinase (MAPK), whereas highly proliferative cells use the Myc pathway, and the two pathways cooperate in cells with both phenotypes.

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Acknowledgments

We dedicate this paper to the memory of our friend and colleague, Dr. Han-Mo Koo. We thank Dr. Carrie Graveel for her comments on the manuscript, Dr. David Petillo and Ping Zhao for their help, and David Nadziejka and Michelle Reed for assistance with preparation of the manuscript. This work was supported in part by the Michigan Life Sciences Corridor and through the generosity of the Jay and Betty Van Andel Foundation.

Acknowledgments

Notes

Abbreviations: DB-P, parental DBTRG-05MG cells; DB-An, subclones of DB-P; HGF/SF, hepatocyte growth factor/scatter factor; MAPK, mitogen-activated protein kinase; uPA, urokinase-type plasminogen activator.

Notes
Abbreviations: DB-P, parental DBTRG-05MG cells; DB-An, subclones of DB-P; HGF/SF, hepatocyte growth factor/scatter factor; MAPK, mitogen-activated protein kinase; uPA, urokinase-type plasminogen activator.

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