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Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

ABSTRACT: BACKGROUND: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. METHODS: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). RESULTS: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. CONCLUSIONS: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size.

SUBMITTER: Toffalorio F

PROVIDER: S-EPMC3950879 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

Toffalorio F F Belloni E E Barberis M M Bucci G G Tizzoni L L Pruneri G G Fumagalli C C Spitaleri G G Catania C C Melotti F F Pelicci P G PG Spaggiari L L De Pas T T

British journal of cancer 20140211 5

<h4>Background</h4>Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after ...[more]

PMID: 24518592

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Project description:BackgroundTransforming growth factor beta (TGFbeta), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFbeta on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown.MethodsWe used Affymetrix oligonucleotide microarrays U95v2, containing approximately 12,000 human genes, to study the transcriptional profile in response to a four hour treatment with TGFbeta in control lung fibroblasts and in fibroblasts from patients with idiopathic and scleroderma-associated pulmonary fibrosis. A combination of the Affymetrix change algorithm (Microarray Suite 5) and of analysis of variance models was used to identify TGFbeta-regulated genes. Additional criteria were an average up- or down- regulation of at least two fold.ResultsExposure of fibroblasts to TGFbeta had a profound impact on gene expression, resulting in regulation of 129 transcripts. We focused on genes not previously found to be regulated by TGFbeta in lung fibroblasts or other cell types, including nuclear co-repressor 2, SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), bone morphogenetic protein 4, and angiotensin II receptor type 1 (AGTR1), and confirmed the microarray results by real time-PCR. Western Blotting confirmed induction at the protein level of AGTR1, the most highly induced gene in both control and fibrotic lung fibroblasts among genes encoding for signal transduction molecules. Upregulation of AGTR1 occurred through the MKK1/MKK2 signalling pathway. Immunohistochemical staining showed AGTR1 expression by lung fibroblasts in fibroblastic foci within biopsies of idiopathic pulmonary fibrosis.ConclusionsThis study identifies several novel TGFbeta targets in lung fibroblasts, and confirms with independent methods the induction of angiotensin II receptor type 1, underlining a potential role for angiotensin II receptor 1 antagonism in the treatment of lung fibrosis.

Dataset Information

Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

Publications

Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

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