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IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions

BACKGROUND: Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown previously that IL-12rb2 KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Aim of the study was to investigate i) IL-12Rβ2 expression in human primary lung adenocarcinoma...

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Autores principales: Airoldi, Irma, Di Carlo, Emma, Cocco, Claudia, Caci, Emanuela, Cilli, Michele, Sorrentino, Carlo, Sozzi, Gabriella, Ferrini, Silvano, Rosini, Sandra, Bertolini, Giulia, Truini, Mauro, Grossi, Francesco, Galietta, Luis Juan Vicente, Ribatti, Domenico, Pistoia, Vito
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702099/
https://www.ncbi.nlm.nih.gov/pubmed/19582164
http://dx.doi.org/10.1371/journal.pone.0006119
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author Airoldi, Irma
Di Carlo, Emma
Cocco, Claudia
Caci, Emanuela
Cilli, Michele
Sorrentino, Carlo
Sozzi, Gabriella
Ferrini, Silvano
Rosini, Sandra
Bertolini, Giulia
Truini, Mauro
Grossi, Francesco
Galietta, Luis Juan Vicente
Ribatti, Domenico
Pistoia, Vito
author_facet Airoldi, Irma
Di Carlo, Emma
Cocco, Claudia
Caci, Emanuela
Cilli, Michele
Sorrentino, Carlo
Sozzi, Gabriella
Ferrini, Silvano
Rosini, Sandra
Bertolini, Giulia
Truini, Mauro
Grossi, Francesco
Galietta, Luis Juan Vicente
Ribatti, Domenico
Pistoia, Vito
author_sort Airoldi, Irma
collection PubMed
description BACKGROUND: Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown previously that IL-12rb2 KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Aim of the study was to investigate i) IL-12Rβ2 expression in human primary lung adenocarcinomas and in their counterparts, i.e. normal bronchial epithelial cells (NBEC), ii) the direct anti-tumor activity of IL-12 on lung adenocarcinoma cells in vitro and vivo, and the mechanisms involved, and iii) IL-12 activity on NBEC. METHODOLOGY/PRINCIPAL FINDINGS: Stage I lung adenocarcinomas showed significantly (P = 0.012) higher frequency of IL-12Rβ2 expressing samples than stage II/III tumors. IL-12 treatment of IL-12R(+) neoplastic cells isolated from primary adenocarcinoma (n = 6) inhibited angiogenesis in vitro through down-regulation of different pro-angiogenic genes (e.g. IL-6, VEGF-C, VEGF-D, and laminin-5), as assessed by chorioallantoic membrane (CAM) assay and PCR array. In order to perform in vivo studies, the Calu6 NSCLC cell line was transfected with the IL-12RB2 containing plasmid (Calu6/β2). Similar to that observed in primary tumors, IL-12 treatment of Calu6/β2(+) cells inhibited angiogenesis in vitro. Tumors formed by Calu6/β2 cells in SCID/NOD mice, inoculated subcutaneously or orthotopically, were significantly smaller following IL-12 vs PBS treatment due to inhibition of angiogenesis, and of IL-6 and VEGF-C production. Explanted tumors were studied by histology, immuno-histochemistry and PCR array. NBEC cells were isolated and cultured from lung specimens of non neoplastic origin. NBEC expressed IL-12R and released constitutively tumor promoting cytokines (e.g. IL-6 and CCL2). Treatment of NBEC with IL-12 down-regulated production of these cytokines. CONCLUSIONS: This study demonstrates that IL-12 inhibits directly the growth of human lung adenocarcinoma and targets the adjacent NBEC. These novel anti-tumor activities of IL-12 add to the well known immune-modulatory properties of the cytokine and may provide a rational basis for the development of a clinical trial.
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spelling pubmed-27020992009-07-07 IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions Airoldi, Irma Di Carlo, Emma Cocco, Claudia Caci, Emanuela Cilli, Michele Sorrentino, Carlo Sozzi, Gabriella Ferrini, Silvano Rosini, Sandra Bertolini, Giulia Truini, Mauro Grossi, Francesco Galietta, Luis Juan Vicente Ribatti, Domenico Pistoia, Vito PLoS One Research Article BACKGROUND: Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown previously that IL-12rb2 KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Aim of the study was to investigate i) IL-12Rβ2 expression in human primary lung adenocarcinomas and in their counterparts, i.e. normal bronchial epithelial cells (NBEC), ii) the direct anti-tumor activity of IL-12 on lung adenocarcinoma cells in vitro and vivo, and the mechanisms involved, and iii) IL-12 activity on NBEC. METHODOLOGY/PRINCIPAL FINDINGS: Stage I lung adenocarcinomas showed significantly (P = 0.012) higher frequency of IL-12Rβ2 expressing samples than stage II/III tumors. IL-12 treatment of IL-12R(+) neoplastic cells isolated from primary adenocarcinoma (n = 6) inhibited angiogenesis in vitro through down-regulation of different pro-angiogenic genes (e.g. IL-6, VEGF-C, VEGF-D, and laminin-5), as assessed by chorioallantoic membrane (CAM) assay and PCR array. In order to perform in vivo studies, the Calu6 NSCLC cell line was transfected with the IL-12RB2 containing plasmid (Calu6/β2). Similar to that observed in primary tumors, IL-12 treatment of Calu6/β2(+) cells inhibited angiogenesis in vitro. Tumors formed by Calu6/β2 cells in SCID/NOD mice, inoculated subcutaneously or orthotopically, were significantly smaller following IL-12 vs PBS treatment due to inhibition of angiogenesis, and of IL-6 and VEGF-C production. Explanted tumors were studied by histology, immuno-histochemistry and PCR array. NBEC cells were isolated and cultured from lung specimens of non neoplastic origin. NBEC expressed IL-12R and released constitutively tumor promoting cytokines (e.g. IL-6 and CCL2). Treatment of NBEC with IL-12 down-regulated production of these cytokines. CONCLUSIONS: This study demonstrates that IL-12 inhibits directly the growth of human lung adenocarcinoma and targets the adjacent NBEC. These novel anti-tumor activities of IL-12 add to the well known immune-modulatory properties of the cytokine and may provide a rational basis for the development of a clinical trial. Public Library of Science 2009-07-01 /pmc/articles/PMC2702099/ /pubmed/19582164 http://dx.doi.org/10.1371/journal.pone.0006119 Text en Airoldi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Airoldi, Irma
Di Carlo, Emma
Cocco, Claudia
Caci, Emanuela
Cilli, Michele
Sorrentino, Carlo
Sozzi, Gabriella
Ferrini, Silvano
Rosini, Sandra
Bertolini, Giulia
Truini, Mauro
Grossi, Francesco
Galietta, Luis Juan Vicente
Ribatti, Domenico
Pistoia, Vito
IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title_full IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title_fullStr IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title_full_unstemmed IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title_short IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions
title_sort il-12 can target human lung adenocarcinoma cells and normal bronchial epithelial cells surrounding tumor lesions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702099/
https://www.ncbi.nlm.nih.gov/pubmed/19582164
http://dx.doi.org/10.1371/journal.pone.0006119
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