Medullary thyroid cancer (MTC) is an endocrine
tumor of the thyroid C-cells which provides an important experimental model for studies of
tumor differentiation and progression. We investigated the effects of
transforming growth factor-beta 1 (
TGF beta 1) on the growth and functional characteristics of a human medullary
thyroid carcinoma cell line (TT). Because the c-myc protooncogene may play an important role in the growth inhibition induced by
TGF beta 1, we also assessed steady state c-myc
messenger RNA (
mRNA) levels in these cells. A 6-day exposure of TT cells to
TGF beta 1 resulted in a dose-dependent inhibition of cell proliferation. In addition,
TGF beta 1 exposure led to a 3-fold increase in nonadherent floating TT cells in the culture supernatants. The floating cells exhibited ultrastructural features of dying or apoptotic cells, including
chromatin condensation, cytoplasmic and nuclear vesicularization, and
DNA degradation with evidence of internucleosomal
DNA "laddering." Despite inhibition of cell proliferation, steady state c-myc
mRNA levels were 3.6 +/- 0.6-fold higher in cells exposed to
TGF beta 1 compared to those in control cells (P < 0.001). Exposure of cells to a 15-base antisense c-myc
oligonucleotide (10 microM) resulted in an attenuation of the
TGF beta 1-induced growth inhibition and induction of cell death.
TGF beta 1 also resulted in an approximately 3-fold decrease in steady state
calcitonin and
calcitonin gene-related peptide mRNA levels. Finally, using a sensitive bioassay for
TGF beta, TT cells were shown to produce and activate significant amounts of
TGF beta, particularly under conditions of serum deprivation. Our data thus indicate that
TGF beta 1 has multiple effects on TT cell growth and function. It induces growth inhibition in the presence of an increase in steady state
mRNA levels of the c-myc protooncogene, which is usually associated with cell proliferation. In addition,
TGF beta 1 accelerates apoptosis in TT cells.