Skip to main content

Advertisement

Log in

The Impact of Anti-tumor Agents on ER-Positive MCF-7 and HER2-Positive SKBR-3 Breast Cancer Cells Biomechanics

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Studying human cancer from a biomechanical perspective may contribute to pathogenesis understanding which leads to the malignancy. In this study, biomechanics of suspended and adhered breast cancer cells were investigated via the micropipette aspiration method with special emphasis on comparing the cell stiffness and viscoelastic parameters of estrogen receptor positive, ER+, MCF-7 and human epidermal growth factor receptor 2 positive, HER2 +, SKBR-3 cancer cell lines prior to and post treatment with tamoxifen and trastuzumab, respectively. Alterations of mechanical parameters included significant increase in cell stiffness, especially after treatment with trastuzumab and changes in viscoelastic parameters, in both cancer cell lines post treatment. According to immunofluorescence analysis, the raised cell stiffness was corresponded to remodeling of F-actin, which peripherally located in tamoxifen treated and perinuclear accumulated in trastuzumab treated cancer cell cytoskeleton, implying a reduced potential for cell deformation and motility. Additionally, these results were in line with the study of single and collective cell migration through Boyden chamber and wound healing assays respectively, where the potential for migration was significantly decreased after treatment. Consequently, these findings lead to an increased interest in biomechanics of cancer progression after treatment with anti-tumor agents, importantly in understanding the effect of the alterations of mechanical properties upon the possibility for change in metastatic potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Acconcia, F., C. J. Barnes, and R. Kumar. Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells. Endocrinology 147:1203–1212, 2006.

    Article  CAS  PubMed  Google Scholar 

  2. Appert-Collin, A., P. Hubert, G. Cremel, and A. Bennasroune. Role of ErbB receptors in cancer cell migration and invasion. Front. Pharmacol. 6:283, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bausch, A. R., and K. Kroy. A bottom-up approach to cell mechanics. Nat. Phys. 2:231, 2006.

    Article  CAS  Google Scholar 

  4. Bonello, T., J. Coombes, G. Schevzov, P. Gunning, and J. Stehn. Therapeutic targeting of the actin cytoskeleton in cancer. In: Cytoskeleton and Human Disease, edited by M. Kavallaris. Totowa, NJ: Humana Press, 2012, pp. 181–200.

    Chapter  Google Scholar 

  5. Borm, B., R. P. Requardt, V. Herzog, and G. Kirfel. Membrane ruffles in cell migration: indicators of inefficient lamellipodia adhesion and compartments of actin filament reorganization. Exp. Cell Res. 302:83–95, 2005.

    Article  CAS  PubMed  Google Scholar 

  6. Clarke, R., N. Brünner, B. S. Katzenellenbogen, E. W. Thompson, M. J. Norman, C. Koppi, S. Paik, M. E. Lippman, and R. B. Dickson. Progression of human breast cancer cells from hormone-dependent to hormone-independent growth both in vitro and in vivo. Proc. Natl. Acad. Sci. USA 86:3649–3653, 1989.

    Article  CAS  PubMed  Google Scholar 

  7. Coughlin, M. F., D. R. Bielenberg, G. Lenormand, M. Marinkovic, C. G. Waghorne, B. R. Zetter, and J. J. Fredberg. Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential. Clin. Exp. Metas. 30:237–250, 2013.

    Article  CAS  Google Scholar 

  8. Dalvai, M., and K. Bystricky. Cell cycle and anti-estrogen effects synergize to regulate cell proliferation and ER target gene expression. PLoS ONE 5:e11011, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Delord, J. P., S. Quideau, P. Rochaix, O. Caselles, B. Couderc, I. Hennebelle, F. Courbon, P. Canal, and B. C. Allal. Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model. Br. J. Cancer 103:61–72, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Evans, E., and A. Yeung. Apparent viscosity and cortical tension of blood granulocytes determined by micropipet aspiration. Biophys. J. 56:151–160, 1989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Even-Ram, S., A. D. Doyle, M. A. Conti, K. Matsumoto, R. S. Adelstein, and K. M. Yamada. Myosin IIA regulates cell motility and actomyosin–microtubule crosstalk. Nat. Cell Biol. 9:299, 2007.

    Article  CAS  PubMed  Google Scholar 

  12. Feldner, J. C., and B. H. Brandt. Cancer cell motility–on the road from c-erbB-2 receptor steered signaling to actin reorganization. Exp. Cell Res. 272:93–108, 2002.

    Article  CAS  PubMed  Google Scholar 

  13. Fletcher, D. A., and R. D. Mullins. Cell mechanics and the cytoskeleton. Nature 463:485–492, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Friedl, P., and K. Wolf. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3:362, 2003.

    Article  CAS  PubMed  Google Scholar 

  15. Gardel, M. L., J. H. Shin, F. C. MacKintosh, L. Mahadevan, P. Matsudaira, and D. A. Weitz. Elastic behavior of cross-linked and bundled actin networks. Science 304:1301–1305, 2004.

    Article  CAS  PubMed  Google Scholar 

  16. Giannopoulou, E., K. E. Siatis, D. Metsiou, I. Kritikou, D. J. Papachristou, M. Kalofonou, A. Koutras, G. Athanassiou, and H. P. Kalofonos. The inhibition of aromatase alters the mechanical and rheological properties of non-small-cell lung cancer cell lines affecting cell migration. Biochim. Biophys. Acta 328–337:2015, 1853.

    Google Scholar 

  17. Gorodeski, G. I. cGMP-dependent ADP depolymerization of actin mediates estrogen increase in cervical epithelial permeability. Am. J. Physiol. Cell Physiol. 279:C2028–C2036, 2000.

    Article  CAS  PubMed  Google Scholar 

  18. Guck, J., S. Schinkinger, B. Lincoln, F. Wottawah, S. Ebert, M. Romeyke, D. Lenz, H. M. Erickson, R. Ananthakrishnan, D. Mitchell, J. Kas, S. Ulvick, and C. Bilby. Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys. J. 88:3689–3698, 2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Head, D. A., A. J. Levine, and F. C. MacKintosh. Distinct regimes of elastic response and deformation modes of cross-linked cytoskeletal and semiflexible polymer networks. Phys. Rev. E 68:061907, 2003.

    Article  CAS  Google Scholar 

  20. Hochmuth, R. M. Micropipette aspiration of living cells. J. Biomech. 33:15–22, 2000.

    Article  CAS  PubMed  Google Scholar 

  21. Hudis, C. A. Trastuzumab–mechanism of action and use in clinical practice. N. Engl. J. Med. 357:39–51, 2007.

    Article  CAS  PubMed  Google Scholar 

  22. Lekka, M. Discrimination between normal and cancerous cells using AFM. Bionanoscience 6:65–80, 2016.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li, X., L. Zhou, and G. I. Gorodeski. Estrogen regulates epithelial cell deformability by modulation of cortical actomyosin through phosphorylation of nonmuscle myosin heavy-chain II-B filaments. Endocrinology 147:5236–5248, 2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lim, C. T., E. H. Zhou, and S. T. Quek. Mechanical models for living cells—a review. J. Biomech. 39:195–216, 2006.

    Article  CAS  PubMed  Google Scholar 

  25. Mittendorf E. A., C. E. Storrer, C. D. Shriver, S. Ponniah and G. E. Peoples. Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer. Ann. Surg. Oncol. 13:1085–1098, 2006.

    Article  Google Scholar 

  26. Mohammadalipour, A., M. M. Burdick, and D. F. J. Tees. Viscoelasticity measurements reveal rheological differences between stem-like and non-stem-like breast cancer cells. Cell. Mol. Bioeng. 10:235–248, 2017.

    Article  CAS  Google Scholar 

  27. Olson, M. F., and E. Sahai. The actin cytoskeleton in cancer cell motility. Clin. Exp. Metas. 26:273–287, 2009.

    Article  Google Scholar 

  28. Osborne, C. K. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339:1609–1618, 1998.

    Article  CAS  PubMed  Google Scholar 

  29. Paszek, M. J., N. Zahir, K. R. Johnson, J. N. Lakins, G. I. Rozenberg, A. Gefen, C. A. Reinhart-King, S. S. Margulies, M. Dembo, D. Boettiger, D. A. Hammer, and V. M. Weaver. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254, 2005.

    Article  CAS  PubMed  Google Scholar 

  30. Pawlak, G., and D. M. Helfman. Cytoskeletal changes in cell transformation and tumorigenesis. Curr. Opin. Genet. Dev. 11:41–47, 2001.

    Article  CAS  PubMed  Google Scholar 

  31. Rondon-Lagos, M., N. Rangel, L. V. Di Cantogno, L. Annaratone, I. Castellano, R. Russo, T. Manetta, C. Marchio, and A. Sapino. Effect of low doses of estradiol and tamoxifen on breast cancer cell karyotypes. Endocr. Relat. Cancer 23:635–650, 2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sato, M., N. Ohshima, and R. M. Nerem. Viscoelastic properties of cultured porcine aortic endothelial cells exposed to shear stress. J. Biomech. 29:461–467, 1996.

    Article  CAS  PubMed  Google Scholar 

  33. Schmid-Schönbein, G. W., K. L. Sung, H. Tözeren, R. Skalak, and S. Chien. Passive mechanical properties of human leukocytes. Biophys. J. 36:243–256, 1981.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Seyedpour, S. M., M. Pachenari, M. Janmaleki, M. Alizadeh, and H. Hosseinkhani. Effects of an antimitotic drug on mechanical behaviours of the cytoskeleton in distinct grades of colon cancer cells. J. Biomech. 48:1172–1178, 2015.

    Article  CAS  PubMed  Google Scholar 

  35. Stricker, J., T. Falzone, and M. L. Gardel. Mechanics of the F-actin cytoskeleton. J. Biomech. 43:9–14, 2010.

    Article  PubMed  Google Scholar 

  36. Suresh, S. Biomechanics and biophysics of cancer cells. Acta Biomater. 3:413–438, 2007.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Swaminathan, V., K. Mythreye, E. T. O’Brien, A. Berchuck, G. C. Blobe, and R. Superfine. Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Can. Res. 71:5075–5080, 2011.

    Article  CAS  Google Scholar 

  38. Thon, J. N., M. T. Devine, A. Jurak Begonja, J. Tibbitts, and J. E. Italiano, Jr. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production. Blood 120:1975–1984, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Turner, M. S., and P. Sens. Inclusions on fluid membranes anchored to elastic media. Biophys. J. 76:564–572, 1999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, L. J., S. X. Han, E. Bai, X. Zhou, M. Li, G. H. Jing, J. Zhao, A. G. Yang, and Q. Zhu. Dose-dependent effect of tamoxifen in tamoxifen-resistant breast cancer cells via stimulation by the ERK1/2 and AKT signaling pathways. Oncol. Rep. 29:1563–1569, 2013.

    Article  CAS  PubMed  Google Scholar 

  41. Welliver, T. P., S. L. Chang, J. J. Linderman, and J. A. Swanson. Ruffles limit diffusion in the plasma membrane during macropinosome formation. J. Cell Sci. 124:4106–4114, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilhelm, J., and E. Frey. Elasticity of stiff polymer networks. Phys. Rev. Lett. 91:108103, 2003.

    Article  CAS  PubMed  Google Scholar 

  43. Xu, W., R. Mezencev, B. Kim, L. Wang, J. McDonald, and T. Sulchek. Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells. PLoS ONE 7:e46609, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, G., M. Long, Z. Z. Wu, and W. Q. Yu. Mechanical properties of hepatocellular carcinoma cells. World J. Gastroenterol. 8:243–246, 2002.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhou, E. H., S. T. Quek, and C. T. Lim. Power-law rheology analysis of cells undergoing micropipette aspiration. Biomech. Model. Mechanobiol. 9:563–572, 2010.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors want to thank Dr. Nickolaos Nikiforos Giakoumakis and Patroula Nathanailidou, Laboratory of General Biology School of Medicine, University of Patras for providing the Leica confocal microscopy.

Funding

Funding was supported by ‘Constantin Carathéodory scholarship 2013, E044’.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George Athanassiou.

Additional information

Associate Editor Stefan M. Duma oversaw the review of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Metsiou, D.N., Siatis, K.E., Giannopoulou, E. et al. The Impact of Anti-tumor Agents on ER-Positive MCF-7 and HER2-Positive SKBR-3 Breast Cancer Cells Biomechanics. Ann Biomed Eng 47, 1711–1724 (2019). https://doi.org/10.1007/s10439-019-02284-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-019-02284-3

Keywords

Navigation