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Dynamics of spheroid self‐assembly in liquid‐overlay culture of DU 145 human prostate cancer cells
Author(s) -
Enmon Richard M.,
O'Connor Kim C.,
Lacks Daniel J.,
Schwartz Daniel K.,
Dotson Robert S.
Publication year - 2001
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/1097-0290(20010320)72:6<579::aid-bit1023>3.0.co;2-l
Subject(s) - spheroid , biophysics , chemistry , cell , extracellular , in vitro , biology , biochemistry
Abstract The in vitro self‐assembly of multicellular spheroids generates highly organized structures in which the three‐dimensional structure and differentiated function frequently mimic that of in vivo tissues. This has led to their use in such diverse applications as tissue regeneration and drug therapy. Using Smoluchowski‐like rate equations, herein we present a model of the self‐aggregation of DU 145 human prostate carcinoma cells in liquid‐overlay culture to elucidate some of the physical parameters affecting homotypic aggregation in attachment‐dependent cells. Experimental results indicate that self‐aggregation in our system is divided into three distinct phases: a transient reorganization of initial cell clusters, an active aggregation characterized by constant rate coefficients, and a ripening phase of established spheroid growth. In contrast to the diffusion‐controlled aggregation previously observed for attachment‐independent cells, the model suggests that active aggregation in our system is reaction‐controlled. The rate equations accurately predict the aggregation kinetics of spheroids containing up to 30 cells and are dominated by spheroid adhesive potential with lesser con‐ tributions from the radius of influence. The adhesion probability increases with spheroid size so that spheroid–spheroid adhesions are a minimum of 2.5 times more likely than those of cell–cell, possibly due to the upregulation of extracellular matrix proteins and cell‐adhesion molecules. The radius of influence is at least 1.5 to 3 times greater than expected for spherical geometry as a result of ellipsoidal shape and possible chemotactic or Fröhlich interactions. Brownian‐type behavior was noted for spheroids larger than 30 μm in diameter, but smaller aggregates were more motile by as much as a factor of 10 for single cells. The model may improve spheroid fidelity for existing applications of spheroids and form the basis of a simple assay for quantitatively evaluating cellular metastatic potential as well as therapies that seek to alter this potential. © 2001 John Wiley & Sons, Inc. Biotechnol Bioeng 72: 579–591, 2001.