SUN-335 The Chemokine Receptor 4 (CXCR4) Plays an Important Role in Adrenocortical Carcinoma Cell Proliferation

Abstract

Backgrounds : Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal cortex with adverse clinical outcome. Patients with unresectable disease require systemic adjuvant chemotherapy and mitotane treatment, but these regimens only have a limited efficacy for the great majority of patients. Therefore, an identification of the new therapeutic targets is urgently needed. C-X-C chemokine receptor type 4 (CXCR4) and macrophage migration inhibitory factor (MIF) were recently reported to be expressed in various human malignancies and targeting the MIF-CXCR4 axis has come to be considered a new therapeutic option to cancers. CXCR4 has also been reported to be highly expressed both in normal human adrenals and in ACC (1)(2). However, its function and clinical significance in ACC have remained largely unknown. Of particular interest, MIF was reported to be released upon glucocorticoid stimulation and act as a counter-regulator of glucocorticoid (3). Therefore, in this study, we attempted to clarify the biological significance of the MIF-CXCR4 axis in ACC in association with glucocorticoid hypersecretion. Methods : CXCR4, MIF, Ki-67, γH2AX which represents double-strand DNA breaks and glucocorticoid synthesis enzymes (3βHSD2, c17 and CYP11B1) were immunolocalized in 10 ACC cases resected at Tohoku University Hospital from 2010 to 2017. The immunoreactivity was evaluated using H-score, which consists of a sum of the percentages of positive cells multiplied by the relative immunointensity of positive cells (0, +1, +2, +3). As for Ki-67 and γH2AX, labeling index (LI in percent) was obtained. In addition, ACC cell line NCI-H295R was used to evaluate the effect of CXCR4 antagonist AMD3100 in cellular proliferation and cellular migration in vitro. Results : CXCR4 H-score was significantly correlated with Ki-67 LI [ρ=0.6485 (p=0.0425)]. Significant correlation was also detected between CXCR4 and γH2AX as well as between MIF and γH2AX [ρ=0.7455 (p=0.0133), ρ=0.7455 (p=0.0133), respectively]. No significant correlation was detected among CXCR4, MIF and steroidogenic enzymes. CXCR4 inhibitor AMD3100 significantly inhibited cell proliferation of H295R at a dose of 100 μg/ml (p=0.0099). Migration was significantly decreased by AMD3100 at a dose of 1, 10, and 100 μg/ml (p=0.0472, p=0.0465, p=0.0479, respectively). Conclusion : Results of our present present study did firstly demonstrate that CXCR4 played an important role in ACC proliferation and migration. In addition, the status of CXCR4 and MIF was also considered to be related to DNA damage. We will report the results with additional ACC cases and potential effects of MIF inhibitor as well. Reference : (1) Heinze B, et al. Hypertinsion. 2018 71(2):317-325. (2) Ido D. Weiss, et al. Oncotarget 2018 9(77):34641. (3) Vignjevic Petrinovic S, et al. Histochem Cell Biol. 2016 146(3):311-24.

Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma

“…The correlation between CXCR4 and Ki67 at membrane level suggests that the activated form of the chemokine receptor is preferentially upregulated in highly proliferative ACCs, that are known to have a dismal prognosis even after complete resection (41). Effectively blocking CXCR4 might therefore interfere with tumor growth and metastasis in ACC in vivo, as also highlighted by the inhibitory effect of the CXCR4 antagonist AMD3100 on the proliferation and migration of the human ACC cell line NCI-H295 reported by Kitawaki et al (42).…”