Differential Display Analysis of Fiber-Induced Carcinogenesis in Rat: Clue for Involvement of Integrin-Mediated Signal Transduction

Our plain-English summary of Differential Display Analysis of Fiber-Induced Carcinogenesis in Rat: Clue for Involvement of Integrin-Mediated Signal Transduction, by H. Sandhu, H. Olbrück, J. Abel, et al (Inhalation Toxicology, 2000).

The study

• Authors: H. Sandhu, H. Olbrück, J. Abel, K. Unfried
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:337-43
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In this study, mRNA expression patterns during mesothelioma carcinogenesis in the peritoneal cavity were investigated. To this purpose, the mRNA expression patterns of fiber-induced mesothelioma and of fiber-treated tissues were compared to untreated tissues, respectively. Suppression subtractive hybridization (SSH) and an array hybridization assay were used to perform differential display analyses. Genes found to be expressed differentially mainly represent proteins of signal transduction pathways and regulatory proteins of the cell cycle. The genes for components of the AP-1 transcription factor, c-jun, c-fos, and fra-1 (fos-related antigen-1) are upregulated in nontumorous tissue treated with asbestos. These data confirm in vivo the involvement of AP-I expression as response to fiber treatment. In addition, osteopontin, zyxin, and integrin-linked kinase were upregulated in tumors and in treated tissues. These genes code for proteins involved in the signal transduction from the extracellular matrix to the nucleus. Using integrin-specific inhibitors, the apoptotic effects of crocidolite fibers could be suppressed significantly. From these results we hypothesize that direct effects of the fibers on the target tissue are mediated by interaction of the fibers with the extracellular matrix molecules.

In plain English

This laboratory study looked at gene activity during asbestos-induced mesothelioma in rats and tested one possible mechanism in cell cultures. Wistar rats were given single doses of crocidolite asbestos into the abdominal (peritoneal) cavity. The gene-activity results, which this article summarizes from a companion paper by the same group, found several genes more active in the resulting tumors than in untreated tissue, including osteopontin and zyxin. In non-tumorous asbestos-treated tissue one year after treatment, four genes were more active, including fra-1, integrin-linked kinase and the epidermal growth factor receptor. These were also raised in tumors. Because several of these genes relate to integrins, which are receptors on the cell surface, the authors exposed rat pleural mesothelial cells to crocidolite in the laboratory. Blocking integrins with an RGD peptide, or with an antibody against the beta-1 integrin chain, reduced asbestos-induced cell death (apoptosis). Cell death caused by the drug actinomycin D was not affected. The scanned text gives no readable numbers or statistical tests for these effects. The authors concluded that integrins help transmit signals that mediate effects of fiber treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (rats given asbestos by intraperitoneal treatment) combined with in vitro cell-culture experiments. The gene-expression results are summarized from a companion paper (Sandhu et al., 2000). The new data are the cell-culture apoptosis experiments.
• Who was studied: Wistar rats (number not stated in this article). Also rat pleural mesothelial (RPM) cells and the nontumorous rat pleural mesothelial cell line 44R.M.-4, grown in the laboratory.
• Exposure: Rats: single intraperitoneal doses of crocidolite asbestos (dose not given in this article); control animals received control substances. Cells: UICC crocidolite at 10 micrograms per square centimetre for 48 hours. Some cells were pretreated with an RGD peptide, a control peptide, or an antibody against the beta-1 integrin chain. Actinomycin D (2 micrograms per mL) was used as a comparison cause of apoptosis.
• Main results:
  • In crocidolite-induced mesothelioma tumors compared with control tissues, genes with raised mRNA levels were cytosolic branched-chain aminotransferase, osteopontin, zyxin and two unidentified sequences.
  • In non-tumorous fiber-treated tissues 1 year after treatment, compared with untreated tissues, four genes were upregulated: a proto-oncogene printed as 'e-mye' in the scanned text, fos-related antigen 1 (fra-1), integrin-linked kinase and epidermal growth factor receptor.
  • In follow-up RT-PCR tests, these four genes were also upregulated in tumors.
  • In rat pleural mesothelial cells treated with crocidolite (acute reaction), only two genes were upregulated: the 'e-mye' proto-oncogene and fra-1.
  • Pretreating cells with RGD peptide before crocidolite reduced the amount of apoptosis. The authors report this reduction was seen in two different apoptosis assays.
  • Pretreatment with an antibody against the beta-1 integrin chain also reduced asbestos-induced apoptosis.
  • Apoptosis induced by actinomycin D was not influenced by the RGD peptide or the beta-1 integrin antibody.
• The authors' conclusion: The authors concluded that integrins take part in transmitting information from extracellular matrix molecules to the cell to mediate effects of fiber treatment, and that crocidolite-induced apoptosis can be mediated through beta-1 integrin-dependent signalling.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Mesothelioma, Peritoneal Cavity, Osteopontin, Crocidolite.

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• New vistas in malignant mesothelioma: MicroRNA architecture and NRF2/MAPK signal transduction — M. Gandhi, S. Nair (2020)
• Cross reactivity between many anti-human antibodies for their hamster homologs provide the tools to study the signal transduction pathway activated by asbestos and SV40 in the malignant mesothelioma model — B. Kroczynska, M. Carbone (2006)
• The role of iNOS-mediated DNA damage in infection- and asbestos-induced carcinogenesis — Y. Hiraku, S. Kawanishi, et al. (2010)
• beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line — A. Berken, J. Abel, et al. (2003)

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