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During epithelial-mesenchymal transition (EMT) epithelial cancer cells transdifferentiate into highly motile, invasive, mesenchymal-like cells, giving rise to disseminating tumor cells. Few of these disseminated cells successfully metastasize. Immune cells and inflammation in the tumor microenvironment were shown to drive EMT, but few studies investigated the consequences of EMT for tumor immunosurveillance. In addition to initiating metastasis, we demonstrate that EMT confers increased susceptibility to natural killer (NK) cells and contributes, in part, to the inefficiency of the metastatic process. Depletion of NK cells allowed spontaneous metastasis without affecting primary tumor growth. EMT-induced modulation of E-cadherin and cell adhesion molecule 1 (CADM1) mediated increased susceptibility to NK cytotoxicity. Higher CADM1 expression correlates with improved patient survival in 2 lung and 1 breast adenocarcinoma patient cohorts and decreased metastasis. Our observations reveal a novel NK-mediated, metastasis-specific immunosurveillance in lung cancer and present a window of opportunity for preventing metastasis by boosting NK cell activity., Introduction Significant progress has been made in determining and defining the key regulators of immunosurveillance in primary tumors, wherein the balance of protumor and antitumor responses dictates tumor progression. Targeting [...]

Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR-[gamma] as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-[gamma] in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-[gamma] agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-[gamma] agonists, including a constitutively active PPAR-[gamma] construct (VP16-PPAR-[gamma]), inhibit the ability of transforming growth factor-[beta]1 to induce myofibroblast differentiation and collagen secretion. PPAR-[gamma] agonists also inhibit fibrosis in a routine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR-[gamma] is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-[gamma] ligands as novel therapeutic agents for fibrotic lung diseases. troglitazone; ciglitazone; transforming growth factor

Peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]), a member of the nuclear hormone receptor family of ligand-dependent transcription factors, is a critical regulator of adipocyte differentiation and glucose metabolism. The expression, regulation, and functional significance of PPAR-[gamma] in alveolar macrophages (AMs), the predominant resident immune effector cell within the alveolus, have not been previously examined. In this study, we show that, in contrast to peritoneal macrophages, resident murine AMs constitutively express high levels of PPAR-[gamma]. Expression was primarily located in the nucleus by immunofluorescence staining. Quantitative real-time RT-PCR demonstrated that the predominant isoform was PPAR-[gamma]2. Expression of PPAR-[gamma] was induced by the anti-inflammatory cytokine IL-4. Treatment of murine AMs with PPAR-[gamma] ligands suppresses PMA-stimulated oxidative burst activity and LPS + IFN-[gamma]-mediated expression of inducible nitric oxide synthase. In addition, LPS-induced IL-12 mRNA and protein expression was inhibited by PPAR-[gamma] ligands. These results support an important immunomodulatory role for PPAR-[gamma] in AM responses. 15-deoxy-[[DELTA].sup.2,14]-prostaglandin [J.sub.2]; rosiglitazone; peroxisome proliferator-activated receptor-[gamma]2

Original citation: J Clin Invest. 2005;115(10):2801-2810. https://doi.org/10.1172/JCI24813. Citation for this retraction: J Clin Invest. 2020;130(1):552. https://doi.org/10.1172/JCI135305. The Office of Research Integrity recently notified the JCI of falsified data reported in [...]

Background: Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population.Methods: We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs.Results: The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-β-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines' metastatic ability.Conclusions: The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further exploration of the biological potential of metastatic and presumably non-metastatic CTCs captured using the microfluidic chip will yield insights into their relevant differences and their effects on tumor progression and cancer outcomes. [ABSTRACT FROM AUTHOR]