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

Giulia Cantini,Letizia Canu,Constanze Hantel,Stefania Gelmini,Gabriella Nesi,Michaela Luconi,Giuseppina De Filpo,Maria Lucia Angelotti,Mariangela Sottili,Elena Lazzeri,Massimo Mannelli,Monica Mangoni,Laura Fei,Mario Maggi,Tonino Ercolino,Michela Francalanci

doi:10.3390/jpm11111097

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.

Highlights

Introduction conditions of the Creative CommonsAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the steroidogenic component of the adrenal gland
The differential quantitative expression of the CXCR4/CXCR7 receptors and their ligand CXCL12 was evident between the tumor samples from a pilot cohort of n = 22 ACC
The ACC expressed one-log-unit higher levels of CXCR4 and CXCR7 compared to the normal adrenals, whereas CXCL12 was expressed at higher levels in the normal adrenals than in the ACCs (Figure 1A)

Summary

Introduction

Introduction conditions of the Creative CommonsAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the steroidogenic component of the adrenal gland. The risk of short-term recurrence is high, leading to a mortality rate of up to 80% in metastatic ACC at 5 years from surgery [3]. Specific and effective anti-cancer therapies are urgently needed to target the metastatic progression of this tumor. The chemokine axis between the C-X-C motif chemokine 12 (CXCL12) ligand and its two receptors, C-X-C-Motif-Chemokine-Receptor (CXCR)-4 (CXCR4) and -7 (CXCR7), is actively involved in controlling the metastatic process of several solid tumors [4]. High levels of CXCL12 are expressed at common sites of cancer metastasis, such as lung, liver, and bone, and the occurrence of the gradients of this chemokine prompts local invasion and subsequent homing from the primary tumor [5] to the secondary sites of metastasis [4]

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