Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its co...

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Autores principales:	Giulia Cantini, Laura Fei, Letizia Canu, Elena Lazzeri, Mariangela Sottili, Michela Francalanci, Maria Lucia Angelotti, Giuseppina De Filpo, Tonino Ercolino, Stefania Gelmini, Monica Mangoni, Gabriella Nesi, Constanze Hantel, Massimo Mannelli, Mario Maggi, Michaela Luconi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chemokines rare cancers ACC xenograft cancer models anti-cancer therapy thiazolidinediones Medicine R
Acceso en línea:	https://doaj.org/article/814e9f34ad2c4aa8be3f47d9b86d050b
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spelling	oai:doaj.org-article:814e9f34ad2c4aa8be3f47d9b86d050b2021-11-25T18:07:08ZStimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression10.3390/jpm111110972075-4426https://doaj.org/article/814e9f34ad2c4aa8be3f47d9b86d050b2021-10-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1097https://doaj.org/toc/2075-4426Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors’ expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan–Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.Giulia CantiniLaura FeiLetizia CanuElena LazzeriMariangela SottiliMichela FrancalanciMaria Lucia AngelottiGiuseppina De FilpoTonino ErcolinoStefania GelminiMonica MangoniGabriella NesiConstanze HantelMassimo MannelliMario MaggiMichaela LuconiMDPI AGarticlechemokinesrare cancersACCxenograft cancer modelsanti-cancer therapythiazolidinedionesMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1097, p 1097 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chemokines rare cancers ACC xenograft cancer models anti-cancer therapy thiazolidinediones Medicine R
spellingShingle	chemokines rare cancers ACC xenograft cancer models anti-cancer therapy thiazolidinediones Medicine R Giulia Cantini Laura Fei Letizia Canu Elena Lazzeri Mariangela Sottili Michela Francalanci Maria Lucia Angelotti Giuseppina De Filpo Tonino Ercolino Stefania Gelmini Monica Mangoni Gabriella Nesi Constanze Hantel Massimo Mannelli Mario Maggi Michaela Luconi Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
description	Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors’ expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan–Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.
format	article
author	Giulia Cantini Laura Fei Letizia Canu Elena Lazzeri Mariangela Sottili Michela Francalanci Maria Lucia Angelotti Giuseppina De Filpo Tonino Ercolino Stefania Gelmini Monica Mangoni Gabriella Nesi Constanze Hantel Massimo Mannelli Mario Maggi Michaela Luconi
author_facet	Giulia Cantini Laura Fei Letizia Canu Elena Lazzeri Mariangela Sottili Michela Francalanci Maria Lucia Angelotti Giuseppina De Filpo Tonino Ercolino Stefania Gelmini Monica Mangoni Gabriella Nesi Constanze Hantel Massimo Mannelli Mario Maggi Michaela Luconi
author_sort	Giulia Cantini
title	Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
title_short	Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
title_full	Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
title_fullStr	Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
title_full_unstemmed	Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression
title_sort	stimulated expression of cxcl12 in adrenocortical carcinoma by the ppargamma ligand rosiglitazone impairs cancer progression
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/814e9f34ad2c4aa8be3f47d9b86d050b
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Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression

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