Restructuring dynamics of du 145 and LNCaP prostate cancer spheroids

  • Hong Song
  • Shamik K. Jain
  • Richard M. Enmon
  • Kim C. O'Connor
Articles Biotechnology


Neoplastic cells acquire multidrug resistance as they assemble into multicellular spheroids. Image analysis and Monte Carlo simulation provided an insight into the adhesion and motility events during spheroid restructuring in liquid-overlay culture of DU 145 and LNCaP human prostate cancer cells. Irregularly shaped, two-dimensional aggregates restructured through incremental cell movements into three-dimensional spheroids. Of the two cultures examined, restructuring was more pronounced for DU 145 aggregates. Motile DU 145 cells formed spheroids with a minimum cell overlay of 30% for 25-mers as estimated by simulation versus 5% for adhesive LNCaP cells in aggregates of the same size. Over 72 h, the texture ratio increased from 0.55±0.05 for DU 145 aggregates with projected areas exceeding 2000 μm2 to a value approaching 0.75±0.02 (P<0.05). For LNCaP aggregates of comparable size, the increase in texture ratio was more modest, less than 15% during the same time period (P<0.05). Combined, these data suggest that motility events govern the overall rate of spheroid restructuring. This information has application to the chemosensitization of solid tumors and kinetic modeling of spheroid production.

Key words

cell aggregation Monte Carlo simulation adhesion motility 


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  1. Allen, M. P.; Tildesley, D. J. Computer simulation of liquids. New York: Oxford University Press; 2002:118–121.Google Scholar
  2. Bauerschmitz, G. J.; Lam, J. T.; Kanerva, A., et al. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res. 62:1266–1270; 2002.PubMedGoogle Scholar
  3. Desoize, B.; Gimonet, D.; Jardiller, J.-C., Cell culture as spheroids: an approach to multicellular resistance. Anticancer Res. 18:4147–4158; 1998.PubMedGoogle Scholar
  4. Enmon, R. M.; O'Connor, K. C.; Lacks, D. J.; Schwartz, D. K.; Dotson, R. S. Dynamics of spheroid self-assembly in liquid-overlay cultures of DU 145 human prostate cancer cells. Biotechnol. Bioeng. 72:579–591; 2001.PubMedCrossRefGoogle Scholar
  5. Enmon, R. M.; O'Connor, K. C.; Song, H.; Lacks D. J.; Schwartz, D. K. Aggregation kinetics of well and poorly differentiated human prostate cancer cells. Biotechnol. Bioeng. 80:580–588; 2002.PubMedCrossRefGoogle Scholar
  6. Francescon, P.; Cora, S.; Chiovati, P. Dose verification of an IMRT treatment planning system with the BEAM EGS4-based Monte Carlo code. Med. Phys. 30:144–157; 2003.PubMedCrossRefGoogle Scholar
  7. Goel, N. S.; Rogers, G.. Computer simulation of engulfment and other movements of embryonic tissues. J. Theor. Biol. 71:103–140; 1978.PubMedCrossRefGoogle Scholar
  8. Hoosein, N. M.; Boyd, D. D.; Hollas, W. J.; Mazar, A.; Henkin, J.; Chung, L. W. Involvement of urokinase and its receptor in the invasiveness of human prostatic carcinoma cell lines. Cancer Commun. 3:255–264; 1991.PubMedGoogle Scholar
  9. Jemal, A.; Murray, T.; Samuels, A.; Ghafoor, A.; Ward, E.; Thun, M. J. Cancer statistics, 2003, CA Cancer J. Clin. 53:5–26; 2003.PubMedGoogle Scholar
  10. Kitahara, M.; Katakura, R.; Suzuki, J.; Sasaki, T. Experimental combination chemotherapy of ACNU and 5-FU against cultured glioma model (spheroid) and subcutaneous rat glioma. Int. J. Cancer 40:557–563; 1987.PubMedCrossRefGoogle Scholar
  11. Lelkes, P. I.; Ramos, E.; Nikolaychik, V. V.; Wankowski, D. M.; Unsworth, B. R.; Goodwin, T. J. GTSF-2: a new, versatile cell culture medium for diverse normal and transformed mammalian cells. In Vitro Cell. Dev. Biol. 33A:344–451; 1997.Google Scholar
  12. Liebovitch, L. S. Fractals and chaos simplified for the life sciences, New York: Oxford University Press; 1998:46–59.Google Scholar
  13. Meakin, P. Diffusion-controlled aggregation on two-dimensional square lattices: results from a new cluster-cluster aggregation model. Phys. Rev. B 29:2930–2942; 1984.CrossRefGoogle Scholar
  14. Meakin, P. The effects of random bond breaking on diffusion limited cluster-cluster aggregation. J. Chem. Phys. 83:3645–3649; 1985.CrossRefGoogle Scholar
  15. Meakin, P.; Jullien, R. Structural readjustment effects in cluster-cluster aggregation. J. Physique 46:1543–1552; 1985.Google Scholar
  16. Moore, G. W.; Berman, J. J. Cell growth simulations predicting polyclonal origins for ‘monoclonal’ tumors. Cancer Lett. 60:113–119; 1991.PubMedCrossRefGoogle Scholar
  17. O'Connor, K. C. Three-dimensional cultures of prostatic cells: tissue models for the development of novel anti-cancer therapies. Pharm. Res. 16:486–493; 1999.PubMedCrossRefGoogle Scholar
  18. Persson, A.-L. Image analysis of shape and size of fine aggregates. Eng. Geol. 50:177–186; 1998.CrossRefGoogle Scholar
  19. Sagvolden, G.; Giaever, I.; Pettersen, E. O.; Felder, J. Cell adhesion force microscopy. Proc. Natl. Acad. Sci. USA 96:471–476; 1999.PubMedCrossRefGoogle Scholar
  20. Saxton, M. J. Lateral diffusion and aggregation: a Monte Carlo study. Biophy. J. 61:119–128; 1992.CrossRefGoogle Scholar
  21. Sokoloff, M. H.; Tso, C.-L.; Kaboo, R.; Taneja, S.; Pang, S.; de Kernion, J. B.; Belldegrun, A. S. In vitro modulation of tumor progression-associated properties of hormone refractory prostate cancer cell lines by cytokines. Cancer 77:1862–1872; 1996.PubMedCrossRefGoogle Scholar
  22. Song, H.; O'Connor, K. C.; Lacks, D. J.; Enmon, R. M.; Jain, S. K. Monte Carlo simulation of LNCaP human prostate cancer cell aggregation in liquid-overlay culture. Biotechnol. Prog. 19:1742–1749; 2003.PubMedCrossRefGoogle Scholar
  23. Song, H.; O'Connor, K. C.; Papadopoulos, K. D.; Jansen, D. A. Differentiation kinetics of in vitro 3T3-L1 preadipocyte cultures. Tissue Eng. 8:1071–1081; 2002.PubMedCrossRefGoogle Scholar
  24. Spruss, T.; Bernhardt, G.; Schonenberger, H.; Schiess, W. Hyaluronidase significantly enhances the efficacy of regional vinblastine chemotherapy of malignant melanoma. J. Cancer Res. Clin. Oncol. 121:193–202; 1995.PubMedCrossRefGoogle Scholar
  25. St. Croix, B.; Rak, J. W.; Kapitain, S.; Sheehan, C.; Graham, C. H.; Kerbel, R. S. Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells. J. Natl. Cancer Inst. 88:1285–1296; 1996.CrossRefGoogle Scholar
  26. Sternberg, C. N. What's new in the treatment of advanced prostate cancer? Eur. J. Cancer 39:136–146; 2003.PubMedCrossRefGoogle Scholar
  27. van Brussel, J.; van Steenbrugge, G. J.; van Krimpen, C.; Bogdanowicz, J. F. A. T.; van der Kwast, T. H.; Schröder, F. H.; Mickisch, G. H. Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer. J. Urol. 165:130–135; 2001.PubMedCrossRefGoogle Scholar
  28. Wartenberg, M.; Frey, C.; Diedershagen, H.; Rigen, J.; Hescheler, J.; Sauer, H. Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids. Int. J. Cancer 75:855–863; 1998.PubMedCrossRefGoogle Scholar
  29. Yu, E. Y.; Oh, W. K. Neoadjuvant therapy for high-risk localized prostate cancer. Curr. Oncol. Rep. 5:250–257; 2003.PubMedGoogle Scholar
  30. Yuhas, J. M.; Li, A. P.; Martinez, A. O.; Ladman, A. J. A simplified method for production and growth of multicellular tumor spheroids. Cancer Res. 37:3639–3643; 1977.PubMedGoogle Scholar
  31. Zhorov, B. S.; Lin, S. X. Monte Carlo-minimized energy profile of estradiol in the ligand-binding tunnel of 17 beta-hydroxysteroid dehydrogenase: atomic mechanisms of steroid recognition. Proteins 38:414–427; 2000.PubMedCrossRefGoogle Scholar

Copyright information

© Society for In Vitro Biology 2004

Authors and Affiliations

  • Hong Song
    • 1
    • 2
  • Shamik K. Jain
    • 1
  • Richard M. Enmon
    • 1
    • 2
  • Kim C. O'Connor
    • 1
    • 2
    • 3
  1. 1.Department of Chemical and Biomolecular Engineering, Lindy Boggs CenterTulane UniversityNew Orleans
  2. 2.Graduale Program in Molecular and Cellular BiologyTulane University Medical SchoolNew Orleans
  3. 3.Tulane Cancer CenterLouisianaNew Orleans

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