Mechanisms of tumor metastasis: cell biological aspects and clinical implications

Engers, Rainer; Gabbert, Helmut E.

doi:10.1007/s004320000148

Cited by 109 publications

(75 citation statements)

References 84 publications

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“…In addition, increased MT nucleation capacity of centrosomes correlated with loss of tissue differentiation. Loss of differentiation as indicated by high histologic grade is an indicator of poor prognosis (27), probably because of the increased metastatic potential of cells with altered cytoskeletons and adherent properties (28).…”

Section: Discussionmentioning

confidence: 99%

Centrosome amplification drives chromosomal instability in breast tumor development

Lingle

Barrett

Negron

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

514

472

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Earlier studies of invasive breast tumors have shown that 60 -80% are aneuploid and Ϸ80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and͞or prognostic value and that the centrosome may be a potential target for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Centrosome amplification drives chromosomal instability in breast tumor development

Lingle

Barrett

Negron

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

514

472

View full text Add to dashboard Cite

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“…When tumor cells are inoculated via the portal vein, tumor cells are first arrested in small vessels, followed by extravasation, invasion of tissues and proliferation of tumor cells. 3 Therefore, blood flows would be, at least transiently, hindered by tumor cells, which could result in a reduction in the oxygen supply. In addition to hypoxia, other processes such as growth factor stimulation and cytokine stimulation are reported to increase HIF-1a expression and activate HIF-1-dependent transcription.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Tumor metastasis is an exceedingly complex process, which occurs through a series of sequential steps that include dissociation from the primary tumor, invasion of adjacent tissues, intravasation, transport through the circulatory system, arrest in small vessels, adhesion to endothelial cells, extravasation and growth in secondary organs. 3 It can be hypothesized that components of the secondary organ, such as endothelial cells, stromal cells, fibroblasts and parenchymal cells, are functionally organized to promote survival and proliferation of metastasizing cancer cells and generate a favorable microenvironment for cancer cells in metastatic sites. 4,5 Hypoxia initiates a variety of cellular responses including the activation of hypoxia-inducible factor-1 (HIF-1).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

2008

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Hypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen-regulated transcription factor composed of a and b subunits. HIF-1 activates transcription of various genes including those involved in metastatic tumor growth. In the present study, HIF-1a expression in tumor-bearing mouse liver was examined after inoculation of tumor cells into portal vein. We found that tumor-bearing liver showed greatly increased HIF-1a expression. Plasmid DNA (pDNA) expressing short hairpin RNA targeting HIF-1a (pshHIF-1a) was effective in suppressing protein expression of HIF-1a in vitro. Intravenous injection of pshHIF-1a by hydrodynamics-based procedure reduced the HIF-1a protein expression in both normal and tumor cells and tumor cell number in the liver. Pre-injection of pshHIF-1a to mice, by which pDNA was delivered only to liver cells, not to tumor cells, was also effective in reducing the number of tumor cells inoculated 3 days after pDNA injection. These findings indicate that HIF-1a expression is increased in normal liver cells as well as tumor cells, and HIF-1a expression plays an important role in tumor progression. Use of the RNA interference (RNAi) of HIF-1 is an effective strategy for inhibiting tumor cell growth, and both tumor and normal cells can be the target for RNAi-based anticancer treatment.

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“…The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions.…”

mentioning

confidence: 99%

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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The leukocyte specific actin-binding protein L-plastin is aberrantly expressed in several nonhematopoetic malignant tumors. However, little is known about the functional consequences of Lplastin expression. Here, we investigated the function of L-plastin in human malignant melanoma cells. Knock-down of endogenous L-plastin by siRNA treatment reduced migration of the melanoma cell line IF6. However, in melanoma patients, no correlation existed between L-plastin expression and tumor stages. This implied that additional factors such as phosphorylation of L-plastin may influence its function in tumor cells. To investigate this further, EGFP-tagged wild-type L-plastin (wt-LPL-EGFP) and a mutated, nonphosphorylatable L-plastin protein (5A7A-LPL-EGFP), were expressed in the L-plastin negative melanoma cell line MV3. Biochemical analysis revealed that wt-LPL-EGFP is phosphorylated in MV3 cells while 5A7A-LPL-EGFP is not. Although both wt-LPL-EGFP and 5A7A-LPL-EGFP were targeted to, and promote the formation of, vinculin-containing adhesion sites, static adhesion to either Matrigel or isolated extracellular matrix molecules was neither influenced by expression of wt-LPL-EGFP nor by expression of 5A7A-LPL-EGFP when compared with EGFP expressing control cells. In contrast, haptotactic, but not chemotactic, migration of melanoma cells towards either Matrigel or isolated extracellular matrix molecules was similarly enhanced, if either 5A7A-LPL-EGFP or wt-LPL-EGFP were expressed in MV3 cells. Interestingly, only cells expressing the phosphorylatable wt-LPL-EGFP protein showed enhanced invasion into Matrigel. In line with these findings the in vivo metastatic capacity of mouse B16 melanoma cells correlates with expression and phosphorylation of L-plastin. These data show that an increase in melanoma cell invasiveness requires not only expression but also phosphorylation of L-plastin. ' 2007 Wiley-Liss, Inc.Key words: migration; invasion; adhesion; L-plastin; melanoma Malignant melanoma is a very aggressive type of cancer that frequently metastasizes to distant organs. The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions. They consist of heterodimers of 2 noncovalently associated a-and b-subunits. 6 The role of integrins in tumor cell metastasis has been intensively studied. 4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical f...

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Mechanisms of tumor metastasis: cell biological aspects and clinical implications

Cited by 109 publications

References 84 publications

Centrosome amplification drives chromosomal instability in breast tumor development

Centrosome amplification drives chromosomal instability in breast tumor development

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

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