Decreased peroxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer

Department of Surgery II, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Lung Cancer (Impact Factor: 3.96). 04/2002; 36(1):71-6. DOI: 10.1016/S0169-5002(01)00449-4
Source: PubMed


Activation of the nuclear hormone receptor perioxisome proliferator-activated receptor gamma (PPARgamma) inhibits cell growth and induces apoptosis in several human cancers. We have hypothesized that PPARgamma mRNA levels could be predictors of the differentiation and survival of lung cancer. The study included 77 lung cancer cases. The mRNA levels were quantified by real time reverse transcription-polymerase chain reaction (RT-PCR) using LightCycler. The PPARgamma mRNA levels were decreased in tumor tissues from lung cancer (0.579 +/- 1.255) compared to the normal adjacent lung tissues (4.191 +/- 2.868) (P = 0.0001). No significant difference in PPARgamma mRNA levels was found among gender, age, and pathological subtype. The PPARgamma mRNA levels were higher in tumor tissues from higher differentiated lung cancer. The NSCLC patients with low PPARgamma mRNA expression (< 0.5) had significantly worse survival than the patients without low PPARgamma mRNA levels (P = 0.0438, Breslow-Gehan-Wilcoxon test; P = 0.0168, Cox's proportional-Hazards regression model). Thus, PPARgamma mRNA levels may serve as a prognostic marker in lung cancer. Using the LightCycler RT-PCR assay, the determination of PPARgamma mRNA levels might provide a potential marker for treatment of lung cancer by PPARgamma agonist. However, further studies and a longer follow up are needed to confirm the impact of PPARgamma in the biological behavior of the tumor.

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    • "PPARγ is a potent transcription factor, which has roles in suppressing inflammatory and immune responses,109 as well as directing the differentiation of adipocytes. Low PPARγ in NSCLC has also been correlated with poor prognosis.110 Additionally, a large trial looking at patients across ten Veterans Affairs medical centers compared patients using thiazolidinediones (which are ligands for PPARγ activation) to those who were not on the drug. "
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    ABSTRACT: Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer.
    Full-text · Article · Apr 2013 · Pharmacogenomics and Personalized Medicine
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    • "TZDs inhibit the growth of colon cancer cell lines in vitro [26] [27] [28] and in xenograft models [29] as well as growth of breast cancer [30] [31] [32] and prostate cancer cells [33] [34] [35]. In lung cancer, decreased expression of PPARγ was correlated with poor prognosis in samples from human lung tumors [36]. Genetic variants in the PPARγ gene have also been identified that are associated with a decreased risk for lung cancer [37]. "
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    ABSTRACT: Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARγ include naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARγ in a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARγ has been reported to be protumorigenic in some in vitro systems and in vivo models. Here, we review the available data that implicate PPARγ in lung carcinogenesis and highlight the challenges of targeting PPARγ in lung cancer treatments.
    Full-text · Article · Aug 2012 · PPAR Research
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    • "Recently, however, PPARγ has also been implicated in regulating multiple types of cancer, including lung cancer. Analysis of human lung tumors has reported that decreased expression of PPARγ is correlated with a poor prognosis [8]. Importantly, a retrospective study examining cancer incidence in diabetic patients using TZDs demonstrated a 33% reduction in lung cancer risk [9], with an even more dramatic reduction in African-American diabetic patients (75%). "
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    ABSTRACT: 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 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 PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγ(flox/flox) mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Mac(neg)), or control PPARγ(flox/flox) mice. In both models, mice receiving PPARγ-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 PPARγ 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.
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