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Do you routinely plate tumor cell lines as monolayers on plasticware for experiments? Although most investigators utilize standard monolayer cultures in their experiments, new insights have been garnered in the past few years from cells grown in three dimensions. Various three-dimensional culture techniques are in use, consisting basically of cellular aggregates in spinner cultures (/); on top of coated plastic surfaces, agarose, or extracellular matrix proteins (2); or embedded within agarose or matrix proteins (3). The article by Graham et al. (/) in this issue of the Journal describes an effect of three-dimensional culture on an important, but poorly understood, aspect of cancer progression, drug resistance. The use of three-dimensional cell culture systems, typically with reconstituted basement membrane components, has revolutionized our understanding of the differentiation of many cell types, including endothelia, salivary gland epithelium, mammary epithelium, hepatocytes, Sertoli's cells, and others (2-4). In a study of mammary epithelial differentiation, for example, Petersen et al. (5) found that three-dimensional culture of human primary mammary epithelial cells within a basementmembrane extract induced the formation of acinus-like structures with central lumens, synthesis of new basement-membrane proteins followed by their secretion to the outside of the acinus, and production of sialomucin and its secretion to the inside of the acinus. None of nine breast carcinoma cultures or cell lines recapitulated these processes (5). Our laboratory also assumed that conventional monolayer culture on plasticware was sufficient until collaborative experiments with Dr. Mina Bissell's laboratory proved otherwise. We recently found that transfection of the human MDA-MB-435 breast carcinoma cell line with nm23-Hl complementary DNA, which had earlier been found to induce a 50%-90% reduction in metastatic potential in vivo (6), resulted in no change in cellular differentiation in twodimensional culture (7). However, in three-dimensional culture, the nm23-HI transfectants formed acinus-like structures, synthesized and directionally secreted basement-membrane proteins, and synthesized sialomucins. Such characteristics were not exhibited by similarly cultured parental cells or control transfectants (7). In this issue of the Journal, a group headed by Dr. Robert Kerbel, Sunnybrook Health Science Centre, reports that a single exposure of either murine EMT-6 mammary cells or human MDA-MB-231 human breast carcinoma cells to either 4hydroperoxycyclophosphamide or cisplatin induced rapid, transient drug resistance upon rechallenge, but only if the cells were exposed to drug as agarose-coated three-dimensional cultures (/). The extent of the observed increase in drug resistance of the EMT-6 cells, measured as surviving fractions, ranged from several fold at lower drug concentrations to several logs at higher drug concentrations. The drug resistance phenotype was accompanied by a more compact three-dimensional spheroid morphology. This report complements previous work by Miller et al. (8), in which murine mammary tumor cell lines were exposed to melphalan, methotrexate, or fluorouracil, either in monolayer culture or as three-dimensional cultures in a collagen gel matrix. The mammary cell lines were as much as several logfold more drug resistant in three-dimensional cultures as compared to the same cells treated as monolayers. Because the tumor cells were not pretreated with a chemotherapeutic agent in that study, Miller and coworkers measured intrinsic drug resistance; however, the principle of increased resistance in pretreated three-dimensional cultures is similar. Several other investigators (9-11) have also noted drug resistance in tumor cells in three-dimensional cultures, but did not directly compare twoand three-dimensional conditions .

An Added Dimension: Will Three-Dimensional Cultures Improve Our Understanding of Drug Resistance?