Abstract
Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the phosphatase of regenerating liver (PRL) phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.
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Abbreviations
- PTK:
-
protein tyrosine kinase
- PTP:
-
protein tyrosine phosphatase
- SH2:
-
Src homology-2
- PRL:
-
phosphatase of regenerating liver
References
Hunter, T. (2000). Signaling—2000 and beyond. Cell, 100, 113–127.
Tonks, N. K. (2006). Protein tyrosine phosphatases: from genes, to function, to disease. Nature Reviews. Molecular Cell Biology, 7, 833–846.
Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., et al. (2004). Protein tyrosine phosphatases in the human genome. Cell, 117, 699–711.
Hunter, T. (1998). The phosphorylation of proteins on tyrosine: its role in cell growth and disease. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 353, 583–605.
Zhang, Z.-Y. (2001). Protein tyrosine phosphatases: prospects for therapeutics. Current Opinion in Chemical Biology, 5, 416–423.
Arena, S., Benvenuti, S., & Bardelli, A. (2005). Genetic analysis of the kinome and phosphatome in cancer. Cellular and Molecular Life Sciences, 62, 2092–2099.
Ventura, J. J., & Nebreda, A. R. (2006). Protein kinases and phosphatases as therapeutic targets in cancer. Clinical & translational oncology: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 8, 153–160.
Krause, D. S., & Van Etten, R. A. (2005). Tyrosine kinases as targets for cancer therapy. New England Journal of Medicine, 353, 172–187.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 275, 1943–1947.
Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K. A., Lin, H., Ligon, A. H., et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23 that is mutated in multiple advanced cancers. Nature Genetics, 15, 356–362.
Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., et al. (2004). Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science, 304, 1164–1166.
Zheng, X. M., Wang, Y., & Pallen, C. J. (1992). Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature, 359, 336–339.
Ponniah, S., Wang, D. Z., Lim, K. L., & Pallen, C. J. (1999). Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. Current Biology, 9, 535–538.
Su, J., Muranjan, M., & Sap, J. (1999). Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Current Biology, 9, 505–511.
Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y., & Kasuga, M. (1994). Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Molecular and Cell Biology, 14, 6674–6682.
Tang, T. L., Freeman Jr., R. M., O’Reilly, A. M., Neel, B. G., & Sokol, S. Y. (1995). The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell, 80, 473–483.
Bennett, A. M., Hausdorff, S. F., O’Reilly, A. M., Freeman, R. M., & Neel, B. G. (1996). Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Molecular and Cell Biology, 16, 1189–1202.
Shi, Z. Q., Yu, D. H., Park, M., Marshall, M., & Feng, G. S. (2000). Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Molecular and Cell Biology, 20, 1526–1536.
Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., et al. (2001). Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2, cause Noonan syndrome. Nature Genetics, 29, 465–468.
Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., et al. (2003). Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genetics, 34, 148–150.
Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., et al. (2004). Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Research, 64, 8816–8820.
Stephens, B. J., Han, H., Gokhale, V., & Von Hoff, D. D. (2005). PRL phosphatases as potential molecular targets in cancer. Advanced Thailand Geographic, 4, 1653–1661.
Blume-Jensen, P., & Hunter, T. (2001). Oncogenic kinase signaling. Nature, 411, 355–365.
Druker, B. J. (2004). Imatinib as a paradigm of targeted therapies. Advanced Cancer Research, 91, 1–30.
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350, 2129–2139.
Ostman, A., Hellberg, C., & Bohmer, F. D. (2006). Protein-tyrosine phosphatases and cancer. Nature Reviews. Nature Reviews. Cancer, 6, 307–320.
Elchelby, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Lee Loy, A., et al. (1999). Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 283, 1544–1548.
Klaman, L. D., Boss, O., Peroni, O. D., Kim, J. K., Martino, J. L., Zabolotny, J. M., et al. (2000). Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Molecular and Cellular Biology, 20, 5479–5489.
Zinker, B. A., Rondinone, C. M., Trevillyan, J. M., Gum, R. J., Clampit, J. E., Waring, J. F., et al. (2002). PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 11357–11362.
Flint, A. J., Tiganis, T., Barford, D., & Tonks, N. K. (1997). Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. Proceedings of the National Academy of Sciences of the United States of America, 94, 1680–1685.
Liu, F., & Chernoff, J. (1997). Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochemical Journal, 327, 139–145.
Bjorge, J. D., Pang, A., & Fujita, D. J. (2000). Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. Journal of Biological Chemistry, 275, 41439–41446.
Cheng, A., Bal, G. S., Kennedy, B. P., & Tremblay, M. L. (2001). Attenuation of adhesion-dependent signaling and cell spreading in transformed fibroblasts lacking protein tyrosine phosphatase-1B. Journal of Biological Chemistry, 276, 25848–25855.
Liang, F., Lee, S.-Y., Liang, J., Lawrence, D. S., & Zhang, Z. Y. (2005). The role of PTP1B in integrin signaling. Journal of Biological Chemistry, 280, 24857–24863.
Dube, N., Cheng, A., & Tremblay, M. L. (2004). The role of protein tyrosine phosphatase 1B in Ras signaling. Proceedings of the National Academy of Sciences of the United States of America, 101, 1834–1839.
Yarden, Y. (2001). Biology of HER2 and its importance in breast cancer. Oncology, 61(Suppl 2), 1–13.
Hynes, N. E., & Lane, H. A. (2005). ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Reviews. Cancer, 5, 341–354.
Zhai, Y. F., Beittenmiller, H., Wang, B., Gould, M. N., Oakley, C., Esselman, W. J., et al. (1993). Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene. Cancer Research, 53, 2272–2278.
Wiener, J. R., Kerns, B. J., Harvey, E. L., Conaway, M. R., Iglehart, J. D., Berchuck, A., et al. (1994). Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. Journal of the National Cancer Institute, 86, 372–378.
Julien, S. G., Dubé, N., Read, M., Penney, J., Paquet, M., Han, Y., et al. (2007). Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nature Genetics, 39, 338–346.
Bentires-Alj, M., & Neel, B. G. (2007). Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Research, 67, 2420–2424.
Zhu, S., Bjorge, J. D., & Fujita, D. J. (2007). PTP1B contributes to oncogenic properties of colon cancer cells through Src activation. Cancer Research, 67, 10129–10137.
Zhang, S., & Zhang, Z.-Y. (2007). PTP1B as a drug target: recent development in PTP1B inhibitor discovery. Drug Discovery Today, 12, 373–381.
Shen, K., Keng, Y. F., Wu, L., Guo, X. L., Lawrence, D. S., & Zhang, Z.-Y. (2001). Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. Journal of Biological Chemistry, 276, 47311–47319.
Sun, J.-P., Fedorov, A. A., Lee, S.-Y., Guo, X.-L., Shen, K., Lawrence, D. S., et al. (2003). Crystal structure of PTP1B in complex with a potent and selective bidentate inhibitor. Journal of Biological Chemistry, 278, 12406–12414.
Xie, L., Lee, S.-Y., Andersen, J. N., Waters, S., Shen, K., Guo, X.-L., et al. (2003). Cellular effects of small molecule PTP1B inhibitors on insulin signalling. Biochemistry, 42, 12792–12804.
Lee, S.-Y., Liang, F., Guo, X.-L., Xie, L., Cahill, S. M., Blumenstein, M., et al. (2005). Design, construction, and intracellular activation of an intramolecularly self-silenced signal transduction inhibitor. Angewandte Chemie. International Edition, 44, 4242–4244.
Boutselis, I. G., Yu, X., Zhang, Z. Y., & Borch, R. (2007). Synthesis and cell-based activity of a potent and selective PTP1B inhibitor prodrug. Journal of Medicinal Chemistry, 50, 856–864.
Morrison, C. D., White, C. L., Wang, Z., Lee, S.-Y., Lawrence, D. S., Cefalu, W. T., et al. (2007). Increased hypothalamic PTP1B contribute to leptin resistance with age. Endocrinology, 148, 433–440.
Black, E., Breed, J., Breeze, A. L., Embrey, K., Garcia, R., Gero, T. W., et al. (2005). Structure-based design of protein tyrosine phosphatase-1B inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 2503–2507.
Combs, A. P., Yue, E. W., Bower, M., Ala, P. J., Wayland, B., Douty, B., et al. (2005). Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics. Journal of Medicinal Chemistry, 48, 6544–6548.
Yue, E. W., Wayland, B., Douty, B., Crawley, M. L., McLaughlin, E., Takvorian, A., et al. (2006). Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold. Bioorganic & Medicinal Chemistry, 14, 5833–5849.
Combs, A. P., Zhu, W., Crawley, M. L., Glass, B., Polam, P., Sparks, R. B., et al. (2006). Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic. Journal of Medicinal Chemistry, 49, 3774–3789.
Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J., & Shoelson, S. E. (1998). Cell, 92, 441–450.
Mohi, M. G., & Neel, B. G. (2007). The role of Shp2 (PTPN11) in cancer. Current Opinion in Genetics & Development, 17, 23–30.
Hatakeyama, M. (2004). Oncogenic mechanisms of the Helicobacter pyroli CagA protein. Nature Reviews. Cancer, 4, 688–694.
Stommel, J. M., Kimmelman, A. C., Ying, H., Nabioullin, R., Ponugoti, A. H., Wiedemeyer, R., et al. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science, 318, 287–290.
Chen, L., Sung, S. S., Yip, M. L., Lawrence, H. R., Ren, Y., Guida, W. C., et al. (2006). Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Molecular Pharmacology, 70, 562–570.
Coleman, T. R., & Dunphy, W. G. (1994). Cdc2 regulatory factors. Current Opinion in Cell Biology, 6, 877–882.
Hoffmann, I., & Karsenti, E. (1994). The role of cdc25 in checkpoints and feedback controls in the eukaryotic cell cycle. Journal of Cell Science. Supplement, 18, 75–79.
Nilsson, I., & Hoffmann, I. (2000). Cell cycle regulation by the Cdc25 phosphatase family. Progress in Cell Cycle Research, 4, 107–114.
Ma, Z. Q., Chua, S. S., DeMayo, F. J., & Tsai, S. Y. (1999). Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B. Oncogene, 18, 4564−4576.
Yao, Y., Slosberg, E. D., Wang, L., Hibshoosh, H., Zhang, Y.-J., Xing, W.-Q., et al. (1999). Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice. Oncogene, 18, 5159−5166.
Galaktionov, K., Lee, A. K., Eckstein, J., Draetta, G., Meckler, J., Loda, M., et al. (1995). Cdc25 phosphatases as potential human oncogenes. Science, 269, 1575–1577.
Cangi, M. G., Cukor, B., Soung, P., Signoretti, S., Moreira Jr., G., Ranashinge, M., et al. (2000). Role of the Cdc25A phosphatase in human breast cancer. Journal of Clinical Investigation, 106, 753–761.
Lyon, M. A., Ducruet, A. P., Wipf, P., & Lazo, J. S. (2002). Dual-specificity phosphatases as targets for antineoplastic agents. Nature reviews. Nature reviews. Drug discovery, 1, 961–976.
Ducruet, A. P., Vogt, A., Wipf, P., & Lazo, J. S. (2005). Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer’s disease. Annual Review of Pharmacology and Toxicology, 45, 725–750.
Gunasekera, S. P., McCarty, P. J., Kelly-Borges, M., Lobkovsky, E., & Clardy, J. (1996). Dysidiolide: a novel protein phosphatase inhibitor from the Caribbean sponge Dysidea etheria de Laubenfels. Journal of the American Chemical Society, 118, 8759–8760.
Dodo, K., Takahashi, M., Yamada, Y., Sugimoto, Y., Hashimoto, Y., & Shirai, R. (2000). Synthesis of a novel class of cdc25A inhibitors from vitamin D3. Bioorganic & Medicinal Chemistry Letters, 10, 615–617.
Horiguchi, T., Nishi, K., Hakoda, S., Tanida, S., Nagata, A., & Okayama, H. (1994). Dnacin A1 and dnacin B1 are antitumor antibiotics that inhibit cdc25B phosphatase activity. Biochemical Pharmacology, 48, 2139–2141.
Loukaci, A., Le Saout, I., Samadi, M., Leclerc, S., Damiens, E., Meijer, L., et al. (2001). Coscinosulfate, a CDC25 phosphatase inhibitor from the sponge Coscinoderma mathewsi. Bioorganic & Medicinal Chemistry, 9, 3049–3054.
Ham, S. W., Park, H. J., & Lim, D. H. (1997). Studies on menadione as an inhibitor of the cdc25 phosphatase. Bioorganic Chemistry, 25, 33–36.
Lazo, J. S., Nemoto, K., Pestell, K. E., Cooley, K., Southwick, E. C., Mitchell, D. A., et al. (2002). Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors. Molecular Pharmacology, 61, 720–728.
Contour-Galcera, M. O., Sidhu, A., Prevost, G., Bigg, D., & Ducommun, B. (2007). What’s new on Cdc25 phosphatase inhibitors. Pharmacology & Therapeutics, 115, 1–12.
Sohn, J., Kiburz, B., Li, Z., Deng, L., Safi, A., Pirrung, M. C. et al. (2003). Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones. Journal of Medicinal Chemistry, 46, 2580–2588.
Diamond, R. H., Cressman, D. E., Laz, T. M., Abrams, C. S., & Taub, R. (1994). PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Molecular and Cellular Biology, 14, 3752–3762.
Wang, J., Kirby, C. E., & Herbst, R. (2002). The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. Journal of Biological Chemistry, 277, 46659–46668.
Cates, C. A., Michael, R. L., Stayrook, K. R., Harvey, K. A., Burke, Y. D., Randall, S. K., et al. (1996). Prenylation of oncogenic human PTP(CAAX) protein tyrosine phosphatase. Cancer Letters, 110, 49–55.
Matter, W. F., Estridge, T., Zhang, C., Belagaje, R., Stancato, L., Dixon, J., et al. (2001). Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. Biochemical and Biophysical Research Communications, 283, 1061–1068.
Zeng, Q., Dong, J. M., Guo, K., Li, J., Tan, H. X., Koh, V., et al. (2003). PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Research, 63, 2716–2722.
Werner, S. R., Lee, P. A., DeCamp, M. W., Crowell, D. N., Randall, S. K., & Crowell, P. L. (2003). Enhanced cell cycle progression and down regulation of p21(Cip1/Waf1) by PRL tyrosine phosphatases. Cancer Letters, 202, 201–211.
Saha, S., Bardelli, A., Buckhaults, P., Velculescu, V. E., Rago, C., St Croix, B., et al. (2001). A phosphatase associated with metastasis of colorectal cancer. Science, 294, 1343–1346.
Bardelli, A., Saha, S., Sager, J. A., Romans, K. E., Xin, B., Markowitz, S. D., et al. (2003). PRL-3 expression in metastatic cancers. Clinical Cancer Research, 9, 5607–5615.
Kato, H., Semba, S., Miskad, U. A., Seo, Y., Kasuga, M., & Yokozaki, H. (2004). High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clinical Cancer Research, 10, 7318–7328.
Liang, F., Liang, J., Wang, W. Q., Sun, J. P., Udho, E., & Zhang, Z. Y. (2007). PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. Journal of Biological Chemistry, 282, 5413–5419.
Fiordalisi, J. J., Keller, P. J., & Cox, A. D. (2006). PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Research, 66, 3153–3161.
Achiwa, H., & Lazo, J. S. (2007). PRL-1 tyrosine phosphatase regulates c-Src levels, adherence, and invasion in human lung cancer cells. Cancer Research, 67, 643–650.
Rouleau, C., Roy, A., St Martin, T., Dufault, M. R., Boutin, P., Liu, D., et al. (2006). Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Clinical Cancer Research, 5, 219–229.
Pathak, M. K., Dhawan, D., Lindner, D. J., Borden, E. C., Farver, C., & Yi, T. (2002). Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Molecular Cancer Therapeutics, 1, 1255–1264.
Ahn, J. H., Kim, S. J., Park, W. S., Cho, S. Y., Ha, J. D., Kim, S. S., et al. (2006). Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors. Bioorganic & Medicinal Chemistry Letters, 16, 2996–2999.
Choi, S. K., Oh, H. M., Lee, S. K., Jeong, D. G., Ryu, S. E., Son, K. H., et al. (2006). Biflavonoids inhibited phosphatase of regenerating liver-3 (PRL-3). Natural Product Research, 20, 341–346.
Jeong, D. G., Kim, S. J., Kim, J. H., Son, J. H., Park, M. R., Lim, S. M., et al. (2005). Trimeric structure of PRL1 phosphatase reveals an active enzyme conformation and regulation mechanisms. Journal of Molecular Biology, 345, 401–413.
Sun, J. P., Wang, W. Q., Yang, H., Liu, S., Liang, F., Fedorov, A. A., et al. (2005). Structure and biochemical properties of PRL1, a phosphatase implicated in cell growth, differentiation, and tumor invasion. Biochemistry, 44, 12009–12021.
Sun, J.-P., Luo, Y., Yu, X., Wang, W.-Q., Zhou, B., Liang, F., et al. (2007). Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for the PRL1-mediated cell growth and migration. Journal of Biological Chemistry, 282, 29043–29051.
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This work was supported by NIH Grants CA69202 and DK68447.
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Jiang, ZX., Zhang, ZY. Targeting PTPs with small molecule inhibitors in cancer treatment. Cancer Metastasis Rev 27, 263–272 (2008). https://doi.org/10.1007/s10555-008-9113-3
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DOI: https://doi.org/10.1007/s10555-008-9113-3