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Interaction of cellular and environmental factors in tumor histogenesis Auersperg, Nelly


The histogenesis of two squamous-carcinoma cell lines, originally derived from the same human cervical tumor but with different morphology in vitro and in vivo, was compared histochemically and electron microscopically. Inoculation into hamster cheek pouches was used to distinguish in vitro from in vivo responses in the two cell lines. Normal cervical epithelium was grown in vitro to determine which histogenetic characteristics were due to the malignant nature of the cell lines. Possible mechanisms underlying histogenetic variation were investigated by chemical and physical modifications of the in vitro environment. In vitro cells of line C-4c were more cohesive, less deformable and less adhesive to substrata than the cells of line C-4s and they formed more compact and highly stratified colonies. Line C-4s responded to crowding in vitro by cell separation (dispersal) while line C-4c increased stratification. Histochemically the cell lines were essentially similar but they differed in ultrastructure, particularly at the level of tissue organization. The C-4s cells were columnar, with a higher nucleo-cytoolasmic ratio, a polarity of the organelles, dispersed cytoplasmic filaments, little stratification and with terminal bars between superficial cells. In contrast, C-4c cells were oval, stratified and with superficial cells flattened, with a lower nucleo-cytoplas-mic ratio, without polarity of organelles, and with more cytoplasmic filaments condensed into bundles that were associated with desrnosomes. In both lines, but particularly in line C-4c, interdigitating microvilli provided the main intercellular contact and the cell surfaces were modified in association with both substrata and the growth medium. Most in vitro differences between the cell lines were retained in vivo, and, in addition, incomplete basement membranes were formed in both lines, though more extensively in line C-4.s. It appeared that the only major difference in vitro between benign squamous cells and the carcinoma cells lay in the ability of the latter to maintain an intercellular organization in the complete absence of any supporting tissue. Possible mechanisms underlying these observed differences in histogenesis were experimentally investigated. Ferritin uptake in vitro indicated that the difference in stratification was not due to more efficient intercellular circulation in the more highly stratified C-4c line. No difference in cell-surface charges or distribution of cell-surface acid mucosubstances could be demonstrated, suggesting no difference in contact inhibition to be associated with the stratification. It was found that C-4c cells were more cohesive and that this cohesion, in both lines, depended predominantly on the presence of divalent cations. In contrast, adhesion to the substrata required extracellular proteins, probably accompanied by the masking of acid groups on the cell surface. These and other described observations suggested a defect in deformability in these cell lines with the probability that the stronger cohesion in line C-4c was due to the more extensive microvillus population. The in vitro maintenance of cell shape, of tissue organization and of cell separation (dispersal) seemed to involve an interaction between these intercellular adhesive forces and the cytoplasmic filaments. On the other hand, the specific, modifications, such as terminal-bar formation and cell flattening, which appeared in relation to growth medium, to other cells and to substrata could be shown to be responses of the cells to the viscosity of the immediate environment and thus experimentally modifiable. The results of this investigation are discussed relative to the specific suggestion that much of the histogenetic variation could be explained by considering that the more cohesive cell line (C-4c) had retained properties of normal epithelium stratum spinosum cells, while the spreading cell line (C-4s) exhibited characteristics of basal cells, and relative to the interaction of differentiation capacity and malignancy in tumor development.

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