IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor LesionsReportar como inadecuado

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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.


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.

Autor: Irma Airoldi , Emma Di Carlo, Claudia Cocco, Emanuela Caci, Michele Cilli, Carlo Sorrentino, Gabriella Sozzi, Silvano Ferrini, Sa



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