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Improving the Subcutaneous Mouse Tumor Model by Effective Manipulation of Magnetic Nanoparticles-Treated Implanted Cancer Cells

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Abstract

Murine tumor models have played a fundamental role in the development of novel therapeutic interventions and are currently widely used in translational research. Specifically, strategies that aim at reducing inter-animal variability of tumor size in transplantable mouse tumor models are of particular importance. In our approach, we used magnetic nanoparticles to label and manipulate colon cancer cells for the improvement of the standard syngeneic subcutaneous mouse tumor model. Following subcutaneous injection on the scruff of the neck, magnetically-tagged implanted cancer cells were manipulated by applying an external magnetic field towards localized tumor formation. Our data provide evidence that this approach can facilitate the formation of localized tumors of similar shape, reducing thereby the tumor size’s variability. For validating the proof-of-principle, a low-dose of 5-FU was administered in small animal groups as a representative anticancer therapy. Under these experimental conditions, the 5-FU-induced tumor growth inhibition was statistically significant only after the implementation of the proposed method. The presented approach is a promising strategy for studying accurately therapeutic interventions in subcutaneous experimental solid tumor models allowing for the detection of statistically significant differences between smaller experimental groups.

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Abbreviations

5-FU:

Fluorouracil

DMEM:

Dulbecco’s modified Eagle medium

DNA:

Deoxyribonucleic acid

ICP-OES:

Inductively coupled plasma optical emission spectrometry

PBS:

Phosphate-buffered saline

SRB:

Sulforhodamine B

SSC:

Side scatter

XTT:

2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide

MNPs:

Magnetic nanoparticles

flMNPs:

Fluorescently-labeled magnetic nanoparticles

CI:

Confidence interval

SD:

Standard deviation

IQR:

Interquartile range

References

  1. Alon, N., T. Havdala, H. Skaat, K. Baranes, M. Marcus, I. Levy, S. Margel, A. Sharoni, and O. Shefi. Magnetic micro-device for manipulating PC12 cell migration and organization. Lab Chip 15:2030–2036, 2015.

    Article  CAS  PubMed  Google Scholar 

  2. Bradshaw, M., T. D. Clemons, D. Ho, L. Gutiérrez, F. J. Lázaro, M. J. House, T. G. St. Pierre, M. W. Fear, F. M. Wood, and K. S. Iyer. Manipulating directional cell motility using intracellular superparamagnetic nanoparticles. Nanoscale 7:4884–4889, 2015.

    Article  CAS  PubMed  Google Scholar 

  3. Castle, J. C., M. Loewer, S. Boegel, J. de Graaf, C. Bender, A. D. Tadmor, V. Boisguerin, T. Bukur, P. Sorn, C. Paret, M. Diken, S. Kreiter, Ö. Türeci, and U. Sahin. Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. BMC Genomics 15:190, 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen, J., N. Huang, B. Ma, M. F. Maitz, J. Wang, J. Li, Q. Li, Y. Zhao, K. Xiong, and X. Liu. Guidance of stem cells to a target destination in vivo by magnetic nanoparticles in a magnetic field. ACS Appl. Mater. Interfaces 5:5976–5985, 2013.

    Article  CAS  PubMed  Google Scholar 

  5. Day, C. P., G. Merlino, and T. Van Dyke. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163:39–53, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Jong, M., and T. Maina. Of mice and humans: are they the same? Implications in cancer translational research. J. Nucl. Med. 51:501–504, 2010.

    Article  PubMed  Google Scholar 

  7. Dranoff, G. Experimental mouse tumour models: what can be learnt about human cancer immunology? Nat. Rev. Immunol. 12:61–66, 2012.

    Article  CAS  Google Scholar 

  8. Farkona, S., E. P. Diamandis, and I. M. Blasutig. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016. https://doi.org/10.1186/s12916-016-0623-5.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Friedrich, R. P., C. Janko, M. Poettler, P. Tripal, J. Zaloga, I. Cicha, S. Dürr, J. Nowak, S. Odenbach, I. Slabu, M. Liebl, L. Trahms, M. Stapf, I. Hilger, S. Lyer, and C. Alexiou. Flow cytometry for intracellular SPION quantification: specificity and sensitivity in comparison with spectroscopic methods. Int. J. Nanomed. 10:4185, 2015.

    Article  CAS  Google Scholar 

  10. Haddad, T. C., and D. Yee. Of mice and (wo)men: is this any way to test a new drug? J. Clin. Oncol. 26:830–832, 2008.

    Article  CAS  PubMed  Google Scholar 

  11. Hughes, C. S., L. M. Postovit, and G. A. Lajoie. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10:1886–1890, 2010.

    Article  CAS  PubMed  Google Scholar 

  12. Kasten, A., C. Grüttner, J.-P. Kühn, R. Bader, J. Pasold, and B. Frerich. Comparative in vitro study on magnetic iron oxide nanoparticles for MRI tracking of adipose tissue-derived progenitor cells. PLoS ONE 9:e108055, 2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim, J. A., C. Åberg, A. Salvati, and K. A. Dawson. Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. Nat. Nanotechnol. 7:62–68, 2011.

    Article  CAS  PubMed  Google Scholar 

  14. Kolosnjaj-Tabi, J., C. Wilhelm, O. Clément, and F. Gazeau. Cell labeling with magnetic nanoparticles: opportunity for magnetic cell imaging and cell manipulation. J. Nanobiotechnology 11:S7, 2013.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lechner, M. G., S. S. Karimi, K. Barry-holson, and T. E. Angell. NIH public access. J. Immunother. 36:477–489, 2014.

    Article  CAS  Google Scholar 

  16. Liu, J., X. Tian, M. Bao, J. Li, Y. Dou, B. Yuan, K. Yang, and Y. Ma. Manipulation of cellular orientation and migration by internalized magnetic particles. Mater. Chem. Front. Mater. Chem. Front 1:933–936, 2017.

    Article  CAS  Google Scholar 

  17. Longley, D. B., D. P. Harkin, and P. G. Johnston. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3:330–338, 2003.

    Article  CAS  PubMed  Google Scholar 

  18. Milotti, E., V. Vyshemirsky, M. Sega, and R. Chignola. Interplay between distribution of live cells and growth dynamics of solid tumours. Sci. Rep. 2:1–10, 2012.

    Article  CAS  Google Scholar 

  19. Qian, L., Y. Liu, S. Wang, W. Gong, X. Jia, L. Liu, F. Ye, J. Ding, Y. Xu, Y. Fu, and F. Tian. NKG2D ligand RAE1ε induces generation and enhances the inhibitor function of myeloid-derived suppressor cells in mice. J. Cell Mol. Med. 21:2046–2054, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rossi, L., E. Laas, P. Mallon, A. Vincent-Salomon, J. M. Guinebretiere, F. Lerebours, R. Rouzier, J. Y. Pierga, and F. Reyal. Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma. Br. J. Cancer 113:996–1002, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sagiv-Barfi, I., D. K. Czerwinski, S. Levy, I. S. Alam, A. T. Mayer, S. S. Gambhir, and R. Levy. Eradication of spontaneous malignancy by local immunotherapy. Sci. Transl. Med. 2018. https://doi.org/10.1126/scitranslmed.aan4488.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Schleich, N., P. Sibret, P. Danhier, B. Ucakar, S. Laurent, R. N. Muller, C. Jérôme, B. Gallez, V. Préat, and F. Danhier. Dual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging. Int. J. Pharm. 447:94–101, 2013.

    Article  CAS  PubMed  Google Scholar 

  23. Seeliger, H., M. Guba, G. E. Koehl, A. Doenecke, M. Steinbauer, C. J. Bruns, C. Wagner, E. Frank, K. W. Jauch, and E. K. Geissler. Blockage of 2-deoxy-D-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clin. Cancer Res. 10:1843–1852, 2004.

    Article  CAS  PubMed  Google Scholar 

  24. Silva, L. H. A., F. F. Cruz, M. M. Morales, D. J. Weiss, and P. R. M. Rocco. Magnetic targeting as a strategy to enhance therapeutic effects of mesenchymal stromal cells. Stem Cell Res. Ther. 8:58, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Spyridopoulou, K., A. Makridis, N. Maniotis, N. Karypidou, E. Myrovali, T. Samaras, M. Angelakeris, K. Chlichlia, and O. Kalogirou. Effect of low frequency magnetic fields on the growth of MNPs-treated HT29 colon cancer cells. Nanotechnology 29:175101, 2018.

    Article  CAS  PubMed  Google Scholar 

  26. Spyridopoulou, K., A. Tiptiri-Kourpeti, E. Lampri, E. Fitsiou, S. Vasileiadis, M. Vamvakias, H. Bardouki, A. Goussia, V. Malamou-Mitsi, M. I. Panayiotidis, A. Galanis, A. Pappa, and K. Chlichlia. Dietary mastic oil extracted from Pistacia lentiscus var. chia suppresses tumor growth in experimental colon cancer models. Sci. Rep. 7:3782, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Suggitt, M., and M. C. Bibby. 50 years of preclinical anticancer drug screening : empirical to target-driven approaches. Clin. Cancer Res. 11:971–981, 2005.

    CAS  PubMed  Google Scholar 

  28. Sullivan, K. M., A. Dean, and M. S. Minn. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 124:471–474, 2009.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Summers, H. Bionanoscience: nanoparticles in the life of a cell. Nat. Nanotechnol. 7:9–10, 2011.

    Article  CAS  PubMed  Google Scholar 

  30. Suzuki, H., T. Toyooka, and Y. Ibuki. Simple and easy method to evaluate uptake potential of nanoparticles in mammalian cells using a flow cytometric light scatter analysis. Environ. Sci. Technol. 41:3018–3024, 2007.

    Article  CAS  PubMed  Google Scholar 

  31. Talmadge, J. E., R. K. Singh, I. J. Fidler, and A. Raz. Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am. J. Pathol. 170:793–804, 2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Theumer, A., C. Gräfe, F. Bähring, C. Bergemann, A. Hochhaus, and J. H. Clement. Superparamagnetic iron oxide nanoparticles exert different cytotoxic effects on cells grown in monolayer cell culture versus as multicellular spheroids. J. Magn. Magn. Mater. 380:27–33, 2015.

    Article  CAS  Google Scholar 

  33. Wagner, M., V. Roh, M. Strehlen, A. Laemmle, D. Stroka, B. Egger, M. Trochsler, K. K. Hunt, D. Candinas, and S. A. Vorburger. Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1. J. Gastrointest. Surg. 13:1781–1790, 2009.

    Article  PubMed  Google Scholar 

  34. Weissleder, R., M. Nahrendorf, and M. J. Pittet. Imaging macrophages with nanoparticles. Nat. Mater. 13:125–138, 2014.

    Article  CAS  PubMed  Google Scholar 

  35. Whiteside, T. The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912, 2013.

    Article  CAS  Google Scholar 

  36. Wilhelm, C., F. Gazeau, J. Roger, J. N. Pons, and J. C. Bacri. Interaction of anionic superparamagnetic nanoparticles with cells: kinetic analyses of membrane adsorption and subsequent internalization. Langmuir 18:8148–8155, 2002.

    Article  CAS  Google Scholar 

  37. Yanai, A., U. O. Häfeli, A. L. Metcalfe, P. Soema, L. Addo, C. Y. Gregory-Evans, K. Po, X. Shan, O. L. Moritz, and K. Gregory-Evans. Focused magnetic stem cell targeting to the retina using superparamagnetic iron oxide nanoparticles. Cell Transplant. 21:1137–1148, 2012.

    Article  PubMed  Google Scholar 

  38. Zitvogel, L., J. M. Pitt, R. Daillère, M. J. Smyth, and G. Kroemer. Mouse models in oncoimmunology. Nat. Rev. Cancer 16:759–773, 2016.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Part of the work was implemented by utilizing the facilities of the ‘OPENSCREEN-GR’ supported by the National Roadmap for Research Infrastructures under the National Strategy for Research, Technological Development, and Innovation (2014–2020) by the General Secretariat for Research and Technology (GSRT), Ministry of Education and Religious Affairs, Hellenic Republic.

Conflict of interest

Authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100, Alexandroupolis, Greece

    Katerina Spyridopoulou, Georgios Aindelis, Evangeli Lampri, Maria Giorgalli, Aglaia Pappa & Katerina Chlichlia

  2. Department of Hematology, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece

    Eleftheria Lamprianidou & Ioannis Kotsianidis

  3. Laboratory of Anatomy, Histology and Embryology, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Anastasia Tsingotjidou

  4. Department of Physics, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Orestis Kalogirou

Authors
  1. Katerina Spyridopoulou
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  2. Georgios Aindelis
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  10. Katerina Chlichlia
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Correspondence to Katerina Chlichlia.

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Associate Editor Michael Gower oversaw the review of this article.

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Spyridopoulou, K., Aindelis, G., Lampri, E. et al. Improving the Subcutaneous Mouse Tumor Model by Effective Manipulation of Magnetic Nanoparticles-Treated Implanted Cancer Cells. Ann Biomed Eng 46, 1975–1987 (2018). https://doi.org/10.1007/s10439-018-2107-6

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