Significance of MTA1 in the molecular characterization of osteosarcoma

Cancer and Metastasis Reviews

Volumn 33, Issue 4, 2014, Pages 981-991

  Kim, Sung Sun ^a   Park, Yong Koo ^b  

^a Chonnam National University Medical School   (South Korea)

^b Kyung Hee University Hospital   (South Korea)

Author keywords

Cancer; Chromatin modifiers; Genetics; Metastasis associated protein; MicroRNA; MTA1; Osteosarcoma

Indexed keywords

METASTASIS ASSOCIATED PROTEIN 1; MICRORNA; REGULATOR PROTEIN; UNCLASSIFIED DRUG; HISTONE DEACETYLASE; MTA1 PROTEIN, HUMAN; REPRESSOR PROTEIN;

ANGIOGENESIS; ANOIKIS; ARTICLE; CANCER GROWTH; CANCER PATIENT; CANCER SURVIVAL; CARCINOGENESIS; EXTRACELLULAR MATRIX; EXTRAVASATION; GENE ACTIVATION; GENE INACTIVATION; HUMAN; METASTASIS; MOLECULARLY TARGETED THERAPY; OSTEOSARCOMA; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTO ONCOGENE; SURVIVAL RATE; TUMOR CELL; TUMOR INVASION; BONE TUMOR; CHROMATIN ASSEMBLY AND DISASSEMBLY; GENETICS; PATHOLOGY;

BONE NEOPLASMS; CHROMATIN ASSEMBLY AND DISASSEMBLY; HISTONE DEACETYLASES; HUMANS; MICRORNAS; NEOPLASM INVASIVENESS; OSTEOSARCOMA; REPRESSOR PROTEINS;

EID: 84913546018     PISSN: 01677659     EISSN: 15737233     Source Type: Journal    
DOI: 10.1007/s10555-014-9523-3     Document Type: Article

References (182)

1. Ottaviani, G., & Jaffe, N. (2009). The epidemiology of osteosarcoma. Cancer Treatment and Research, 152, 3–13.
2. Mirabello, L., Troisi, R. J., & Savage, S. A. (2009). Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer, 115(7), 1531–1543.
3. Siegel, R., Ma, J., Zou, Z., & Jemal, A. (2014). Cancer statistics, 2014. CA: A Cancer Journal for Clinicians, 64(1), 9–29.
4. Hansen, M. F., Seton, M., & Merchant, A. (2006). Osteosarcoma in Paget’s disease of bone. Journal of Bone and Mineral Research, 21(Suppl 2), 58–63.
5. Ottaviani, G., & Jaffe, N. (2009). The etiology of osteosarcoma. Cancer Treatment and Research, 152, 15–32.
6. Doganavsargil, B., Argin, M., Kececi, B., Sezak, M., Sanli, U. A., & Oztop, F. (2009). Secondary osteosarcoma arising in fibrous dysplasia, case report. Archives of Orthopaedic and Traumatic Surgery, 129(4), 439–444.
7. Carnevale, A., Lieberman, E., & Cardenas, R. (1997). Li-Fraumeni syndrome in pediatric patients with soft tissue sarcoma or osteosarcoma. Archives of Medical Research, 28(3), 383–386.
8. Wang, L. L., Gannavarapu, A., Kozinetz, C. A., Levy, M. L., Lewis, R. A., Chintagumpala, M. M., et al. (2003). Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. Journal of the National Cancer Institute, 95(9), 669–674.
9. Liu, J. J., Liu, S., Wang, J. G., Zhu, W., Hua, Y. Q., Sun, W., et al. (2013). Telangiectatic osteosarcoma: a review of literature. OncoTargets and Therapy, 6, 593–602.
10. DeLaney, T. F., Park, L., Goldberg, S. I., Hug, E. B., Liebsch, N. J., Munzenrider, J. E., et al. (2005). Radiotherapy for local control of osteosarcoma. International Journal of Radiation Oncology, Biology, Physics, 61(2), 492–498.
11. Davis, A. M., Bell, R. S., & Goodwin, P. J. (1994). Prognostic factors in osteosarcoma: a critical review. Journal of Clinical Oncology, 12(2), 423–431.
12. Bieling, P., Rehan, N., Winkler, P., Helmke, K., Maas, R., Fuchs, N., et al. (1996). Tumor size and prognosis in aggressively treated osteosarcoma. Journal of Clinical Oncology, 14(3), 848–858.
13. Bacci, G., Bertoni, F., Longhi, A., Ferrari, S., Forni, C., Biagini, R., et al. (2003). Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer, 97(12), 3068–3075.
14. Lee, J. A., Kim, M. S., Kim, D. H., Lim, J. S., Yoo, J. Y., Koh, J. S., et al. (2008). Relative tumor burden predicts metastasis-free survival in pediatric osteosarcoma. Pediatric Blood & Cancer, 50(2), 195–200.
15. Bacci, G., Longhi, A., Versari, M., Mercuri, M., Briccoli, A., & Picci, P. (2006). Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer, 106(5), 1154–1161.
16. Han, I., Oh, J. H., Na, Y. G., Moon, K. C., & Kim, H. S. (2008). Clinical outcome of parosteal osteosarcoma. Journal of Surgical Oncology, 97(2), 146–149.
17. Revell, M. P., Deshmukh, N., Grimer, R. J., Carter, S. R., & Tillman, R. M. (2002). Periosteal osteosarcoma: a review of 17 cases with mean follow-up of 52 months. Sarcoma, 6(4), 123–130.
18. Toh, Y., & Nicolson, G. L. (2009). The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clinical & Experimental Metastasis, 26(3), 215–227.
19. Li, D. Q., Pakala, S. B., Nair, S. S., Eswaran, J., & Kumar, R. (2012). Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. Cancer Research, 72(2), 387–394.
20. Martin, M. D., Fischbach, K., Osborne, C. K., Mohsin, S. K., Allred, D. C., & O’Connell, P. (2001). Loss of heterozygosity events impeding breast cancer metastasis contain the MTA1 gene. Cancer Research, 61(9), 3578–3580.
21. Toh, Y., Ohga, T., Endo, K., Adachi, E., Kusumoto, H., Haraguchi, M., et al. (2004). Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. International Journal of Cancer, 110(3), 362–367.
22. Toh, Y., Oki, E., Oda, S., Tokunaga, E., Ohno, S., Maehara, Y., et al. (1997). Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. International Journal of Cancer, 74(4), 459–463.
23. Kidd, M., Modlin, I. M., Mane, S. M., Camp, R. L., Eick, G., & Latich, I. (2006). The role of genetic markers—NAP1L1, MAGE-D2, and MTA1—in defining small-intestinal carcinoid neoplasia. Annals of Surgical Oncology, 13(2), 253–262.
24. Sasaki, H., Moriyama, S., Nakashima, Y., Kobayashi, Y., Yukiue, H., Kaji, M., et al. (2002). Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer, 35(2), 149–154.
25. Dannenmann, C., Shabani, N., Friese, K., Jeschke, U., Mylonas, I., & Bruning, A. (2008). The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO. Cancer Biology & Therapy, 7(9), 1460–1467.
26. Hofer, M. D., Kuefer, R., Varambally, S., Li, H., Ma, J., Shapiro, G. I., et al. (2004). The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Research, 64(3), 825–829.
27. Park, H. R., Jung, W. W., Kim, H. S., Bacchini, P., Bertoni, F., & Park, Y. K. (2005). Overexpression of metastatic tumor antigen in osteosarcoma: comparison between conventional high-grade and central low-grade osteosarcoma. Cancer Research and Treatment, 37(6), 360–364.
28. Ferrari, S., Smeland, S., Mercuri, M., Bertoni, F., Longhi, A., Ruggieri, P., et al. (2005). Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. Journal of Clinical Oncology, 23(34), 8845–8852.
29. Ta, H. T., Dass, C. R., Choong, P. F., & Dunstan, D. E. (2009). Osteosarcoma treatment: state of the art. Cancer Metastasis Reviews, 28(1–2), 247–263.
30. Briccoli, A., Rocca, M., Salone, M., Guzzardella, G. A., Balladelli, A., & Bacci, G. (2010). High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985–2005. Surgical Oncology, 19(4), 193–199.
31. Toh, Y., Pencil, S. D., & Nicolson, G. L. (1995). Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene, 159(1), 97–104.
32. Molli, P. R., Singh, R. R., Lee, S. W., & Kumar, R. (2008). MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene, 27(14), 1971–1980.
33. Yoo, Y. G., Na, T. Y., Seo, H. W., Seong, J. K., Park, C. K., Shin, Y. K., et al. (2008). Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene, 27(24), 3405–3413.
34. Jang, K. S., Paik, S. S., Chung, H., Oh, Y. H., & Kong, G. (2006). MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Science, 97(5), 374–379.
35. Li, S. H., Tian, H., Yue, W. M., Li, L., Li, W. J., Chen, Z. T., et al. (2011). Overexpression of metastasis-associated protein 1 is significantly correlated with tumor angiogenesis and poor survival in patients with early-stage non-small cell lung cancer. Annals of Surgical Oncology, 18(7), 2048–2056.
36. Kai, L., Wang, J., Ivanovic, M., Chung, Y. T., Laskin, W. B., Schulze-Hoepfner, F., et al. (2011). Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). Prostate, 71(3), 268–280.
37. Li, S. H., Tian, H., Yue, W. M., Li, L., Gao, C., Li, W. J., et al. (2012). Metastasis-associated protein 1 nuclear expression is closely associated with tumor progression and angiogenesis in patients with esophageal squamous cell cancer. World Journal of Surgery, 36(3), 623–631.
38. Deng, X., Du, L., Wang, C., Yang, Y., Li, J., Liu, H., et al. (2013). Close association of metastasis-associated protein 1 overexpression with increased angiogenesis and poor survival in patients with histologically node-negative gastric cancer. World Journal of Surgery, 37(4), 792–798.
39. Park, H. R., Cabrini, R. L., Araujo, E. S., Paparella, M. L., Brandizzi, D., & Park, Y. K. (2009). Expression of ezrin and metastatic tumor antigen in osteosarcomas of the jaw. Tumori, 95(1), 81–86.
40. Choi, K. S., Bae, M. K., Jeong, J. W., Moon, H. E., & Kim, K. W. (2003). Hypoxia-induced angiogenesis during carcinogenesis. Journal of Biochemistry and Molecular Biology, 36(1), 120–127.
41. Ito, T. K., Ishii, G., Chiba, H., & Ochiai, A. (2007). The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene, 26(51), 7194–7203.
42. Figueras, A., Arbos, M. A., Quiles, M. T., Vinals, F., Germa, J. R., & Capella, G. (2013). The impact of KRAS mutations on VEGF-A production and tumour vascular network. BMC Cancer, 13, 125.
43. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994). Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79(2), 315–328.
44. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997). Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 88(2), 277–285.
45. Tsuchida, R., Osawa, T., Wang, F., Nishii, R., Das, B., Tsuchida, S., et al. (2014). BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors. Oncogene, 33(29), 3803–3811.
46. Kim, H. S., Lim, S. J., & Park, Y. K. (2009). Anti-angiogenic factor endostatin in osteosarcoma. APMIS, 117(10), 716–723.
47. Lammli, J., Fan, M., Rosenthal, H. G., Patni, M., Rinehart, E., Vergara, G., et al. (2012). Expression of vascular endothelial growth factor correlates with the advance of clinical osteosarcoma. International Orthopaedics, 36(11), 2307–2313.
48. Rastogi, S., Kumar, R., Sankineani, S. R., Marimuthu, K., Rijal, L., Prakash, S., et al. (2012). Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study. International Orthopaedics, 36(11), 2315–2321.
49. Roncuzzi, L., Pancotti, F., & Baldini, N. (2014). Involvement of HIF-1alpha activation in the doxorubicin resistance of human osteosarcoma cells. Oncology Reports, 32(1), 389–394.
50. Yang, Q. C., Zeng, B. F., Dong, Y., Shi, Z. M., Jiang, Z. M., & Huang, J. (2007). Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome. Japanese Journal of Clinical Oncology, 37(2), 127–134.
51. Yoo, Y. G., Kong, G., & Lee, M. O. (2006). Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO Journal, 25(6), 1231–1241.
52. Moon, H. E., Cheon, H., Chun, K. H., Lee, S. K., Kim, Y. S., Jung, B. K., et al. (2006). Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncology Reports, 16(4), 929–935.
53. Birner, P., Schindl, M., Obermair, A., Breitenecker, G., & Oberhuber, G. (2001). Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clinical Cancer Research, 7(6), 1661–1668.
54. Schindl, M., Schoppmann, S. F., Samonigg, H., Hausmaninger, H., Kwasny, W., Gnant, M., et al. (2002). Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clinical Cancer Research, 8(6), 1831–1837.
55. Shibaji, T., Nagao, M., Ikeda, N., Kanehiro, H., Hisanaga, M., Ko, S., et al. (2003). Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Research, 23(6C), 4721–4727.
56. El Naggar, A., Clarkson, P., Zhang, F., Mathers, J., Tognon, C., & Sorensen, P. H. (2012). Expression and stability of hypoxia inducible factor 1alpha in osteosarcoma. Pediatric Blood & Cancer, 59(7), 1215–1222.
57. Chen, Y., Yang, Y., Yuan, Z., Wang, C., & Shi, Y. (2012). Predicting chemosensitivity in osteosarcoma prior to chemotherapy: an investigational study of biomarkers with immunohistochemistry. Oncology Letters, 3(5), 1011–1016.
58. McMahon, G. (2000). VEGF receptor signaling in tumor angiogenesis. The Oncologist, 5(Suppl 1), 3–10.
59. Dong, G., Chen, Z., Li, Z. Y., Yeh, N. T., Bancroft, C. C., & Van Waes, C. (2001). Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Research, 61(15), 5911–5918.
60. Yu, X. W., Wu, T. Y., Yi, X., Ren, W. P., Zhou, Z. B., Sun, Y. Q., et al. (2014). Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis. Tumour Biology, 35(1), 155–160.
61. Qu, J. T., Wang, M., He, H. L., Tang, Y., & Ye, X. J. (2012). The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: a meta-analysis and systemic review. Journal of Cancer Research and Clinical Oncology, 138(5), 819–825.
62. Nagaraj, S. R., Shilpa, P., Rachaiah, K., & Salimath, B. P. (2013). Crosstalk between VEGF and MTA1 signaling pathways contribute to aggressiveness of breast carcinoma. Molecular Carcinogenesis. doi:10.1002/mc.22104.
63. Garcia, A., & Kandel, J. J. (2012). Notch: a key regulator of tumor angiogenesis and metastasis. Histology and Histopathology, 27(2), 151–156.
64. Hughes, D. P. (2009). How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treatment and Research, 152, 479–496.
65. Mu, X., Isaac, C., Greco, N., Huard, J., & Weiss, K. (2013). Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Frontiers in Oncology, 3, 143.
66. Won, K. Y., Kim, Y. W., Kim, H. S., Lee, S. K., Jung, W. W., & Park, Y. K. (2013). MicroRNA-199b-5p is involved in the Notch signaling pathway in osteosarcoma. Human Pathology, 44(8), 1648–1655.
67. Morley, M. E., Riches, K., Peers, C., & Porter, K. E. (2007). Hypoxic inhibition of human cardiac fibroblast invasion and MMP-2 activation may impair adaptive myocardial remodelling. Biochemical Society Transactions, 35(Pt 5), 905–907.
68. Jodele, S., Blavier, L., Yoon, J. M., & DeClerck, Y. A. (2006). Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Reviews, 25(1), 35–43.
69. Wang, G., Wang, W., Zhou, J., & Yang, X. (2013). Correlation between telomerase activity and matrix metalloproteinases 2 expression in gastric cancer. Cancer Biomarkers, 13(1), 21–28.
70. Zhao, S., Ma, W., Zhang, M., Tang, D., Shi, Q., Xu, S., et al. (2013). High expression of CD147 and MMP-9 is correlated with poor prognosis of triple-negative breast cancer (TNBC) patients. Medical Oncology, 30(1), 335.
71. Jiang, Q., Zhang, H., & Zhang, P. (2011). ShRNA-mediated gene silencing of MTA1 influenced on protein expression of ER alpha, MMP-9, CyclinD1 and invasiveness, proliferation in breast cancer cell lines MDA-MB-231 and MCF-7 in vitro. Journal of Experimental & Clinical Cancer Research, 30, 60.
72. Weng, W., Yin, J., Zhang, Y., Qiu, J., & Wang, X. (2014). Metastasis-associated protein 1 promotes tumor invasion by downregulation of E-cadherin. International Journal of Oncology, 44(3), 812–818.
73. Wen, X., Liu, H., Yu, K., & Liu, Y. (2014). Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: a meta-analysis. Tumour Biology, 35(1), 845–848.
74. Li, H., Zhang, K., Liu, L. H., Ouyang, Y., Bu, J., Guo, H. B., et al. (2014). A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma. Tumour Biology, 35(6), 5487–5491.
75. Jin, J., Cai, L., Liu, Z. M., & Zhou, X. S. (2013). miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pacific Journal of Cancer Prevention, 14(6), 3681–3684.
76. Husmann, K., Arlt, M. J., Muff, R., Langsam, B., Bertz, J., Born, W., et al. (2013). Matrix metalloproteinase 1 promotes tumor formation and lung metastasis in an intratibial injection osteosarcoma mouse model. Biochimica et Biophysica Acta, 1832(2), 347–354.
77. Decock, J., Long, J. R., Laxton, R. C., Shu, X. O., Hodgkinson, C., Hendrickx, W., et al. (2007). Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis. Cancer Research, 67(21), 10214–10221.
78. Balbin, M., Fueyo, A., Tester, A. M., Pendas, A. M., Pitiot, A. S., Astudillo, A., et al. (2003). Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genetics, 35(3), 252–257.
79. Korpi, J. T., Hagstrom, J., Lehtonen, N., Parkkinen, J., Sorsa, T., Salo, T., et al. (2011). Expression of matrix metalloproteinases-2, −8, −13, −26, and tissue inhibitors of metalloproteinase-1 in human osteosarcoma. Surgical Oncology, 20(1), e18–e22.
80. Cai, Y., Cai, T., & Chen, Y. (2014). Wnt pathway in osteosarcoma, from oncogenic to therapeutic. Journal of Cellular Biochemistry, 115(4), 625–631.
81. Kumar, R., Balasenthil, S., Pakala, S. B., Rayala, S. K., Sahin, A. A., & Ohshiro, K. (2010). Metastasis-associated protein 1 short form stimulates Wnt1 pathway in mammary epithelial and cancer cells. Cancer Research, 70(16), 6598–6608.
82. Yan, D., Avtanski, D., Saxena, N. K., & Sharma, D. (2012). Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires beta-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways. Journal of Biological Chemistry, 287(11), 8598–8612.
83. Lu, Y., Wei, C., & Xi, Z. (2014). Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/beta-catenin pathway. In Vitro Cellular & Developmental Biology. Animal. doi:10.1007/s11626-014-9779-5.
84. Guo, Y., Rubin, E. M., Xie, J., Zi, X., & Hoang, B. H. (2008). Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model. Clinical Orthopaedics and Related Research, 466(9), 2039–2045.
85. Guo, Y., Zi, X., Koontz, Z., Kim, A., Xie, J., Gorlick, R., et al. (2007). Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. Journal of Orthopaedic Research, 25(7), 964–971.
86. Ma, Y., Ren, Y., Han, E. Q., Li, H., Chen, D., Jacobs, J. J., et al. (2013). Inhibition of the Wnt-beta-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochemical and Biophysical Research Communications, 431(2), 274–279.
87. Yang, G., Yuan, J., & Li, K. (2013). EMT transcription factors: implication in osteosarcoma. Medical Oncology, 30(4), 697.
88. Tuncay Cagatay, S., Cimen, I., Savas, B., & Banerjee, S. (2013). MTA-1 expression is associated with metastasis and epithelial to mesenchymal transition in colorectal cancer cells. Tumour Biology, 34(2), 1189–1204.
89. Yang, H., Zhang, Y., Zhou, Z., Jiang, X., & Shen, A. (2014). Transcription factor Snai1-1 induces osteosarcoma invasion and metastasis by inhibiting E-cadherin expression. Oncology Letters, 8(1), 193–197.
90. Sharili, A. S., Allen, S., Smith, K., Hargreaves, J., Price, J., & McGonnell, I. (2011). Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy. Tumour Biology, 32(3), 515–526.
91. Sharili, A. S., Allen, S., Smith, K., Price, J., & McGonnell, I. M. (2013). Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development. Cancer Letters, 333(2), 170–179.
92. Fan, L., Wang, H., Xia, X., Rao, Y., Ma, X., Ma, D., et al. (2012). Loss of E-cadherin promotes prostate cancer metastasis via upregulation of metastasis-associated gene 1 expression. Oncology Letters, 4(6), 1225–1233.
93. Wang, H., Fan, L., Wei, J., Weng, Y., Zhou, L., Shi, Y., et al. (2012). Akt mediates metastasis-associated gene 1 (MTA1) regulating the expression of E-cadherin and promoting the invasiveness of prostate cancer cells. PloS One, 7(12), e46888.
94. Khan, M. A., Chen, H. C., Zhang, D., & Fu, J. (2013). Twist: a molecular target in cancer therapeutics. Tumour Biology, 34(5), 2497–2506.
95. Zhou, Y., Zang, X., Huang, Z., & Zhang, C. (2013). TWIST interacts with endothelin-1/endothelin A receptor signaling in osteosarcoma cell survival against cisplatin. Oncology Letters, 5(3), 857–861.
96. Wu, J., Liao, Q., He, H., Zhong, D., & Yin, K. (2014). TWIST interacts with beta-catenin signaling on osteosarcoma cell survival against cisplatin. Molecular Carcinogenesis, 53(6), 440–446.
97. Zhou, Y., Huang, Z., Wu, S., Zang, X., Liu, M., & Shi, J. (2014). miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. Journal of Experimental & Clinical Cancer Research, 33, 12.
98. Yin, K., Liao, Q., He, H., & Zhong, D. (2012). Prognostic value of Twist and E-cadherin in patients with osteosarcoma. Medical Oncology, 29(5), 3449–3455.
99. Egloff, A. M., & Grandis, J. R. (2008). Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Seminars in Oncology, 35(3), 286–297.
100. Mori, S., Ronnstrand, L., Yokote, K., Engstrom, A., Courtneidge, S. A., Claesson-Welsh, L., et al. (1993). Identification of two juxtamembrane autophosphorylation sites in the PDGF beta-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO Journal, 12(6), 2257–2264.
101. Playford, M. P., & Schaller, M. D. (2004). The interplay between Src and integrins in normal and tumor biology. Oncogene, 23(48), 7928–7946.
102. Cheranov, S. Y., Karpurapu, M., Wang, D., Zhang, B., Venema, R. C., & Rao, G. N. (2008). An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis. Blood, 111(12), 5581–5591.
103. Brunton, V. G., & Frame, M. C. (2008). Src and focal adhesion kinase as therapeutic targets in cancer. Current Opinion in Pharmacology, 8(4), 427–432.
104. Hingorani, P., Zhang, W., Gorlick, R., & Kolb, E. A. (2009). Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. Clinical Cancer Research, 15(10), 3416–3422.
105. Strauss, S. J., Ng, T., Mendoza-Naranjo, A., Whelan, J., & Sorensen, P. H. (2010). Understanding micrometastatic disease and Anoikis resistance in ewing family of tumors and osteosarcoma. The Oncologist, 15(6), 627–635.
106. Frisch, S. M., & Francis, H. (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. Journal of Cell Biology, 124(4), 619–626.
107. Jost, M., Huggett, T. M., Kari, C., & Rodeck, U. (2001). Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway. Molecular Biology of the Cell, 12(5), 1519–1527.
108. Jost, M., Huggett, T. M., Kari, C., Boise, L. H., & Rodeck, U. (2001). Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. Journal of Biological Chemistry, 276(9), 6320–6326.
109. Sakuma, Y., Yamazaki, Y., Nakamura, Y., Yoshihara, M., Matsukuma, S., Nakayama, H., et al. (2012). WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors. Laboratory Investigation, 92(3), 371–383.
110. Mahoney, M. G., Simpson, A., Jost, M., Noe, M., Kari, C., Pepe, D., et al. (2002). Metastasis-associated protein (MTA)1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes. Oncogene, 21(14), 2161–2170.
111. Diaz-Montero, C. M., Wygant, J. N., & McIntyre, B. W. (2006). PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation. European Journal of Cancer, 42(10), 1491–1500.
112. Cantiani, L., Manara, M. C., Zucchini, C., De Sanctis, P., Zuntini, M., Valvassori, L., et al. (2007). Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. Cancer Research, 67(16), 7675–7685.
113. Wan, X., Kim, S. Y., Guenther, L. M., Mendoza, A., Briggs, J., Yeung, C., et al. (2009). Beta4 integrin promotes osteosarcoma metastasis and interacts with ezrin. Oncogene, 28(38), 3401–3411.
114. Jeffree, G. M., Price, C. H., & Sissons, H. A. (1975). The metastatic patterns of osteosarcoma. British Journal of Cancer, 32(1), 87–107.
115. Laverdiere, C., Hoang, B. H., Yang, R., Sowers, R., Qin, J., Meyers, P. A., et al. (2005). Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clinical Cancer Research, 11(7), 2561–2567.
116. Sun, X., Cheng, G., Hao, M., Zheng, J., Zhou, X., Zhang, J., et al. (2010). CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Reviews, 29(4), 709–722.
117. Kaplan, R. N., Psaila, B., & Lyden, D. (2006). Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Reviews, 25(4), 521–529.
118. Ando, K., Mori, K., Verrecchia, F., Marc, B., Redini, F., & Heymann, D. (2012). Molecular alterations associated with osteosarcoma development. Sarcoma, 2012, 523432.
119. Balkwill, F. (2004). Cancer and the chemokine network. Nature Reviews Cancer, 4(7), 540–550.
120. Zagzag, D., Lukyanov, Y., Lan, L., Ali, M. A., Esencay, M., Mendez, O., et al. (2006). Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Laboratory Investigation, 86(12), 1221–1232.
121. Brennecke, P., Arlt, M. J., Muff, R., Campanile, C., Gvozdenovic, A., Husmann, K., et al. (2013). Expression of the chemokine receptor CXCR7 in CXCR4-expressing human 143B osteosarcoma cells enhances lung metastasis of intratibial xenografts in SCID mice. PloS One, 8(9), e74045.
122. Brennecke, P., Arlt, M. J., Campanile, C., Husmann, K., Gvozdenovic, A., Apuzzo, T., et al. (2014). CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice. Clinical & Experimental Metastasis, 31(3), 339–349.
123. Zhang, Y., Zhang, L., Zhang, G., Li, S., Duan, J., Cheng, J., et al. (2014). Osteosarcoma metastasis: prospective role of ezrin. Tumour Biology, 35(6), 5055–5059.
124. Khanna, C., Wan, X., Bose, S., Cassaday, R., Olomu, O., Mendoza, A., et al. (2004). The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nature Medicine, 10(2), 182–186.
125. Ferrari, S., Zanella, L., Alberghini, M., Palmerini, E., Staals, E., & Bacchini, P. (2008). Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma. Pediatric Blood & Cancer, 50(4), 752–756.
126. Li, H., Min, D., Zhao, H., Wang, Z., Qi, W., Zheng, S., et al. (2013). The prognostic role of ezrin immunoexpression in osteosarcoma: a meta-analysis of published data. PloS One, 8(6), e64513.
127. Lun, D. X., Hu, Y. C., Xu, Z. W., Xu, L. N., & Wang, B. W. (2014). The prognostic value of elevated ezrin in patients with osteosarcoma. Tumour Biology, 35(2), 1263–1266.
128. Zhu, J., Feng, Y., Ke, Z., Yang, Z., Zhou, J., Huang, X., et al. (2012). Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin. American Journal of Pathology, 180(6), 2440–2451.
129. Mu, Y., Zhang, H., Che, L., & Li, K. (2014). Clinical significance of microRNA-183/Ezrin axis in judging the prognosis of patients with osteosarcoma. Medical Oncology, 31(2), 821.
130. Li, D. Q., Divijendra Natha Reddy, S., Pakala, S. B., Wu, X., Zhang, Y., Rayala, S. K., et al. (2009). MTA1 coregulator regulates p53 stability and function. Journal of Biological Chemistry, 284(50), 34545–34552.
131. Li, D. Q., Pakala, S. B., Reddy, S. D., Ohshiro, K., Peng, S. H., Lian, Y., et al. (2010). Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway. Journal of Biological Chemistry, 285(13), 10044–10052.
132. Lee, M. H., Na, H., Kim, E. J., Lee, H. W., & Lee, M. O. (2012). Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1. Oncogene, 31(49), 5099–5107.
133. Birch, J. M., Alston, R. D., McNally, R. J., Evans, D. G., Kelsey, A. M., Harris, M., et al. (2001). Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene, 20(34), 4621–4628.
134. Gokgoz, N., Wunder, J. S., Mousses, S., Eskandarian, S., Bell, R. S., & Andrulis, I. L. (2001). Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma. Cancer, 92(8), 2181–2189.
135. Tsuchiya, T., Sekine, K., Hinohara, S., Namiki, T., Nobori, T., & Kaneko, Y. (2000). Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. Cancer Genetics and Cytogenetics, 120(2), 91–98.
136. Pakos, E. E., Kyzas, P. A., & Ioannidis, J. P. (2004). Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma: a meta-analysis. Clinical Cancer Research, 10(18 Pt 1), 6208–6214.
137. Jiang, L., Tao, C., & He, A. (2013). Prognostic significance of p53 expression in malignant bone tumors: a meta-analysis. Tumour Biology, 34(2), 1037–1043.
138. Fu, H. L., Shao, L., Wang, Q., Jia, T., Li, M., & Yang, D. P. (2013). A systematic review of p53 as a biomarker of survival in patients with osteosarcoma. Tumour Biology, 34(6), 3817–3821.
139. Florenes, V. A., Maelandsmo, G. M., Forus, A., Andreassen, A., Myklebost, O., & Fodstad, O. (1994). MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. Journal of the National Cancer Institute, 86(17), 1297–1302.
140. Miller, C. W., Aslo, A., Won, A., Tan, M., Lampkin, B., & Koeffler, H. P. (1996). Alterations of the p53, Rb and MDM2 genes in osteosarcoma. Journal of Cancer Research and Clinical Oncology, 122(9), 559–565.
141. Mejia-Guerrero, S., Quejada, M., Gokgoz, N., Gill, M., Parkes, R. K., Wunder, J. S., et al. (2010). Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes, Chromosomes & Cancer, 49(6), 518–525.
142. Wadayama, B., Toguchida, J., Shimizu, T., Ishizaki, K., Sasaki, M. S., Kotoura, Y., et al. (1994). Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Research, 54(11), 3042–3048.
143. Eng, C., Li, F. P., Abramson, D. H., Ellsworth, R. M., Wong, F. L., Goldman, M. B., et al. (1993). Mortality from second tumors among long-term survivors of retinoblastoma. Journal of the National Cancer Institute, 85(14), 1121–1128.
144. Brehm, A., Miska, E. A., McCance, D. J., Reid, J. L., Bannister, A. J., & Kouzarides, T. (1998). Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature, 391(6667), 597–601.
145. Feugeas, O., Guriec, N., Babin-Boilletot, A., Marcellin, L., Simon, P., Babin, S., et al. (1996). Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. Journal of Clinical Oncology, 14(2), 467–472.
146. Heinsohn, S., Evermann, U., Zur Stadt, U., Bielack, S., & Kabisch, H. (2007). Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. International Journal of Oncology, 30(5), 1205–1214.
147. Patino-Garcia, A., & Sierrasesumaga, L. (1997). Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients. Cancer Genetics and Cytogenetics, 98(1), 50–55.
148. Maitra, A., Roberts, H., Weinberg, A. G., & Geradts, J. (2001). Loss of p16(INK4a) expression correlates with decreased survival in pediatric osteosarcomas. International Journal of Cancer, 95(1), 34–38.
149. Borys, D., Canter, R. J., Hoch, B., Martinez, S. R., Tamurian, R. M., Murphy, B., et al. (2012). P16 expression predicts necrotic response among patients with osteosarcoma receiving neoadjuvant chemotherapy. Human Pathology, 43(11), 1948–1954.
150. Wei, G., Lonardo, F., Ueda, T., Kim, T., Huvos, A. G., Healey, J. H., et al. (1999). CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. International Journal of Cancer, 80(2), 199–204.
151. Wunder, J. S., Eppert, K., Burrow, S. R., Gokgoz, N., Bell, R. S., & Andrulis, I. L. (1999). Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene, 18(3), 783–788.
152. Yoshida, A., Ushiku, T., Motoi, T., Beppu, Y., Fukayama, M., Tsuda, H., et al. (2012). MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. American Journal of Surgical Pathology, 36(3), 423–431.
153. Nakayama, H. (2002). RecQ family helicases: roles as tumor suppressor proteins. Oncogene, 21(58), 9008–9021.
154. Nishijo, K., Nakayama, T., Aoyama, T., Okamoto, T., Ishibe, T., Yasura, K., et al. (2004). Mutation analysis of the RECQL4 gene in sporadic osteosarcomas. International Journal of Cancer, 111(3), 367–372.
155. Yen, C. C., Chen, W. M., Chen, T. H., Chen, W. Y., Chen, P. C., Chiou, H. J., et al. (2009). Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma. International Journal of Oncology, 35(4), 775–788.
156. Pasic, I., Shlien, A., Durbin, A. D., Stavropoulos, D. J., Baskin, B., Ray, P. N., et al. (2010). Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma. Cancer Research, 70(1), 160–171.
157. Kresse, S. H., Ohnstad, H. O., Paulsen, E. B., Bjerkehagen, B., Szuhai, K., Serra, M., et al. (2009). LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes, Chromosomes & Cancer, 48(8), 679–693.
158. Leaner, V. D., Chick, J. F., Donninger, H., Linniola, I., Mendoza, A., Khanna, C., et al. (2009). Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma. American Journal of Pathology, 174(1), 265–275.
159. Kimura, R., Ishikawa, C., Rokkaku, T., Janknecht, R., & Mori, N. (2011). Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. Biochimica et Biophysica Acta, 1813(8), 1543–1553.
160. Kunita, A., Kashima, T. G., Ohazama, A., Grigoriadis, A. E., & Fukayama, M. (2011). Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma. American Journal of Pathology, 179(2), 1041–1049.
161. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235(4785), 177–182.
162. Akatsuka, T., Wada, T., Kokai, Y., Kawaguchi, S., Isu, K., Yamashiro, K., et al. (2002). ErbB2 expression is correlated with increased survival of patients with osteosarcoma. Cancer, 94(5), 1397–1404.
163. Anninga, J. K., van de Vijver, M. J., Cleton-Jansen, A. M., Kristel, P. M., Taminiau, A. H., Nooij, M., et al. (2004). Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. European Journal of Cancer, 40(7), 963–970.
164. Somers, G. R., Ho, M., Zielenska, M., Squire, J. A., & Thorner, P. S. (2005). HER2 amplification and overexpression is not present in pediatric osteosarcoma: a tissue microarray study. Pediatric and Developmental Pathology, 8(5), 525–532.
165. Baumhoer, D., Smida, J., Specht, K., Bink, K., Quintanilla-Martinez, L., Rosemann, M., et al. (2011). Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma. Human Pathology, 42(6), 859–866.
166. Yoshida, C. A., Furuichi, T., Fujita, T., Fukuyama, R., Kanatani, N., Kobayashi, S., et al. (2002). Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nature Genetics, 32(4), 633–638.
167. Galindo, M., Pratap, J., Young, D. W., Hovhannisyan, H., Im, H. J., Choi, J. Y., et al. (2005). The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. Journal of Biological Chemistry, 280(21), 20274–20285.
168. van Harn, T., Foijer, F., van Vugt, M., Banerjee, R., Yang, F., Oostra, A., et al. (2010). Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes & Development, 24(13), 1377–1388.
169. Lengner, C. J., Steinman, H. A., Gagnon, J., Smith, T. W., Henderson, J. E., Kream, B. E., et al. (2006). Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. Journal of Cell Biology, 172(6), 909–921.
170. Thomas, D. M., Johnson, S. A., Sims, N. A., Trivett, M. K., Slavin, J. L., Rubin, B. P., et al. (2004). Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. Journal of Cell Biology, 167(5), 925–934.
171. Won, K. Y., Park, H. R., & Park, Y. K. (2009). Prognostic implication of immunohistochemical Runx2 expression in osteosarcoma. Tumori, 95(3), 311–316.
172. Sadikovic, B., Thorner, P., Chilton-Macneill, S., Martin, J. W., Cervigne, N. K., Squire, J., et al. (2010). Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy. BMC Cancer, 10, 202.
173. Zhang, B., Pan, X., Cobb, G. P., & Anderson, T. A. (2007). microRNAs as oncogenes and tumor suppressors. Developmental Biology, 302(1), 1–12.
174. Shenouda, S. K., & Alahari, S. K. (2009). MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Reviews, 28(3–4), 369–378.
175. Zhou, G., Shi, X., Zhang, J., Wu, S., & Zhao, J. (2013). MicroRNAs in osteosarcoma: from biological players to clinical contributors, a review. Journal of International Medical Research, 41(1), 1–12.
176. Miao, J., Wu, S., Peng, Z., Tania, M., & Zhang, C. (2013). MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects. Tumour Biology, 34(4), 2093–2098.
177. Liu, L. H., Li, H., Li, J. P., Zhong, H., Zhang, H. C., Chen, J., et al. (2011). miR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of STAT3. Biochemical and Biophysical Research Communications, 416(1–2), 31–38.
178. Duan, Z., Choy, E., Harmon, D., Liu, X., Susa, M., Mankin, H., et al. (2011). MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration. Molecular Cancer Therapeutics, 10(8), 1337–1345.
179. Zhang, H., Cai, X., Wang, Y., Tang, H., Tong, D., & Ji, F. (2010). microRNA-143, down-regulated in osteosarcoma, promotes apoptosis and suppresses tumorigenicity by targeting Bcl-2. Oncology Reports, 24(5), 1363–1369.
180. Osaki, M., Takeshita, F., Sugimoto, Y., Kosaka, N., Yamamoto, Y., Yoshioka, Y., et al. (2011). MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Molecular Therapy, 19(6), 1123–1130.
181. Tang, M., Lin, L., Cai, H., Tang, J., & Zhou, Z. (2013). MicroRNA-145 downregulation associates with advanced tumor progression and poor prognosis in patients suffering osteosarcoma. OncoTargets and Therapy, 6, 833–838.
182. Ziyan, W., Shuhua, Y., Xiufang, W., & Xiaoyun, L. (2011). MicroRNA-21 is involved in osteosarcoma cell invasion and migration. Medical Oncology, 28(4), 1469–1474.