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Liver metastatic ability of human melanoma cell line is associated with losses of chromosomes 4, 9p21-pter and 10p

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Abstract

Genetic changes underlying the aggressive progression of human cutaneous melanoma are not completely understood. In order to characterise genetic alterations associated with the metastatic behaviour of this neoplasm we used comparative genomic hybridisation (CGH) in combination with fluorescence in situ hybridisation (FISH) on an experimental metastatic model of three related human melanoma cell lines. Tumour lines were selected based on their various metastatic capacity to liver in immunosuppressed mice. The parental cell line (A2058) was a human amelanotic melanoma cell line, adaptation of this line to in vivo growth as xenograft the HT168 tumour and its cell line was established. After intrasplenic transplantation of HT168 cells into immunosuppressed mice, a highly metastatic variant (HT168-M1) was selected. Several chromosomal aberrations common to all three lines indicating common clonal origin, as well as additional non-shared chromosomal changes were found. The original cell line (A2058) exhibited the highest number of genetic changes. Chromosomal alterations present only in the highly metastatic line (HT168-M1) involved losses on chromosome 4, 9p21.3-pter and 10p. Chromosome copy number patterns and the nature of chromosome 4 loss were further investigated by FISH using different centromeric probes and a chromosome 4 painting probe. According to our CGH and FISH results we assume that alterations present only in the aggressive metastatic subline are associated with the increased – metastatic potential. Our observations further support the hypothesis, based on some recently published data, that certain (so far unidentified) suppressor genes having an important role in tumour progression are located on these chromosomes.

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References

  1. Welch DR, Goldberg SF. Molecular mechanisms controlling human melanoma progression and metastasis. Pathobiology 1997; 65(6): 311–30.

    PubMed  CAS  Google Scholar 

  2. Sauter ER, Herlyn M. Molecular Biology of human melanoma development and progression. Mol Carcinog 1998; 23(3): 132–43.

    Article  PubMed  CAS  Google Scholar 

  3. Castellano M, Parmiani G. Genes involved in melanoma: An overview of INK4a and other loci. Melanoma Res 1999; 9(5): 421–32.

    PubMed  CAS  Google Scholar 

  4. Yeatman TJ, Cher ML, Mao W et al. Identification of genetic alterations associated with the process of human experimental colon cancer liver metastasis in the nude mouse. Clin Exp Metastasis 1996; 14(3): 246–52.

    PubMed  CAS  Google Scholar 

  5. Schmidt CM, Settle SL, Keene JL et al. Characterisation of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry. Clin Exp Metastasis 1999; 17(6): 537–44.

    Article  PubMed  CAS  Google Scholar 

  6. Akslen LA, Hove LM, Hartveit MN. Metastasis distribution in malignant melanoma. Invas Metast 1987; 7(5): 253–63.

    CAS  Google Scholar 

  7. Ladányi A, Timár J, Paku S et al. Selection and characterization of human melanoma lines with different liver-colonizing capacity. Int J Cancer 1990; 46(3): 456–61.

    PubMed  Google Scholar 

  8. Kallioniemi A, Kallioniemi OP, Sudar D et al. Comparative genomic hybridisation for molecular cytogenetic analysis of solid tumours. Science 1992; 258(5083): 818–21.

    PubMed  CAS  Google Scholar 

  9. Knuutila S, Bjorkqvist AM, Autio K et al. DNA copy number amplifications in human neoplasms: Review of comparative genomic hybridization studies. Am J Pathol 1998; 152(6): 1107–23.

    PubMed  CAS  Google Scholar 

  10. Knuutila S, Bjorkqvist AM, Autio K, et al. DNA copy number losses in human neoplasms. Am J Pathol 1999; 155(3): 683–94.

    PubMed  CAS  Google Scholar 

  11. Bastian BC, LeBoit PE, Hamm H et al. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridisation. Cancer Res 1998; 58(10): 2170–75.

    PubMed  CAS  Google Scholar 

  12. Wiltshire RN, Duray P, Bittner ML et al Direct visualization of the clonal progression of primary cutaneous melanoma application of tissue microdissection and comparative genomic hybridization. Cancer Res 1995; 55(18): 3954–57.

    PubMed  CAS  Google Scholar 

  13. Balázs M., Ádám Zs, Bégány Á et al. Chromosomal copy number changes in primary and metastic melanomas detected by CGH and FISH. Proceedings of the American Assoc for Cancer Res 2000; 41: 420.

    Google Scholar 

  14. Todaro J, Fryling C, DeLarco JE. Transforming growth factors produced by certain human tumour cells; polypeptides that interact with epidermal growth factor receptor. Proc Natl Acad Sci 1980; 77(6): 5258–62.

    Article  PubMed  CAS  Google Scholar 

  15. Tímár J, Ladányi A, Lapis K et al. Differential expression of proteoglycans on the surface of human melanoma cells characterised by altered experimental metastatic potential. Am J Pathol 1992(2); 141: 467–74.

    PubMed  Google Scholar 

  16. Tímár J, Jeney A, Kovalszky I et al. Role of proteoglycans in tumour progression. Pathol Oncol Res 1995; 1(2): 85–93.

    Article  PubMed  Google Scholar 

  17. Tímár J, Kovalszky I. Differential expression of proteoglycans on the surface of malignant cells and in the tumour stroma. In Ádány R (ed): Tumour Matrix Biology. Boca Raton, Florida: CRC Press 1995; 23–53.

    Google Scholar 

  18. Tímár J, Rásó E, Fazakas Zs et al. Multiple use of a signal transduction pathway in tumour cell invasion. Anticancer Res. 1996; 16(6A): 3299–306.

    PubMed  Google Scholar 

  19. Hovey RM, Chu L, Balázs M et al. Genetic alterations in primary bladder cancer and in their metastases. Cancer Res 1998; 58(16): 3555–60.

    PubMed  CAS  Google Scholar 

  20. Balázs M, Ádám Zs Bégány Á et al. Involvement of chromosome losses in the progression and metastasis formation of a human malignant Melanoma Cancer Genet Cytogenet 1999; 109(2): 114–18.

    Article  Google Scholar 

  21. Balázs M, Carrol P, Kerschmann R et al. Frequent homozygous deletion of Cyclin-dependent kinase inhibitor 2 (MTS1) in superficial bladder cancer detected by fluorescence in situ hybridisation Genes Chromosomes Cancer 1997; 19(2): 84–9.

    Article  PubMed  Google Scholar 

  22. Dhingra K, Sneige N, Pandita TK et al. Quantitative analysis of chromosome in situ hybridization signal in paraffin-embedded tissue sections. Cytometry 1994; 16(2): 100–12.

    Article  PubMed  CAS  Google Scholar 

  23. Thompson FH, Emerson J, Olson S et al. Cytogenetics of 158 patients with regional or disseminated melanoma. Subset analysis of neardiploid and simple karyotypes. Cancer Genet Cytogenet 1995; 83(2): 93–104.

    Article  PubMed  CAS  Google Scholar 

  24. Tanner mm, Karhu RA, Nupponen NN et al. Genetic aberrations in hypodiploid breast cancer: frequent loss of chromosome 4 and amplification of cyclin D1 oncogene. Am J Pathol 1998; 153(1): 191–9.

    PubMed  CAS  Google Scholar 

  25. Bjorkqvist AM, Tammilehto L, Anttila S et al. Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. 1. Br J Cancer 1997; 75(4): 523–7.

    PubMed  CAS  Google Scholar 

  26. Bigner SH, Matthews MR, Rasheed BK et al. Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 1999; 155(2): 375–86.

    PubMed  CAS  Google Scholar 

  27. Shivapurkar N, Sood S, Witsuba II et al. Multiple regions of chromosome 4 demonstrating allelic losses in breast carcinomas. Cancer Res 1999; 59(15): 3576–80.

    PubMed  CAS  Google Scholar 

  28. Kamb A, Gruis NA, Weaver Feldhaus J et al. A cell cycle regulator potentially involved in genesis of many tumour types. Science 1994; 264(5157): 436–40.

    PubMed  CAS  Google Scholar 

  29. Morita R, Fujimoto A, Hatta N et al. Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression. J Invest Dermatol 1998; 111(6): 919–24.

    Article  PubMed  CAS  Google Scholar 

  30. Ohta M, Berd D, Shimizu M et al. Deletion mapping of chromosome region 9p21-p22 surrounding the CDKN2 locus in melanoma. Int J Cancer 1996; 65(6): 762–7.

    Article  PubMed  CAS  Google Scholar 

  31. Rubben A, Babilas P, Baron JM et al. Analysis of tumour cell evolution in a melanoma: Evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability. J Invest Dermatol 2000; 114(1): 14–20.

    Article  PubMed  CAS  Google Scholar 

  32. Robertson GP, Herbst RA, Nagane M et al. The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci. Cancer Res 1999; 59(15): 3596–601.

    PubMed  CAS  Google Scholar 

  33. Guldberg P, Thor-Straten P, Birck A et al. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997; 57(17): 3660–3.

    PubMed  CAS  Google Scholar 

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Ádám, Z., Ádány, R., Ladányi, A. et al. Liver metastatic ability of human melanoma cell line is associated with losses of chromosomes 4, 9p21-pter and 10p. Clin Exp Metastasis 18, 295–302 (2000). https://doi.org/10.1023/A:1011043412634

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  • DOI: https://doi.org/10.1023/A:1011043412634

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