Dataset Information

Activation of PPAR? in myeloid cells promotes lung cancer progression and metastasis.

ABSTRACT: Activation of peroxisome proliferator-activated receptor-? (PPAR?) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPAR? is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPAR? in the macrophages. To assess the contribution of PPAR? in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPAR?(flox/flox) mice, in which PPAR? is deleted specifically in myeloid cells (PPAR?-Mac(neg)), or control PPAR?(flox/flox) mice. In both models, mice receiving PPAR?-Mac(neg) bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPAR? may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells.

SUBMITTER: Li H

PROVIDER: S-EPMC3228753 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis.

Li Howard H Sorenson Amber L AL Poczobutt Joanna J Amin Jay J Joyal Teresa T Sullivan Timothy T Crossno Joseph T JT Weiser-Evans Mary C M MC Nemenoff Raphael A RA

PloS one 20111201 12

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an or ...[more]

PMID: 22145026

Similar Datasets

Project description:Emerging evidence shows that signal transducer and activator of transcription 6 (STAT6) plays critical roles in tumor development. We previously found high-level expression of STAT6 in human lung adenocarcinoma and squamous cell carcinoma, specifically in infiltrated immune cells located in the lung interstitium. Nevertheless, the role of STAT6 signaling in lung carcinogenesis and lung cancer proliferation and its underlying mechanisms remain unclear. This study aimed to investigate the role of STAT6 and the interaction between STAT6 and the tumor microenvironment in pulmonary tumorigenesis. We established a murine model of primary lung carcinogenesis in STAT6-deficient (STAT6-/-) and STAT6 wild-type (WT) BALB/c mice using the carcinogen urethane. Two-month-old male mice were intraperitoneally injected with urethane (1 g/kg) dissolved in phosphate buffered saline (PBS). Primary tumors were monitored in vivo by positron emission tomography scanning. At 4, 6, and 9 months after urethane injection, lung tumors were harvested from the STAT6-/- and WT mice for analysis. Small interfering RNA was used to downregulate the expression of STAT6 in tumor cells. Fluorescence activated cell sorting analysis was used to analyze fluorescence-conjugated cell markers. Transwell assays were used in coculturing experiments. STAT6 protein expression was detected by Western blotting, immunohistochemistry, and immunofluorescence. STAT6 mRNA expression was detected by quantitative real time-polymerase chain reaction. Cell Counting Kit-8 and colony formation assays were performed to evaluate cell proliferation. We detected high expression of STAT6 in CD11b+ cells of lung carcinoma. Our results indicate that STAT6 deficiency inhibits carcinogen-induced tumor growth and improves prognosis. STAT6 deficiency also decreased the mobilization and differentiation of CD11b+ cells. STAT6 deficiency in CD11b+ cells but not tumor cells decreased interleukin (IL)-4 secretion and the differentiation of CD11b+ cells into M2 macrophage cells. In conclusion, our findings indicate that IL-4/STAT6 signaling in CD11b+ cells promotes lung cancer progression by triggering an IL-4 positive feedback loop and increasing M2 myeloid cells. STAT6 may be a new therapeutic target for the prevention and treatment of lung cancer.

Dataset Information

Activation of PPAR? in myeloid cells promotes lung cancer progression and metastasis.

Publications

Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets