Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

Abstract

In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.

Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo

“…As shown in Figure c , Patched is also strongly expressed in the ACC cell line H295R which was initially isolated from a patient diagnosed with ACC . Interestingly, Patched expression was found to be significantly lower in the MUC‐1 cell line which had recently been established from an ACC metastasis obtained from a patient with a primary diagnosis of ACC …”

Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

“…and maintained as suggested. MUC-1 cells were kindly given by Dr. Hantel and were maintained according to [37]. Media and supplements were supplied by Sigma Aldrich Italia, (Milano, Italy).…”

“…The SW13 cell line was established from a small cell carcinoma in the adrenal cortex, but its histopathologic characteristics are still under investigation [40]. Finally, MUC-1 cells were derived from a neck metastasis of an EDP-M treated patient [37].…”

“…Primary ACC cultures were obtained according to the previously published procedure [41]. The adrenal origin of primary cells was confirmed by the positivity to the steroidogenic factor 1 gene expression [37,42].…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…The most widely used cell line for xenograft experiments is H295R (Logié et al 2000), even if the recently described SJ-ACC3 (only growing as xenografts; Pinto et al 2013) and MUC-1 (xenografts and cell line; Hantel et al 2016) hold promise to enlarge the representation of the spectrum of heterogeneity present in human tumors. We need to underline here that the SW-13 cell line that has been used in several studies, derived from a metastasis of a small cell carcinoma in the adrenal cortex, does NOT express markers of adrenocortical differentiation and as such is not a valid model for human ACC.…”