Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma

Schweitzer, Sophie; Kunz, Meik; Kurlbaum, Max; Vey, Johannes A; Kendl, Sabine; Deutschbein, Timo; Hahner, Stefanie; Fassnacht, Martin; Dandekar, Thomas; Kroiß, Matthias

doi:10.1530/eje-18-0782

Cited by 72 publications

(74 citation statements)

References 28 publications

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“…Steroid hormones in cell culture supernatants of NCI-H295R and CU-ACC1 cells were quantified with the MassChrom steroids kit (Chromsystems) on a Qtrap 6500 + (Sciex) mass spectrometer coupled to a 1290 Infinity HPLC System (Agilent). Signal analysis was performed with Analyst Software (1.6.3, Sciex) as described elsewhere 61 .…”

Section: Lc-ms/ms Of Steroid Hormonesmentioning

confidence: 99%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an irondependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC 50 values of 5.7 × 10 −8 , 8.1 × 10 −7 and 2.1 × 10 −8 M, respectively, while all nonsteroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

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Section: Lc-ms/ms Of Steroid Hormonesmentioning

confidence: 99%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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“…Another useful tool would be using steroid profiling as an early diagnostic as well as prognostic marker. Initial data have been in favor of its use [71][72][73]; however, this tool is not prospectively validated, which limits its use in clinical practice. Based on the data we have regarding genetic markers in patients with ACC [41][42][43]74], using genetic profiling to predict recurrence risk is another important tool.…”

Section: Future Directionsmentioning

confidence: 99%

Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions

Bedrose

Daher

Altameemi

et al. 2020

Cancers

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Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with high risk of recurrence despite macroscopically complete surgical resection. The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index). Mitotane has been the mainstay adjuvant therapy of ACC. However, the use of mitotane is based on retrospective and occasionally conflicting evidence. As mitotane levels can take a few months before reaching therapeutic levels, there is an emerging practice of combining platinum-based chemotherapy with mitotane in the adjuvant setting. Retrospective data indicate that radiotherapy is an option for select patients, particularly those with positive resection margins. There are multiple knowledge gaps in selecting patients for adjuvant therapy. It is of great importance to establish risk calculators to predict recurrence and to implement molecular profiling of ACC to guide adjuvant therapy. The role of immunotherapy in metastatic ACC is emerging and if deemed efficacious, then future studies will be needed to ascertain the role of adjuvant immunotherapy in ACC.

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“…This so-called heterogeneity of steroidogenesis observed is a reflection of immature and dedifferentiated cell features, which are the hallmark of ACC [11,13,[15][16][17]. To our knowledge, no serum or urinary steroid metabolites associated with prognostic factors in ACC have been demonstrated to date, but several papers have reported these were useful for the diagnosis of ACC [11][12][13][14][15][16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, steroid profiling has emerged as a powerful novel diagnostic tool for ACC [11][12][13][14]. Previous reports demonstrated that examination of serum steroid metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) [12,13] or urine steroid metabolites using gas chromatography mass spectrometry (GC-MS) [15][16][17][18][19] are useful for distinguishing ACC from adrenocortical adenoma. Furthermore, the ENSAT recommends a biochemical workup for suspected ACC that includes serum cortisol, aldosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, and 17-beta-estradiol (http://www.ensat.org/page-1317312).…”

Section: Introductionmentioning

confidence: 99%

Steroid Metabolites for Diagnosing and Predicting Clinicopathological Features in Cortisol-Producing Adrenocortical Carcinoma.

Suzuki

Minamidate

Shiga

et al. 2020

Preprint

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About 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis which has been revealed to have particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or its urine metabolites, using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from adrenocortical adenoma. However, whether steroid metabolites can predict pathological characteristics or prognosis has not been elucidated. Here, we examined 12 serum steroid metabolites using immunoassay, which is a more rapid and less costly method compared to LC-MS/MS, in cortisol-producing ACC and cortisol-producing adenomas (CPA). Further, the correlation of each steroid metabolite to the stage classification and pathological status in ACC was analyzed. Reflected disorganized steroidogenesis, immunoassay revealed all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; especially 17- hydroxypregnenolone (androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed large area under ROC curve with high sensitivity and specificity, when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations to predictive prognostic factors of ENSAT classification, while testosterone showed significant positive correlations to Ki67-index in both men and women. In conclusion, measurement of serum steroid metabolites using immunoassay has great potential not only for diagnosis but also for prediction of the clinicopathological features associated with disease prognosis of ACC, as a simple non-invasive method.

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Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma

Cited by 72 publications

References 28 publications

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions

Steroid Metabolites for Diagnosing and Predicting Clinicopathological Features in Cortisol-Producing Adrenocortical Carcinoma.

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