Changes in response to, and production of, transforming growth factor type β during neoplastic progression in cultured rat tracheal epithelial cells

Abstract

As rat tracheal epithelial cells progress from a normal to a neoplastic phenotype there are systematic changes in their ability to produce and activate latent transforming growth factor type beta (TGF-beta) as well as systematic changes in their response to this growth factor. Using a TGF-beta radioreceptor binding competition assay it was found that normal proliferating rat tracheal cells in early primary culture produced latent TGF-beta. With the emergence of terminally differentiated cell populations active TGF-beta was also detected in the conditioned medium. When normal cells were cultured under conditions allowing for continued proliferation, no active TGF-beta was detected in the conditioned medium. Colonies of proliferating epithelial cells in 4-6 week primary cultures or subculturable tracheal cell lines did not produce detectable levels of active or latent growth factor. With neoplastic progression there was likewise a change in response to active TGF-beta. Normal tracheal cells in primary culture were highly sensitive to growth-factor-induced decreases in thymidine uptake as well as to the induction of terminal differentiation. Proliferating epithelial cells in late (4-6 week) primary cultures and preneoplastic, subculturable cell lines were often as sensitive as normal cells to the growth factor-induced decline in thymidine uptake. None of these altered populations, however, was induced to differentiate (to form cornified, cross-linked envelopes) in the presence of TGF-beta.

Changes in responsiveness of rat tracheal epithelial cells to transforming growth factor‐β1 with time in culture

“…This suggests that separate pathways are involved in TGFp's effects on proliferation and on fibronectin expression, and that the receptors or pathways involved in the fibronectin response are not down-regulated or altered by time in culture. Howe et al (1989) also found that TGFp effects on fibronectin and c-myc expression in AKR-ZB fibroblast cells were through distinct pathways, with only the latter being sensitive to cholera toxin pretreatment.…”

“…We and others have shown that normal RTE cells secrete TGFp (Steigerwalt et al, 1992;Terzaghi-Howe, 1989) and are highly sensitive to growth inhibition by exogenous TGFPl (Steigerwalt et al, 1992;Hubbs et al, 1989;Terzaghi-Howe, 1989). However, growth inhibition by TGFp in all these studies was measured when TGFp was added 1-2 days after plating.…”

Radiation Carcinogenesis in Context: How Do Irradiated Tissues Become Tumors?

“…Terzaghi-Howe demonstrated that the expression of dysplasia in vivo and neoplastic transformation in cultures of irradiated tracheal epithelial cells is inversely correlated with the number of cells seeded (Terzaghi and Little 1976; Terzaghi and Nettesheim 1979; Terzaghi-Howe 1986; Terzaghi-Howe 1989) and identified TGFβ as a key mediator (Terzaghi-Howe 1990). Greenberger proposed in 1996 that irradiated stromal cells function as biologic tumor promoters in leukemia through their release of reactive oxygen species, and production of altered adhesion molecules or growth factors that block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells (Greenberger et al 1996c).…”

Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice.

“…In a mouse skin model, we have shown that TGF-~I expression is rapidly induced in suprabasal keratinocytes in vivo, in response to hyperplasia (Akhurst et al 1988;Fowlis et al 1992), thus implicating this growth factor in regulation of epidermal homeostasis. Furthermore, perturbations in the production of, or response to, TGF-~ are thought to be involved in multistage carcinogenesis in several types of epithelia (Terzaghi-Howe 1989;Krieg et al 1991;Glick et al 1991Glick et al , 1993Manning et al 1991;Missero et al 1991;Fowlis et al 1992;Cui et al 1994). Elucidation of the molecular mechanisms of control of epithelial homeostasis by TGF-f3 is therefore central to our under-standing of the molecular pathology of both neoplastic and nonneoplastic skin diseases.…”