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A Differentiation Therapy Model for Squamous Cell Carcinoma

Peter G. Sacks, PhD; Tomas Racz, MD; Stimson P. Schantz, MD; Michael G. Rosenblum, PhD

Arch Otolaryngol Head Neck Surg. 1994;120(11):1267-1272.

Abstract
Objective
The ability of interferon beta (IFN-β) and interferon gamma (IFN-) to modulate growth and differentiation of squamous carcinoma was studied.

Design
Two squamous carcinoma models (MDA 886Ln monolayer cells and multicellular tumor spheroids [MTSs], an in vitro system with three-dimensional in vivo—like structure) were used. Effects of interferons were examined with growth and differentiation assays.

Results
In 5-day monolayer growth assays, both interferons (IFNs) exhibited dose-dependent growth inhibition between 0 and 10⁴ U/mL; IFN- was more inhibitory than IFN-β (inhibitory concentration for 50% inhibition of 9 and 900 U/mL for IFN- and IFN-β, respectively). Multicellular tumor spheroid growth was examined by sizing MTSs over a 9-day growth period. Multicellular tumor spheroids were resistant to IFN-β with exposures of up to 50 000 U/mL. Similarly, MTSs were resistant to IFN- for the first several days, with growth inhibition becoming evident between days 7 to 9 of culture. As a marker of differentiation, transglutaminase activity was quantified after 5 days of treatment. Both IFNs induced increased transglutaminase activity in monolayer cells: IFN-β was twice as effective as IFN-. In contrast, 5-day treated MTSs showed no induction although their endogenous activity was higher. Flow cytometric analysis of monolayer cells for induction of class I and II major histocompatibility complex showed that both IFNs induced class I antigens but only IFN- could induce class II.

Conclusions
With their three-dimensional architecture, MTSs were more resistant to IFN-induced growth inhibition and differentiation induction than monolayer cells. Thus, mode of growth (monolayer vs MTS) is an important factor in responsiveness to IFN treatment; this suggests that MTSs may produce information that is more relevant to in vivo usage than monolayer cells.

(Arch Otolaryngol Head Neck Surg. 1994;120:1267-1272)

Author Affiliations
From the Memorial Sloan-Kettering Cancer Center, New York, NY (Drs Sacks and Schantz); R-Klinika Felsozoldmali, Budapest, Hungary (Dr Racz); and the University of Texas M. D. Anderson Cancer Center, Houston (Dr Rosenblum).

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ABSTRACT