Abstract
BackgroundNon 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 FindingsStage 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.ConclusionsThis 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.
Highlights
IL-12 is a cytokine that exerts potent anti-tumor activity through a combination of immunostimulatory and anti-angiogenic mechanisms [1,2,3]
Expression of IL-12Rb2 in human lung adenocarcinomas We first investigated the expression of the IL-12Rb2 in lung tissue samples from seventy lung adenocarcinoma patients
Immunohistochemical analyses revealed that 29/70 lung adenocarcinomas (41.4%), 22/49 of which were adenocarcinomas with bronchioloalveolar features (ADBF), 4/13 pure bronchioloalveolar carcinomas (BAC) and 3/8 conventional adenocarcinomas (ADC) [15], did not express IL-12Rb2 (Table 1 and Fig. 1A, panel b)
Summary
IL-12 is a cytokine that exerts potent anti-tumor activity through a combination of immunostimulatory and anti-angiogenic mechanisms [1,2,3]. The latter are related to induction of IFN-c, which in turn triggers the release of the anti-angiogenic chemokines CXCL9, CXCL10 and CXCL11. We [10] have demonstrated that IL-12rb deficient mice develop spontaneously multiorgan lymphoid infiltrates, systemic IL-6 up-regulation and in the second year of life, lung adenocarcinomas and brochioalveolar carcinomas, possibly in relation to IL-6 over-expression [10]. We have shown previously that IL-12rb KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Aim of the study was to investigate i) IL-12Rb2 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
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