Advertisement

Cancer and Metastasis Reviews

, Volume 37, Issue 4, pp 633–642 | Cite as

Mitochondrial polymorphisms contribute to aging phenotypes in MNX mouse models

  • Carolyn J. Vivian
  • Travis M. Hagedorn
  • Roy A. Jensen
  • Amanda E. Brinker
  • Danny R. WelchEmail author
Article

Abstract

Many inbred strains of mice develop spontaneous tumors as they age. Recent awareness of the impacts of mitochondrial DNA (mtDNA) on cancer and aging has inspired developing a mitochondrial-nuclear exchange (MNX) mouse model in which nuclear DNA is paired with mitochondrial genomes from other strains of mouse. MNX mice exhibit mtDNA influences on tumorigenicity and metastasis upon mating with transgenic mice. However, we also wanted to investigate spontaneous tumor phenotypes as MNX mice age. Utilizing FVB/NJ, C57BL/6J, C3H/HeN, and BALB/cJ wild-type inbred strains, previously documented phenotypes were observed as expected in MNX mice with the same nuclear background. However, aging nuclear matched MNX mice exhibited decreased occurrence of mammary tumors in C3H/HeN mice containing C57BL/6J mitochondria compared to wild-type C3H/HeN mice. Although aging tumor phenotypes appear to be driven by nuclear genes, evidence suggesting that some differences are modified by the mitochondrial genome is presented.

Keywords

Cancer Mitochondria Mouse Aging 

Notes

Acknowledgements

We want to thank members of the Welch lab for their helpful comments and suggestions. We also thank the Transgenic and Gene-Targeting Institutional Facility at University of Kansas Cancer Center.

Funding information

These studies were funded primarily by Susan G. Komen for the Cure (SAC110037) and the National Foundation for Cancer Research with additional funding from the National Cancer Institute P30-CA168524 (RAJ; DRW).

Compliance with ethical standards

Conflict of interest

D.R. Welch is a co-holder of a patent on the MNX mice. The other authors declare no conflicts of interest.

Supplementary material

10555_2018_9773_Fig5_ESM.png (1.6 mb)
Figure S1

HC MNX mice have a lower incidence of HCC. A-F. Hematoxylin and eosin stained sections of normal liver. A-D. livers obtained from female mice. E-F. livers obtained from male mice. Unlike HH mice which develop hepatomas in 85% of male and female mice. (PNG 1630 kb)

10555_2018_9773_MOESM1_ESM.tif (3.8 mb)
High resolution image (TIF 3884 kb)

References

  1. 1.
    Dragani, T. A. (2003). 10 years of mouse cancer modifier loci: human relevance. Cancer Research, 63(12), 3011–3018.Google Scholar
  2. 2.
    Altman, P. L., & Katz, D. D. (1979). Inbred and genetically defined strains of laboratory animals. Part 2. Hamster, guinea pig, rabbit and chicken (Vol. 1). Bethesda: Federation of American Societies for Experimental Biology.Google Scholar
  3. 3.
    Altman, P. L., & Katz, D. D. (1979). Inbred and genetically defined strains of laboratory animals. Part 1. Mouse and rat (Vol. 1). Bethesda: Federation of American Societies for Experimental Biology.Google Scholar
  4. 4.
    Stern, M. C., & Conti, C. J. (1996). Genetic susceptibility to tumor progression in mouse skin carcinogenesis. Progress in Clinical and Biological Research, 395, 47–55.Google Scholar
  5. 5.
    Pettan-Brewer, C., & Treuting, P. M. (2011). Practical pathology of aging mice. Pathobiology of Aging and Age Related Diseases, 1.  https://doi.org/10.3402/pba.v1i0.7202.
  6. 6.
    Heston, W. E., & Vlahakis, G. (1971). Mammary tumors, plaques, and hyperplastic alveolar nodules in various combinations of mouse inbred strains and the different lines of the mammary tumor virus. International Journal of Cancer, 7(1), 141–148.CrossRefGoogle Scholar
  7. 7.
    Guy, C. T., Cardiff, R. D., & Muller, W. J. (1992). Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Molecular and Cellular Biology, 12(3), 954–961.CrossRefGoogle Scholar
  8. 8.
    Cardiff, R. D., & Muller, W. J. (1993). Transgenic mouse models of mammary tumorigenesis. Cancer Surveys, 16, 97–113.Google Scholar
  9. 9.
    Muller, W. J., Ho, J., & Siegel, P. M. (1998). Oncogenic activation of Neu/ErbB-2 in a transgenic mouse model for breast cancer. Biochemical Society Symposia, 63, 149–157.Google Scholar
  10. 10.
    Walrath, J. C., Hawes, J. J., Van Dyke, T., & Reilly, K. M. (2010). Genetically engineered mouse models in cancer research. Advances in Cancer Research, 106, 113–164.CrossRefGoogle Scholar
  11. 11.
    Walton, J. B., Farquharson, M., Mason, S., Port, J., Kruspig, B., Dowson, S., Stevenson, D., Murphy, D., Matzuk, M., Kim, J., Coffelt, S., Blyth, K., & McNeish, I. A. (2017). CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Scientific Reports, 7(1), 16827.CrossRefGoogle Scholar
  12. 12.
    Lampreht Tratar, U., Horvat, S., & Cemazar, M. (2018). Transgenic mouse models in cancer research. Frontiers in Oncology, 8, 268.CrossRefGoogle Scholar
  13. 13.
    Taketo, M., Schroeder, A. C., Mobraaten, L. E., Gunning, K. B., Hanten, G., Fox, R. R., Roderick, T. H., Stewart, C. L., Lilly, F., & Hansen, C. T. (1991). FVB/N: an inbred mouse strain preferable for transgenic analyses. Proceedings of the National Academy of Sciences of the United States of America, 88(6), 2065–2069.CrossRefGoogle Scholar
  14. 14.
    Mahler, J. F., Stokes, W., Mann, P. C., Takaoka, M., & Maronpot, R. R. (1996). Spontaneous lesions in aging FVB/N mice. Toxicologic Pathology, 24(6), 710–716.CrossRefGoogle Scholar
  15. 15.
    Fetterman, J. L., Zelickson, B. R., Johnson, L. W., Moellering, D. R., Westbrook, D. G., Pompilius, M., Sammy, M. J., Johnson, M., Dunham-Snary, K. J., Cao, X., Bradley, W. E., Zhang, J., Wei, C. C., Chacko, B., Schurr, T. G., Kesterson, R. A., Dell’italia, L. J., Darley-Usmar, V. M., Welch, D. R., & Ballinger, S. W. (2013). Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochemical Journal, 455(2), 157–167.CrossRefGoogle Scholar
  16. 16.
    Zheng, Q. Y., Johnson, K. R., & Erway, L. C. (1999). Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hearing Research, 130(1–2), 94–107.CrossRefGoogle Scholar
  17. 17.
    Bult, C. J., Krupke, D. M., Begley, D. A., Richardson, J. E., Neuhauser, S. B., Sundberg, J. P., & Eppig, J. T. (2015). Mouse tumor biology (MTB): a database of mouse models for human cancer. Nucleic Acids Research, 43(Database issue), D818–D824.CrossRefGoogle Scholar
  18. 18.
    Smith, C. L., Blake, J. A., Kadin, J. A., Richardson, J. E., Bult, C. J., & Mouse Genome Database, G. (2018). Mouse genome database (MGD)-2018: knowledgebase for the laboratory mouse. Nucleic Acids Research, 46(D1), D836–D842.CrossRefGoogle Scholar
  19. 19.
    Bagg, H. J. (1936). Functional activity of the mammary gland in relation to extra-chromosomal influence in the incidence of mammary tumors. Science, 83(2155), 374–375.CrossRefGoogle Scholar
  20. 20.
    Adair, F. E., & Bagg, H. J. (1931). Experimental and clinical studies on the treatment of cancer by dichlorethylsulphide mustard gas. Annals of Surgery, 93(1), 190–199.CrossRefGoogle Scholar
  21. 21.
    Ebbesen, P. (1971). Reticulosarcoma and amyloid development in BALB/c mice inoculated with syngeneic cells from young and old donors. Journal of the National Cancer Institute, 47(6), 1241–1245.Google Scholar
  22. 22.
    Myers, D. D., Meier, H., & Huebner, R. J. (1970). Prevalence of murine C-type RNA virus group specific antigen in inbred strains of mice. Life Sciences. Part 2: Biochemistry, General and Molecular Biology, 9(18), 1071–1080.CrossRefGoogle Scholar
  23. 23.
    Hoag, W. G. (1963). Spontaneous cancer in mice. Annals of the New York Academy of Sciences, 108, 805–831.CrossRefGoogle Scholar
  24. 24.
    Cunliffe-Beamer, T. L., & Feldman, D. B. (1976). Vaginal septa in mice: incidence, inheritance, and effect on reproductive, performance. Laboratory Animal Science, 26(6 Pt 1), 895–898.Google Scholar
  25. 25.
    Crow, J. F. (2002). C. C. Little, cancer and inbred mice. Genetics, 161(4), 1357–1361.Google Scholar
  26. 26.
    Braunschweiger, P. G., Poulakos, L., & Schiffer, L. M. (1977). Cell kinetics in vivo and in vitro for C3H/He spontaneous mammary tumors. Journal of the National Cancer Institute, 59(4), 1197–1204.CrossRefGoogle Scholar
  27. 27.
    Lacour, F., Delage, G., & Chianale, C. (1975). Reduced incidence of spontaneous mammary tumors in C3H/He mice after treatment with polyadenylate-polyuridylate. Science, 187(4173), 256–257.CrossRefGoogle Scholar
  28. 28.
    Manenti, G., Binelli, G., Gariboldi, M., Canzian, F., De Gregorio, L., Falvella, F. S., et al. (1994). Multiple loci affect genetic predisposition to hepatocarcinogenesis in mice. Genomics, 23(1), 118–124.CrossRefGoogle Scholar
  29. 29.
    Sidman, R. L., & Green, M. C. (1965). Retinal degeneration in the mouse: location of the Rd locus in linkage group Xvii. Journal of Heredity, 56, 23–29.CrossRefGoogle Scholar
  30. 30.
    Abiola, O., Angel, J. M., Avner, P., Bachmanov, A. A., Belknap, J. K., Bennett, B., Blankenhorn, E. P., Blizard, D. A., Bolivar, V., Brockmann, G. A., Buck, K. J., Bureau, J. F., Casley, W. L., Chesler, E. J., Cheverud, J. M., Churchill, G. A., Cook, M., Crabbe, J. C., Crusio, W. E., Darvasi, A., de Haan, G., Dermant, P., Doerge, R. W., Elliot, R. W., Farber, C. R., Flaherty, L., Flint, J., Gershenfeld, H., Gibson, J. P., Gu, J., Gu, W., Himmelbauer, H., Hitzemann, R., Hsu, H. C., Hunter, K., Iraqi, F. F., Jansen, R. C., Johnson, T. E., Jones, B. C., Kempermann, G., Lammert, F., Lu, L., Manly, K. F., Matthews, D. B., Medrano, J. F., Mehrabian, M., Mittlemann, G., Mock, B. A., Mogil, J. S., Montagutelli, X., Morahan, G., Mountz, J. D., Nagase, H., Nowakowski, R. S., O'Hara, B. F., Osadchuk, A. V., Paigen, B., Palmer, A. A., Peirce, J. L., Pomp, D., Rosemann, M., Rosen, G. D., Schalkwyk, L. C., Seltzer, Z., Settle, S., Shimomura, K., Shou, S., Sikela, J. M., Siracusa, L. D., Spearow, J. L., Teuscher, C., Threadgill, D. W., Toth, L. A., Toye, A. A., Vadasz, C., van Zant, G., Wakeland, E., Williams, R. W., Zhang, H. G., Zou, F., & Complex Trait Consortium. (2003). The nature and identification of quantitative trait loci: a community’s view. Nature Reviews Genetics, 4(11), 911–916.CrossRefGoogle Scholar
  31. 31.
    Little, C. C., & Tyzzer, E. E. (1916). Further experimental studies on the inheritance of susceptibility to a transplantable tumor, carcinoma (J. W. A.) of the Japanese waltzing mouse. Journal of Medical Research, 33(3), 393–453.Google Scholar
  32. 32.
    Albert, F. W., & Kruglyak, L. (2015). The role of regulatory variation in complex traits and disease. Nature Reviews Genetics, 16(4), 197–212.CrossRefGoogle Scholar
  33. 33.
    Mackay, T. F. C. (2014). Epistasis and quantitative traits: using model organisms to study gene-gene interactions. Nature Reviews Genetics, 15(1), 22–33.CrossRefGoogle Scholar
  34. 34.
    Drinkwater, N. R., & Gould, M. N. (2012). The long path from QTL to gene. PLoS Genetics, 8(9), e1002975.CrossRefGoogle Scholar
  35. 35.
    Plomin, R., Haworth, C. M., & Davis, O. S. (2009). Common disorders are quantitative traits. Nature Reviews Genetics, 10(12), 872–878.CrossRefGoogle Scholar
  36. 36.
    Beadnell, T. C., Scheid, A. D., Vivian, C. J., & Welch, D. R. (2018). Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer. Cancer and Metastasis Reviews.  https://doi.org/10.1007/s10555-018-9772-7.
  37. 37.
    Brinker, A. E., Vivian, C. J., Koestler, D. C., Tsue, T. T., Jensen, R. A., & Welch, D. R. (2017). Mitochondrial haplotype alters mammary cancer tumorigenicity and metastasis in an oncogenic driver-dependent manner. Cancer Research, 77(24), 6941–6949.CrossRefGoogle Scholar
  38. 38.
    Vivian, C. J., Brinker, A. E., Graw, S., Koestler, D. C., Legendre, C., Gooden, G. C., Salhia, B., & Welch, D. R. (2017). Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression. Cancer Research, 77(22), 6202–6214.CrossRefGoogle Scholar
  39. 39.
    Feeley, K. P., Bray, A. W., Westbrook, D. G., Johnson, L. W., Kesterson, R. A., Ballinger, S. W., & Welch, D. R. (2015). Mitochondrial genetics regulate breast cancer tumorigenicity and metastatic potential. Cancer Research, 75(20), 4429–4436.CrossRefGoogle Scholar
  40. 40.
    Gorman, G. S., Chinnery, P. F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D. R., Zeviani, M., & Turnbull, D. M. (2016). Mitochondrial diseases. Nature Reviews Disease Primers, 2, 16080.CrossRefGoogle Scholar
  41. 41.
    Wallace, D. C., & Chalkia, D. (2013). Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harbor Perspectives in Biology, 5(11), a021220.CrossRefGoogle Scholar
  42. 42.
    Wallace, D. C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annual Review of Genetics, 39, 359–407.CrossRefGoogle Scholar
  43. 43.
    Wallace, D. C., & Fan, W. (2010). Energetics, epigenetics, mitochondrial genetics. Mitochondrion, 10(1), 12–31.CrossRefGoogle Scholar
  44. 44.
    Picard, M., Zhang, J., Hancock, S., Derbeneva, O., Golhar, R., Golik, P., O'Hearn, S., Levy, S., Potluri, P., Lvova, M., Davila, A., Lin, C. S., Perin, J. C., Rappaport, E. F., Hakonarson, H., Trounce, I. A., Procaccio, V., & Wallace, D. C. (2014). Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proceedings of the National Academy of Sciences of the United States of America, 111(38), E4033–E4042.CrossRefGoogle Scholar
  45. 45.
    Wallace, D. C. (2016). Genetics: Mitochondrial DNA in evolution and disease. Nature, 535(7613), 498–500.CrossRefGoogle Scholar
  46. 46.
    Mishmar, D., Ruiz-Pesini, E., Golik, P., Macaulay, V., Clark, A. G., Hosseini, S., Brandon, M., Easley, K., Chen, E., Brown, M. D., Sukernik, R. I., Olckers, A., & Wallace, D. C. (2003). Natural selection shaped regional mtDNA variation in humans. Proceedings of the National Academy of Sciences of the United States of America, 100(1), 171–176.CrossRefGoogle Scholar
  47. 47.
    Takibuchi, G., Imanishi, H., Morimoto, M., Ishikawa, K., Nakada, K., Toyama-Sorimachi, N., Kikkawa, Y., Takenaga, K., & Hayashi, J. I. (2013). Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype. Mitochondrion, 13(6), 881–887.CrossRefGoogle Scholar
  48. 48.
    Goios, A., Gusmao, L., Rocha, A. M., Fonseca, A., Pereira, L., Bogue, M., et al. (2008). Identification of mouse inbred strains through mitochondrial DNA single-nucleotide extension. Electrophoresis, 29(23), 4795–4802.CrossRefGoogle Scholar
  49. 49.
    Sflomos, G., Dormoy, V., Metsalu, T., Jeitziner, R., Battista, L., Scabia, V., Raffoul, W., Delaloye, J. F., Treboux, A., Fiche, M., Vilo, J., Ayyanan, A., & Brisken, C. (2016). A preclinical model for ERalpha-positive breast cancer points to the epithelial microenvironment as determinant of luminal phenotype and hormone response. Cancer Cell, 29(3), 407–422.CrossRefGoogle Scholar
  50. 50.
    Goios, A., Pereira, L., Bogue, M., Macaulay, V., & Amorim, A. (2007). mtDNA phylogeny and evolution of laboratory mouse strains. Genome Research, 17(3), 293–298.CrossRefGoogle Scholar
  51. 51.
    Kiebish, M. A., & Seyfried, T. N. (2005). Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. BMC Cancer, 5, 102.CrossRefGoogle Scholar
  52. 52.
    Roubertoux, P. L., Sluyter, F., Carlier, M., Marcet, B., Maarouf-Veray, F., Cherif, C., et al. (2003). Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nature Genetics, 35(1), 65–69.CrossRefGoogle Scholar
  53. 53.
    Bussard, K. M., & Siracusa, L. D. (2017). Understanding mitochondrial polymorphisms in cancer. Cancer Research, 77(22), 6051–6059.CrossRefGoogle Scholar
  54. 54.
    Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., Törnell, J., Jacobs, H. T., & Larsson, N. G. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429(6990), 417–423.CrossRefGoogle Scholar
  55. 55.
    Chatterjee, A., Mambo, E., & Sidransky, D. (2006). Mitochondrial DNA mutations in human cancer. Oncogene, 25(34), 4663–4674.CrossRefGoogle Scholar
  56. 56.
    Park, C. B., & Larsson, N. G. (2011). Mitochondrial DNA mutations in disease and aging. Journal of Cell Biology, 193(5), 809–818.CrossRefGoogle Scholar
  57. 57.
    Asano, T., Yao, Y., Zhu, J., Li, D., Abbruzzese, J. L., & Reddy, S. A. (2004). The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene, 23(53), 8571–8580.CrossRefGoogle Scholar
  58. 58.
    Stewart, J. B., Freyer, C., Elson, J. L., & Larsson, N. G. (2008). Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nature Reviews Genetics, 9(9), 657–662.CrossRefGoogle Scholar
  59. 59.
    Kesterson, R. A., Johnson, L. W., Lambert, L. J., Vivian, J. L., Welch, D. R., & Ballinger, S. W. (2016). Generation of mitochondrial-nuclear eXchange mice via pronuclear transfer. BioProtocols, 6(20).  https://doi.org/10.21769/BioProtoc.1976.
  60. 60.
    McCredie, J. A., Inch, W. R., & Sutherland, R. M. (1971). Differences in growth and morphology between the spontaneous C3H mammary carcinoma in the mouse and its syngeneic transplants. Cancer, 27(3), 635–642.CrossRefGoogle Scholar
  61. 61.
    Pontual, E. V., Carvalho, B. E., Bezerra, R. S., Coelho, L. C., Napoleao, T. H., & Paiva, P. M. (2012). Caseinolytic and milk-clotting activities from Moringa oleifera flowers. Food Chemistry, 135(3), 1848–1854.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Carolyn J. Vivian
    • 1
  • Travis M. Hagedorn
    • 2
  • Roy A. Jensen
    • 1
    • 3
    • 4
  • Amanda E. Brinker
    • 1
    • 4
  • Danny R. Welch
    • 1
    • 4
    Email author
  1. 1.Department of Cancer BiologyUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Laboratory Animal ResourcesUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityUSA
  4. 4.The University of Kansas Cancer CenterKansas CityUSA

Personalised recommendations