Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Antonelli, Alessandro; Ferrari, Silvia; Fallahi, Poupak; Frascerra, Silvia; Piaggi, Simona; Gelmini, Stefania; Lupi, Cristiana; Minuto, Michele; Berti, Piero; Benvenga, Salvatore; Basolo, Fulvio; Orlando, Claudio; Miccoli, Paolo

doi:10.1677/erc-08-0337

Cited by 75 publications

(62 citation statements)

References 43 publications

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“…Antonelli and colleagues have reported that patients with autoimmune thyroiditis and Grave disease have elevated serum levels of CXCR3 ligands and that primary thyrocytes can be stimulated to secrete CXCL11 after treatment with IFNa, b, and g (31, 32). Moreover, it has been shown that PTC cells are more prone to secrete CXCL10 than normal thyroid follicular cells upon stimulation with IFNg (33). We show that ATC cells secrete significantly higher levels of CXCL10 than PTC cells after stimulation with minute doses of IFNg.…”

Section: Discussionmentioning

confidence: 55%

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Wennerberg

Pfefferle

Ekblad

et al. 2014

Clinical Cancer Research

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Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.Experimental Design: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.Results: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.Conclusions: ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy. Clin Cancer Res; 20(22); 5733-44. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 55%

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Wennerberg

Pfefferle

Ekblad

et al. 2014

Clinical Cancer Research

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“…In addition, besides type I and Type II interferons which were previously shown to inhibit the secretion of CXCL8 [13,15], other potentially interesting molecules to be tested for their CXCL8 inhibiting effects could include PPAR-c agonists. This appears to be supported by the evidences provided by Antonelli et al who reported that PPAR-c agonists display antineoplastic activity [25,26] and inhibit the secretion of several chemokines in primary cultures of thyroid cancer cells [27,28]. With specific regards to CXCL8, pioglitazone (a potent PPAR-c agonist) was demonstrated to inhibit the TNF-a induced CXCL8 secretion in endometriotic stromal cells [29] and to suppress CXCL8 mRNA expression in pancreatic cancer cell lines [30].…”

Section: Discussionmentioning

confidence: 66%

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

et al. 2015

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CXCL8 is secreted by both normal human thyrocytes (NHT) and thyroid cancer cell lines. CXCL8 displays several tumor-promoting effects and recent evidences indicate that its concentrations within the tumor microenvironment can impact the clinical course of the malignancy. Aim of this study was to compare the basal secretion of CXCL8 among NHT and thyroid cancer cell lines (TPC-1 and BCPAP), and to assess the specific cell response to TNF-α in terms of CXCL8 secretion. NHT primary cultures, TPC-1 and BCPAP cell lines were cultured with or without TNF-α (0, 0.1, 1, 10, and 100 ng/ml). CXCL8 levels were measured in the cell supernatants after 24 h. In basal condition, significant differences in the mean levels of CXCL8 were observed among the three cell types: NHT (110.5 ± 56.2 pg/ml), TPC1 (467.4 ± 43.2 pg/ml), and BCPAP (1731.8 ± 493.3 pg/ml), (F = 35.06; p < 0.0001). TNF-α significantly and in a dose-response manner induced CXCL8 secretion in NHT (F = 25.53; p < 0.00001), TPC-1 (F = 13.38; p < 0.0001), and BCPAP (F = 9.88; p < 0.001) cells. The magnitude of the TNF-α effect (fold-increase vs. basal level of CXCL8) differed significantly among the three cell types (F = 10.47; p < 0.0001). BCPAP were identified as the cells showing the highest basal secretion of CXCL8 and the less responsive to TNF-α. NHT, TPC-1, and BCPAP display significant differences in the secretion of both basal and TNF-α-induced CXCL8 secretion. These results indicate that the mechanisms regulating the secretion of CXCL8 differ in tumor cells harboring different genetic alterations suggesting that specific strategies aimed at inhibiting CXCL8 secretion will be required.

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“…However, the relative potency of PPARa agonists on the inhibition of the secretion of CXC chemokine is higher than that of PPARg ligands. This could suggest that PPARa agonists may act, at least in part, through different pathways than PPARg agonists (Marx et al 2000, Schaefer et al 2005, Lombardi et al 2008, Antonelli et al 2009b.…”

Section: Discussionmentioning

confidence: 99%

β (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy

Antonelli

Ferrari²,

Frascerra³

et al. 2012

Journal of Endocrinology

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No data are present in the literature about the effect of cytokines on the prototype b chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor a (PPARa (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon g (IFNg (IFNG)) and tumor necrosis factor a (TNFa) on CCL2, and for comparison on the prototype a chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARa activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNg alone, or in combination with TNFa, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNg and TNFa also stimulated CXCL10 chemokine secretion as expected. The presence of PPARa and PPARg (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARa activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARg activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARa activators were stronger inhibitors of chemokine secretions than PPARg agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNg and TNFa in GO. PPARa activators inhibit the secretion of the main prototype a (CXCL10) and b (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARa may be involved in the modulation of the immune response in GO.

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Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Cited by 75 publications

References 43 publications

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

β (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy

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