Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

11 pages, 9 figures.[Background]: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients [Methodology/Principal Findings]: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRβ1–expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRβ–expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs. [Conclusions/Significance]: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.This work was supported by grants BFU2007-62402 from MEC; RD06/0020/0036 from FIS and from the EU Project CRESCENDO (FP6-018652.Peer reviewe

Glucocorticoid receptor mRNA levels in bronchial epithelial cells of patients with COPD: influence of glucocorticoids

AbstractGlucocorticoids (gcs) are known to be effective in the treatment of asthma. In chronic obstructive pulmonary disease (COPD), however, no beneficial effects are demonstrated in most patients. Hypothetically, this may be explained by an overexpressed β-glucocorticoid receptor (GR) compared to the α-GR. The aim of this study was to investigate α- and β-GR mRNA levels and ratios in patients with COPD with or without glucocorticoid treatment.GR and, as a control, metallothionein (MT) 2 mRNA levels were compared between patients with COPD receiving glucocorticoids (COPD + gcs), glucocorticoid naive COPD-patients (COPD − gcs) and non-COPD control patients not using gcs. Bronchoscopy was performed and bronchial epithelial cells were sampled with brushing.Smoking did not influence α- and β-GR levels and ratios, nor the MT2 mRNA expression level. The α-GR mRNA expression was lower in the COPD − gcs group than in controls. Both GR forms were higher in the COPD+ gcs patients than in the COPD − gcs patients, but not different from the levels measured in the controls. α1β-GR mRNA ratios did not differ between the groups and averaged 1·7, suggesting no inhibitory effect of the β-GR on the α1 form. MT2 levels were upregulated in the COPD + gcs patients as compared to the COPD − gcs group, indicating a pharmacological glucocorticoid effect.In the present study it is demonstrated that basal GR mRNA levels are lower in patients with COPD. Although this needs to be investigated further, this might explain, in part, the non-responsiveness of patients with COPD to gcs