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ABSTRACT: Over the past 20 years, cancer research has gained major insights into the complexity of tumor development, in particular into the molecular mechanisms that underlie the progressive transformation of normal cells into highly malignant derivatives. It is estimated that the transformation of a normal cell to a malignant tumor cell is dependent upon a small number of genetic alterations, estimated to be within the range of four to seven rate-limiting events. Critical events in the evolution of neoplastic disease include the loss of proliferative control, the failure to undergo programmed cell death (apoptosis), the onset of neoangiogenesis, tissue remodeling, invasion of tumor cells into surrounding tissue and, finally, metastatic dissemination of tumor cells to distant organs. In patients, the molecular analysis of these multiple steps is hampered by the unavailability of tumor biopsies from all tumor stages. In contrast, mouse models of tumorigenesis allow the reproducible isolation of all tumor stages, including normal tissue, which are then amenable to pathological, genetic and biochemical analyses and, hence, have been instrumental in investigating cancer-related genes and their role in carcinogenesis. In this review, we discuss mouse tumor models that have contributed substantially to the identification and characterization of novel tumor pathways. In particular, we focus on transgenic and knockout mouse models that closely mimic human cancer and thus can be used as model systems for cancer research.
Biochimica et Biophysica Acta 07/2002; 1602(2):97-113. · 4.66 Impact Factor
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ABSTRACT: Multistep carcinogenesis involves more than six discrete events also important in normal development and cell behavior. Of these, local invasion and metastasis cause most cancer deaths but are the least well understood molecularly. We employed a combined in vitro/in vivo carcinogenesis model, that is, polarized Ha-Ras-transformed mammary epithelial cells (EpRas), to dissect the role of Ras downstream signaling pathways in epithelial cell plasticity, tumorigenesis, and metastasis. Ha-Ras cooperates with transforming growth factor beta (TGFbeta) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers. EMT requires continuous TGFbeta receptor (TGFbeta-R) and oncogenic Ras signaling and is stabilized by autocrine TGFbeta production. In contrast, fibroblast growth factors, hepatocyte growth factor/scatter factor, or TGFbeta alone induce scattering, a spindle-like cell phenotype fully reversible after factor withdrawal, which does not involve sustained marker changes. Using specific inhibitors and effector-specific Ras mutants, we show that a hyperactive Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas activation of phosphatidylinositol 3-kinase (PI3K) causes scattering and protects from TGFbeta-induced apoptosis. Hyperactivation of the PI3K pathway or the Raf/MAPK pathway are sufficient for tumorigenesis, whereas EMT in vivo and metastasis required a hyperactive Raf/MAPK pathway. Thus, EMT seems to be a close in vitro correlate of metastasis, both requiring synergism between TGFbeta-R and Raf/MAPK signaling.
The Journal of Cell Biology 02/2002; 156(2):299-313. · 10.26 Impact Factor
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[show abstract]
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ABSTRACT: Multistep carcinogenesis involves more than six discrete events also important in normal development and cell behavior. Of
these, local invasion and metastasis cause most cancer deaths but are the least well understood molecularly. We employed a
combined in vitro/in vivo carcinogenesis model, that is, polarized Ha-Ras–transformed mammary epithelial cells (EpRas), to
dissect the role of Ras downstream signaling pathways in epithelial cell plasticity, tumorigenesis, and metastasis. Ha-Ras
cooperates with transforming growth factor β (TGFβ) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like
cell morphology, loss of epithelial markers, and induction of mesenchymal markers. EMT requires continuous TGFβ receptor (TGFβ-R)
and oncogenic Ras signaling and is stabilized by autocrine TGFβ production. In contrast, fibroblast growth factors, hepatocyte
growth factor/scatter factor, or TGFβ alone induce scattering, a spindle-like cell phenotype fully reversible after factor
withdrawal, which does not involve sustained marker changes. Using specific inhibitors and effector-specific Ras mutants,
we show that a hyperactive Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas activation of phosphatidylinositol
3-kinase (PI3K) causes scattering and protects from TGFβ-induced apoptosis. Hyperactivation of the PI3K pathway or the Raf/MAPK
pathway are sufficient for tumorigenesis, whereas EMT in vivo and metastasis required a hyperactive Raf/MAPK pathway. Thus,
EMT seems to be a close in vitro correlate of metastasis, both requiring synergism between TGFβ-R and Raf/MAPK signaling.
The Journal of Cell Biology 01/2002; 156(2):299-314. · 10.26 Impact Factor
