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Erschienen in: Clinical & Experimental Metastasis 8/2012

01.12.2012 | Research Paper

BTG2 suppresses cancer cell migration through inhibition of Src-FAK signaling by downregulation of reactive oxygen species generation in mitochondria

verfasst von: Seo-Kyung Lim, Yong Won Choi, In Kyoung Lim, Tae Jun Park

Erschienen in: Clinical & Experimental Metastasis | Ausgabe 8/2012

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Abstract

BTG2 is a tumor suppressor gene. It is frequently downregulated in human cancer tissues, and its loss is associated with cancer cell metastasis, suggesting that the suppression of BTG2 plays a critical role in cancer cell migration and invasion. Here, we report that re-expression of BTG2 decreased cell migration and invasion in A549 and PC3 cancer cells. Furthermore, BTG2 expression was correlated with downregulation of focal adhesion kinase (FAK) Tyr576 and Tyr925 residues phosphorylation, while Tyr397 which is the autophosphorylation site was not influenced by BTG2 expression. c-Src phosphorylation which is the upstream of FAK was not influenced, whereas c-Src kinase activity was significantly decreased by BTG2 expression. BTG2 overexpression increased Src reduction state and inhibited reactive oxygen species (ROS) generation by being localized in mitochondria. Mitochondria-target BTG2 also inhibited cell migration via downregulation of Src-FAK signaling. In conclusion, our study reveals that BTG2 negatively regulated cancer cell migration by inhibiting Src activity through downregulation of ROS generation in mitochondria.
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Literatur
1.
Zurück zum Zitat Lim IK, Lee MS, Lee SH, Kim NK, Jou I, Seo JS, Park SC (1995) Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. J Cancer Res Clin Oncol 121:279–284PubMedCrossRef Lim IK, Lee MS, Lee SH, Kim NK, Jou I, Seo JS, Park SC (1995) Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. J Cancer Res Clin Oncol 121:279–284PubMedCrossRef
2.
Zurück zum Zitat Ficazzola MA, Fraiman M, Gitlin J, Woo K, Melamed J, Rubin MA, Walden PD (2001) Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis. Carcinogenesis 22:1271–1279PubMedCrossRef Ficazzola MA, Fraiman M, Gitlin J, Woo K, Melamed J, Rubin MA, Walden PD (2001) Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis. Carcinogenesis 22:1271–1279PubMedCrossRef
3.
Zurück zum Zitat Struckmann K, Schraml P, Simon R, Elmenhorst K, Mirlacher M, Kononen J, Moch H (2004) Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer Res 64:1632–1638PubMedCrossRef Struckmann K, Schraml P, Simon R, Elmenhorst K, Mirlacher M, Kononen J, Moch H (2004) Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer Res 64:1632–1638PubMedCrossRef
4.
Zurück zum Zitat Park TJ, Kim JY, Oh SP, Kang SY, Kim BW, Wang HJ, Song KY, Kim HC, Lim IK (2008) TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop. Hepatology 47:1533–1543PubMedCrossRef Park TJ, Kim JY, Oh SP, Kang SY, Kim BW, Wang HJ, Song KY, Kim HC, Lim IK (2008) TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop. Hepatology 47:1533–1543PubMedCrossRef
5.
Zurück zum Zitat Melamed J, Kernizan S, Walden PD (2002) Expression of B-cell translocation gene 2 protein in normal human tissues. Tissue Cell 34:28–32PubMedCrossRef Melamed J, Kernizan S, Walden PD (2002) Expression of B-cell translocation gene 2 protein in normal human tissues. Tissue Cell 34:28–32PubMedCrossRef
6.
Zurück zum Zitat Takahashi F, Chiba N, Tajima K, Hayashida T, Shimada T, Takahashi M, Moriyama H, Brachtel E, Edelman EJ, Ramaswamy S, Maheswaran S (2011) Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib. Oncogene 30:3084–3095PubMedCrossRef Takahashi F, Chiba N, Tajima K, Hayashida T, Shimada T, Takahashi M, Moriyama H, Brachtel E, Edelman EJ, Ramaswamy S, Maheswaran S (2011) Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib. Oncogene 30:3084–3095PubMedCrossRef
7.
Zurück zum Zitat van‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536CrossRef van‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536CrossRef
8.
Zurück zum Zitat Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68:5405–5413PubMedCrossRef Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68:5405–5413PubMedCrossRef
9.
Zurück zum Zitat Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J, Zhao YZ, Wang Z, Chen F, Lee KY (2009) Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 101:327–334PubMedCrossRef Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J, Zhao YZ, Wang Z, Chen F, Lee KY (2009) Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 101:327–334PubMedCrossRef
10.
Zurück zum Zitat McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5:505–515PubMedCrossRef McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5:505–515PubMedCrossRef
11.
Zurück zum Zitat Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692:77–102PubMedCrossRef Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692:77–102PubMedCrossRef
12.
Zurück zum Zitat Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar-Shavit R (2005) Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer 113:372–378PubMedCrossRef Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar-Shavit R (2005) Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer 113:372–378PubMedCrossRef
13.
Zurück zum Zitat Sieg DJ, Hauck CR, Ilic D, Klinqbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256PubMedCrossRef Sieg DJ, Hauck CR, Ilic D, Klinqbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256PubMedCrossRef
14.
Zurück zum Zitat Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D, Guan JL (1994) Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol Biol Cell 5:413–421PubMed Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D, Guan JL (1994) Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol Biol Cell 5:413–421PubMed
15.
Zurück zum Zitat Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT (1994) Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 14:1680–1688PubMed Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT (1994) Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 14:1680–1688PubMed
16.
Zurück zum Zitat Calalb MB, Polte TR, Hanks SK (1995) Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 15:954–963PubMed Calalb MB, Polte TR, Hanks SK (1995) Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 15:954–963PubMed
17.
Zurück zum Zitat Schlaepfer DD, Hunter T (1996) Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol Cell Biol 16:5623–5633PubMed Schlaepfer DD, Hunter T (1996) Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol Cell Biol 16:5623–5633PubMed
18.
Zurück zum Zitat Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY, Jove R (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9189PubMedCrossRef Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY, Jove R (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9189PubMedCrossRef
19.
Zurück zum Zitat Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB (2006) Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res 66:5542–5548PubMedCrossRef Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB (2006) Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res 66:5542–5548PubMedCrossRef
20.
Zurück zum Zitat Clark EA, Brugge JS (1993) Redistribution of activated pp60c-src to integrin-dependent cytoskeletal complexes in thrombin-stimulated platelets. Mol Cell Biol 13:1863–1871PubMed Clark EA, Brugge JS (1993) Redistribution of activated pp60c-src to integrin-dependent cytoskeletal complexes in thrombin-stimulated platelets. Mol Cell Biol 13:1863–1871PubMed
21.
22.
Zurück zum Zitat Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochim Biophys Acta 1287:121–149PubMed Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochim Biophys Acta 1287:121–149PubMed
23.
Zurück zum Zitat Xu W, Harrison SC, Eck MJ (1997) Three-dimensional structure of the tyrosine kinase c-Src. Nature 385:595–602PubMedCrossRef Xu W, Harrison SC, Eck MJ (1997) Three-dimensional structure of the tyrosine kinase c-Src. Nature 385:595–602PubMedCrossRef
24.
Zurück zum Zitat Giannoni E, Buricchi F, Raugei G, Ramponi G, Chiarugi P (2005) Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol 25:6391–6403PubMedCrossRef Giannoni E, Buricchi F, Raugei G, Ramponi G, Chiarugi P (2005) Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol 25:6391–6403PubMedCrossRef
25.
Zurück zum Zitat Gould KL, Hunter T (1988) Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity. Mol Cell Biol 8:3345–3356PubMed Gould KL, Hunter T (1988) Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity. Mol Cell Biol 8:3345–3356PubMed
26.
Zurück zum Zitat Orie NN, Zidek W, Tepel M (1999) Chemoattractant- and mitogen-induced generation of reactive oxygen species in human lymphocytes: the role of calcium. Exp Physiol 84:515–520PubMedCrossRef Orie NN, Zidek W, Tepel M (1999) Chemoattractant- and mitogen-induced generation of reactive oxygen species in human lymphocytes: the role of calcium. Exp Physiol 84:515–520PubMedCrossRef
27.
Zurück zum Zitat Rizzuto R, Brini M, Pizzo P, Murgia M, Pozzan T (1995) Chimeric green fluorescent protein as a tool for visualizing subcellular organelles in living cells. Curr Biol 5:635–642PubMedCrossRef Rizzuto R, Brini M, Pizzo P, Murgia M, Pozzan T (1995) Chimeric green fluorescent protein as a tool for visualizing subcellular organelles in living cells. Curr Biol 5:635–642PubMedCrossRef
28.
Zurück zum Zitat Giannoni E, Taddei ML, Chiarugi P (2010) Src redox regulation: again in the front line. Free Radic Biol Med 49:516–527PubMedCrossRef Giannoni E, Taddei ML, Chiarugi P (2010) Src redox regulation: again in the front line. Free Radic Biol Med 49:516–527PubMedCrossRef
29.
Zurück zum Zitat Varnum BC, Reddy ST, Koski RA, Herschman HR (1994) Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3. J Cell Physiol 158:205–213PubMedCrossRef Varnum BC, Reddy ST, Koski RA, Herschman HR (1994) Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3. J Cell Physiol 158:205–213PubMedCrossRef
30.
Zurück zum Zitat Guardavaccaro D, Corrente G, Covone F, Micheli L, D’Agnano I, Starace G, Caruso M, Tirone F (2000) Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription. Mol Cell Biol 20:1797–1815PubMedCrossRef Guardavaccaro D, Corrente G, Covone F, Micheli L, D’Agnano I, Starace G, Caruso M, Tirone F (2000) Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription. Mol Cell Biol 20:1797–1815PubMedCrossRef
31.
Zurück zum Zitat Prevot D, Voeltzel T, Birot AM, Morel AP, Rostan MC, Magaud JP, Corbo L (2000) The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem 275:147–153PubMedCrossRef Prevot D, Voeltzel T, Birot AM, Morel AP, Rostan MC, Magaud JP, Corbo L (2000) The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem 275:147–153PubMedCrossRef
32.
Zurück zum Zitat Hu XD, Meng QH, Xu JY, Jiao Y, Ge CM, Jacob A, Wang P, Rosen EM, Fan S (2011) BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity. Biochem Biophys Res Commun 404:903–909PubMedCrossRef Hu XD, Meng QH, Xu JY, Jiao Y, Ge CM, Jacob A, Wang P, Rosen EM, Fan S (2011) BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity. Biochem Biophys Res Commun 404:903–909PubMedCrossRef
33.
Zurück zum Zitat Passeri D, Marcucci A, Rizzo G, Billi M, Panigada M, Leonardi L, Tirone F, Grignani F (2006) Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Mol Cell Biol 26:5023–5032PubMedCrossRef Passeri D, Marcucci A, Rizzo G, Billi M, Panigada M, Leonardi L, Tirone F, Grignani F (2006) Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Mol Cell Biol 26:5023–5032PubMedCrossRef
34.
Zurück zum Zitat Prévôt D, Morel AP, Voeltzel T, Rostan MC, Rimokh R, Magaud JP, Corbo L (2001) Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem 276:9640–9648PubMedCrossRef Prévôt D, Morel AP, Voeltzel T, Rostan MC, Rimokh R, Magaud JP, Corbo L (2001) Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem 276:9640–9648PubMedCrossRef
35.
Zurück zum Zitat Lin WJ, Gary JD, Yang MC, Clarke S, Herschman HR (1996) The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem 271:15034–15044PubMedCrossRef Lin WJ, Gary JD, Yang MC, Clarke S, Herschman HR (1996) The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem 271:15034–15044PubMedCrossRef
36.
Zurück zum Zitat Horiuchi M, Takeuchi K, Noda N, Muroya N, Suzuki T, Nakamura T, Kawamura-Tsuzuku J, Takahasi K, Yamamoto T, Inagaki F (2009) Structural basis for the antiproliferative activity of the Tob-hCaf1 complex. J Biol Chem 284:13244–13255PubMedCrossRef Horiuchi M, Takeuchi K, Noda N, Muroya N, Suzuki T, Nakamura T, Kawamura-Tsuzuku J, Takahasi K, Yamamoto T, Inagaki F (2009) Structural basis for the antiproliferative activity of the Tob-hCaf1 complex. J Biol Chem 284:13244–13255PubMedCrossRef
37.
Zurück zum Zitat Rouault JP, Prevot D, Berthet C, Birot AM, Billaud M, Magaud JP, Corbo L (1998) Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem 273:22563–22569PubMedCrossRef Rouault JP, Prevot D, Berthet C, Birot AM, Billaud M, Magaud JP, Corbo L (1998) Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem 273:22563–22569PubMedCrossRef
38.
Zurück zum Zitat Yang X, Morita M, Wang H, Suzuki T, Yang W, Luo Y, Zhao C, Yu Y, Bartlam M, Yamamoto T, Rao Z (2008) Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic Acids Res 36:6872–6881PubMedCrossRef Yang X, Morita M, Wang H, Suzuki T, Yang W, Luo Y, Zhao C, Yu Y, Bartlam M, Yamamoto T, Rao Z (2008) Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic Acids Res 36:6872–6881PubMedCrossRef
39.
Zurück zum Zitat Mauxion F, Faux C, Séraphin B (2008) The BTG2 protein is a general activator of mRNA deadenylation. EMBO J 27:1039–1048PubMedCrossRef Mauxion F, Faux C, Séraphin B (2008) The BTG2 protein is a general activator of mRNA deadenylation. EMBO J 27:1039–1048PubMedCrossRef
40.
Zurück zum Zitat Lluis JM, Buricchi F, Chiarugi P, Morales A, Fernandez-Checa JC (2007) Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Res 67:7368–7377PubMedCrossRef Lluis JM, Buricchi F, Chiarugi P, Morales A, Fernandez-Checa JC (2007) Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Res 67:7368–7377PubMedCrossRef
41.
Zurück zum Zitat Krasnowska EK, Pittaluga E, Brunati AM, Brunelli R, Costa G, De Spirito M, Serafino A, Ursini F, Parasassi T (2008) N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src. Free Radic Biol Med 45:1566–1572PubMedCrossRef Krasnowska EK, Pittaluga E, Brunati AM, Brunelli R, Costa G, De Spirito M, Serafino A, Ursini F, Parasassi T (2008) N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src. Free Radic Biol Med 45:1566–1572PubMedCrossRef
Metadaten
Titel
BTG2 suppresses cancer cell migration through inhibition of Src-FAK signaling by downregulation of reactive oxygen species generation in mitochondria
verfasst von
Seo-Kyung Lim
Yong Won Choi
In Kyoung Lim
Tae Jun Park
Publikationsdatum
01.12.2012
Verlag
Springer Netherlands
Erschienen in
Clinical & Experimental Metastasis / Ausgabe 8/2012
Print ISSN: 0262-0898
Elektronische ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-012-9479-z

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