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Adaptation to 5‐fluorouracil of the heterogeneous human colon tumor cell line ht‐29 results in the selection of cells committed to differentiation
Author(s) -
Lesuffleur Thécla,
Kornowski Anne,
Luccioni Catherine,
Muleris Martine,
Barbat Alain,
Beaumatin Jacqueline,
Dussaulx Elisabeth,
Dutrillaux Bernard,
Zweibaum Alain
Publication year - 1991
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910490516
Subject(s) - biology , cell culture , population , cellular differentiation , cell , immunology , microbiology and biotechnology , genetics , gene , medicine , environmental health
The HT‐29 cell line contains a small proportion of differentiated polarized, enterocytic and mucus‐secreting cell types (< 95%) which can be selected under various pressure conditions, e.g., glucose deprivation or methotrexate. The purpose of the present work was to investigate whether this also applies to 5‐fluorouracil (FUra). Stepwise adaptation of exponentially growing cells to 1, 5, 10 and 20 μM FUra results, after a phase of high mortality, in the emergence of adapted sub‐populations with stable growth rates and curves, and IC 50 6, 18, 37, and 110 times higher than in untreated cells respectively. FUra‐adapted cells are all differentiated, according to 2 phenotypes: (1) polarized dome‐forming cells which express carcinoembryonic antigen at their apical surface and (2) goblet cells which secrete a mucus of colonic immunoreactivity. These phenotypes are present in the parental population and are different from those selected e.g., by glucose deprivation or methotrexate. This differentiation pattern is maintained when the cells are sub‐cultured in drug‐free medium. Resistance to FUra is acquired through gene amplification as substantiated by a 4‐ to 6‐fold increase of thymidylate synthase gene copies in cells stably adapted to the drug. Whether the same mechanism or others are responsible for the first steps of resistance to FUra remains to be elucidated. Altogether, these results support the hypothesis that some of the cells which are present in the parental line and are committed to differentiation possess advantages which allow them to immediately resist and secondarily adapt to FUra. Comparison of the differentiation characteristics of FUra‐adapted cells with those from cells selected under other pressure conditions suggests that resistance and adaptation to either type of pressure may depend on the differentiated phenotype to which the cells are committed.