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Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC.

ABSTRACT: Preclinical evidence suggests that stromal expression of platelet-derived growth factor receptors (PDGFRs) stimulates tumor development and diminishes intratumoral drug uptake. In non-small cell lung cancer (NSCLC), the clinical relevance of stromal PDGFR expression remains uncertain. Tumor specimens from 553 patients with primary operable stage I-IIIB NSCLC was obtained and tissue micro-arrays (TMA) were constructed (Norwegian cohort). Immunohistochemistry (IHC) was used to evaluate the expression of PDGFR? and -? in stromal cells and to explore their impact on patient survival. Results were validated in a non-related cohort consisting of TMAs of 367 stage I (A and B) NSCLC patients (Swedish cohort). High stromal PDGFR? expression was an independent predictor of increased survival in the overall populations and SCC (squamous cell carcinoma) subgroups of both investigated cohorts. PDGFR? was an independent predictor of poor survival in the overall Norwegian cohort and an independent predictor of increased survival in the ADC (adenocarcinoma) subgroup of the Swedish cohort. Tumors displaying the combination PDGFR?-low/PDGFR?-high exhibited inferior survival according to increasing stage in the Norwegian cohort. This study confirms that high stromal expression of PDGFR? is a predictor of increased survival in NSCLC. Further exploration of the prognostic impact of PDGFR? and the relationship between PDGFR? and -? is warranted.

SUBMITTER: Kilvaer TK

PROVIDER: S-EPMC6629689 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC.

Kilvaer Thomas Karsten TK Rakaee Mehrdad M Hellevik Turid T Vik Jørg J Petris Luigi De L Donnem Tom T Strell Carina C Ostman Arne A Busund Lill-Tove Rasmussen LR Martinez-Zubiaurre Inigo I

Scientific reports 20190715 1

Preclinical evidence suggests that stromal expression of platelet-derived growth factor receptors (PDGFRs) stimulates tumor development and diminishes intratumoral drug uptake. In non-small cell lung cancer (NSCLC), the clinical relevance of stromal PDGFR expression remains uncertain. Tumor specimens from 553 patients with primary operable stage I-IIIB NSCLC was obtained and tissue micro-arrays (TMA) were constructed (Norwegian cohort). Immunohistochemistry (IHC) was used to evaluate the express ...[more]

PMID: 31308421

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Project description:Although the importance of platelet-derived growth factor receptor (PDGFR)-? signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-?-expressing cells induce ? smooth muscle actin (?-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-? activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-? signaling in differentiation of myofibroblasts from PDGFR-?-positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-? signaling was activated by administration of rosiglitazone. Changes in ?-SMA and PDGFR-? protein expression were assessed in PDGFR-?-green fluorescent protein (GFP) reporter mice using immunohistochemistry, flow cytometry, and real-time PCR. Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of PDGFR-?-GFP changed dynamically during alveolar regeneration and that ?-SMA expression was induced in a subset of PDGFR-?-GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of ?-SMA in PDGFR-?-positive fibroblasts and formation of new septae. Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy, and results demonstrated that inhibition of FGFR2 signaling and increase in PPAR-? signaling altered the expression of Shh, FGF, Wnt, and Bmp4, genes that are also important for epithelial-mesenchymal crosstalk during early lung development. Our data demonstrate for the first time that a comparable epithelial-mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation.

Dataset Information

Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC.

Publications

Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC.

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