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Morphological Differentiation of Human Choriocarcinoma Cells Induced by Methotrexate¹

Department of Pharmacology, University of Colorado Medical Center, Denver, Colorado 80262

BeWo is a malignant human choriocarcinoma line derived from a methotrexate-resistant tumor. Under normal conditions, two BeWo phenotypes coexist in culture. The predominant form, 96 to 99% of the total population, consists of cytotrophoblast-like (CTL) cells that are proliferative, mononucleate, and moderate in size. The remaining cells are syncytiotrophoblast-like (STL), being giant, nonproliferative, and multinucleated. Treatment of BeWo cultures with 1 µM methotrexate causes a total inhibition of cell division but does not stop nuclear division or DNA or protein synthesis. Consequently, there arises a population of giant, multinucleated, nonproliferative cells that is morphologically indistinguishable from the naturally occurring STL cells. CTL BeWo cells possess prominent surface ruffles, contain moderate numbers of microvilli and filopodia, contain a prominent network of interlacing filament bundles, and are connected by fascia adherens and desmosomes. STL BeWo cells are 3 to 10 times larger than CTL's; have reduced ruffles, filopodia, cytoplasmic filament bundles, and desmosome and fascia adherens junctions; but possess increased microvilli, Golgi apparatus, smooth and dilated endoplasmic reticulum, and a variety of vesicles and granules. The methotrexate induction of STL cells is reversible upon drug removal. A comparison of our observations with literature data for the normal in utero trophoblast indicates that CTL BeWo cells are ultrastructurally similar to cells of the cytotrophoblast, while STL BeWo cells are ultrastructurally similar to the normal syncytiotrophoblast. Our findings indicate that the BeWo line provides an excellent culture model system for investigating the nontoxic, cytodifferentiative changes that chemotherapeutic agents induce in human tumor cells and raise the possibility that the BeWo line may also prove a valuable culture model system for the investigation of mammalian trophoblast development.

¹ These studies were supported in part by an American Cancer Society Institutional Research Grant and by National Cancer Institute Grants CA-16154 and CA-23985. A portion of this work was presented at the American Society of Cell Biology Meeting, San Diego, Calif. 1977 (7).

Received 1/18/78. Accepted 2/27/79.

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