Tumor promotion: Models and assay systems

Abstract

Tumor promotion is defined operationally from two-stage models of experimental carcinogenesis. It is, therefore, in a strict sense, possible to identify tumor promoters only from such models. The development and use of in vitro two-stage cell transformation assays was a logical extension toward in vitro short-term testing for tumor promoters. Another approach is to apply mechanistic knowledge of the tumor promotion process in developing end points for such assays. In this context, we have been examining the role of blocked gap-junctional intercellular communication (GJIC) in tumor promotion, using in vitro and in vivo systems. Many promoters have been shown to block GJIC in vitro; our studies support the idea that inhibition of GJIC does play an important role in the promotion stage of BALB/c 3T3 cell transformation. In animal studies, we have shown that the rat liver tumor promoter phenobarbital can decrease the level of expression of the 32 Kd gap junction protein gene specifically in liver upon systemic exposure in rats. Further examination of the role of GJIC in tumor promotion is indeed warranted. Also, deployment of in vitro GJIC and transformation assay systems should provide useful short-term tests for detecting tumor promoting activity of environmental chemicals.

Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation

“…The correlation between neoplastic transformation and reduced gap junctional communication (Atkinson et al, 1981;Azarnia and Loewenstein, 1984;de Feijter et al, 1990) has led to the hypothesis that reduced cell-cell communication is a critical step in multistage carcinogenesis (Fitzgerald and Yamasaki, 1990;Trosko et al, 1990). PKC has received considerable attention because PKC activators (e.g.…”

A relação do uso crônico de fenobarbital com áreas potencialmente pré-neoplásicas em fígado de ratos

“…Em trabalhos prévios, após utilização de protocolo de iniciação da carcinogênese, a atividade de GSTP é signifi cativamente aumentada em fígado de ratos púberes, assim como em adultos, quando comparados com animais controle não submetidos a processo de iniciação (10) . Focos espontâneos aumentam com a idade e são mais visíveis em ratos machos (20) .…”

“…A carcinogênese é um processo dinâmico que envolve os estágios de iniciação, promoção e progressão e nesse processo as alterações gênicas são acompanhadas de modifi cações no fenótipo das células (5,7,8,9,10,21,23) .…”

“…Em ratos idosos, após a administração de agentes hepatocarcinogênicos, detectaram-se hepatócitos individualmente aberrantes, expressando GSTP e sugerindo que essas células constituem uma população hepatocitária iniciada (5,6,7,8,9,10,16,20,21,24,25,28) .…”

Risk Assessment of Toxaphene and its Breakdown Products: Time for a Change?

“…• Phenobarbital has been tested in multiple studies of GJIC, and was used as a positive control in rodent cell lines by several different investigators. It has been evaluated in studies using several different measures of GJIC, including dye coupling, electron microscopy, gap junction gene expression, and in vivo assays (Fitzgerald and Yamasaki, 1990). • In vitro studies using phenobarbital in liver cell cultures from multiple species have demonstrated a speciesspecific tumor promoting capability, in that phenobarbital is an effective inhibitor of intracellular gap junction communication in rodent cells, but not in primate or human liver cells (Kamendulis et al, 2002); • Phenobarbital has not been shown to be associated with liver cancer in humans, even after long-term relatively high-dose administration (Whysner et al, 1996) suggesting that a "threshold dose" model applies.…”