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

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.

A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma

“…In two therapeutic studies, NCI-H295R, MUC-1 and TVBF-7 (as primary culture ACC115m) have been already implemented. Interestingly, independent from genetic status both metastatic models often shared rather less therapeutic responsiveness compared to NCI-H295R [27,29], a therapeutic phenotype which is already well known from further studies implementing MUC-1 [20][21][22][23]25,26,28]. It should be mentioned in this context that, in contrast to the primary derived chemo-naive NCI-H295R, both metastatic models were obtained from EDP-M treated patients [15,27].…”

“…MUC-1 was previously presented to be SF-1 and 3βHSD positive and mice bearing MUC-1 xenografts had increased plasma cortisol [15]. Meanwhile, MUC-1 has been implemented in a variety of preclinical ACC studies and demonstrated repeatedly a different response pattern and clinically frequently observed drug resistance phenotype compared to NCI-H295R [20][21][22][23][24][25][26][27][28][29].…”

An update on adrenocortical cell lines of human origin

“…com/). Recently published experiments on the chemokine axis and related tumor aggressiveness confirm differential regulations for CXCR4 and CXCL12 in NCI-H295R and MUC-1, which also suggest varying potential in terms of metastasization [34].…”

“…The model shows the for metastases frequently observed increased cellular plasticity, which can be e.g. seen in highly elevated drug tolerance for a wide range of chemotherapeutic, phytochemical, molecular targeted drugs and also combinatory regimens which is far beyond resistance against the originally applied EDP-M scheme [10,[27][28][29][30][31][32][33][34][35][36]. Recently, a broad comparative drug screen of clinically relevant chemotherapies and targeted therapies has been performed in NCI-H295R and MUC-1.…”

Bridging the Scientific Gaps to Identify Effective Treatments in Adrenocortical Cancer

“…This axis has recently been studied in ACC which showed that high CXCL12 expression correlated with improved DFS (81.9 vs 24.1 months, p = 0.01, PFS (81.9 months vs. 24.6 months, p = 0.01), and risk of recurrence or metastasis (HR 0.12, p = 0.04) [ 116 ]. In vitro and preclinical in vivo studies of this axis with rosiglitazone, known to inhibit the downstream signaling of CXCR4, caused the increased expression of CXCL12 in the tumor cells and decreased invasion [ 117 ]. This pathway is an important element of the TME that warrants further study and consideration as a target for clinical use.…”