Back to Search Start Over

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

Authors :
Massimo Mannelli
Maria Lucia Angelotti
Michela Francalanci
Letizia Canu
Constanze Hantel
Giulia Cantini
Stefania Gelmini
Gabriella Nesi
Tonino Ercolino
Mario Maggi
Michaela Luconi
Laura Fei
Giuseppina De Filpo
Monica Mangoni
Elena Lazzeri
Mariangela Sottili
University of Zurich
Luconi, Michaela
Source :
Journal of Personalized Medicine, Vol 11, Iss 1097, p 1097 (2021), Journal of Personalized Medicine, Volume 11, Issue 11
Publication Year :
2021

Abstract

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Journal of Personalized Medicine, Vol 11, Iss 1097, p 1097 (2021), Journal of Personalized Medicine, Volume 11, Issue 11
Accession number :
edsair.doi.dedup.....cda57db2250fd8c3f3af30772778a822