Next Article in Journal
Prognostic Value of [18F]FDG PET Radiomics to Detect Peritoneal and Distant Metastases in Locally Advanced Gastric Cancer—A Side Study of the Prospective Multicentre PLASTIC Study
Next Article in Special Issue
The Role of Microbiota in Pancreatic Cancer
Previous Article in Journal
Calcium Homeostasis in the Development of Resistant Breast Tumors
Previous Article in Special Issue
The MAL Family of Proteins: Normal Function, Expression in Cancer, and Potential Use as Cancer Biomarkers
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 11
10.3390/cancers15112873
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Preclinical Models of Adrenocortical Cancer

by
Andrew J. H. Sedlack
1,
Samual J. Hatfield
2,
Suresh Kumar
3,
Yasuhiro Arakawa
3,
Nitin Roper
3,
Nai-Yun Sun
3,
Naris Nilubol
4,
Katja Kiseljak-Vassiliades
5,
Chuong D. Hoang
6,
Emily K. Bergsland
7,
Jonathan M. Hernandez
4,
Yves Pommier
3 and
Jaydira del Rivero
3,*
1
Medical Scientist Training Program, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
2
Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
3
Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
4
Surgical Oncology Program National Cancer Institute, NIH, Bethesda, MD 20892, USA
5
Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO 80016, USA
6
Thoracic Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
7
University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(11), 2873; https://doi.org/10.3390/cancers15112873
Submission received: 13 April 2023 / Revised: 14 May 2023 / Accepted: 15 May 2023 / Published: 23 May 2023
(This article belongs to the Special Issue Advanced Research in Oncology in 2023)
Review Reports Versions Notes

Abstract

:

Simple Summary

Adrenocortical cancer is a very rare form of endocrine cancer with dismal prognosis. Preclinical models such as cell lines, organoids, and mouse models are essential for both improving basic understanding of this disease and developing treatments. Herein, we review a currently available model for adrenocortical cancers, with a special focus on adrenocortical carcinoma. Recent developments in in vitro models have included cell and 3D culture models with improved recapitulation of the tumor microenvironment and genetics. We hope to improve visibility and access to these models through this review.

Abstract

Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area.

1. Introduction

Cancers of the adrenal gland, such as adrenocortical carcinoma (ACC), require a unique approach in treatment, diagnosis, and research, owing to their rarity and the multifunctional environment of the adrenal gland. The adrenal gland comprises two embryologically distinct regions: the medulla and the cortex [1]. Within the medulla, chromaffin cells serve the neuroendocrine function of manufacturing epinephrine (adrenaline), a core stimulant of the fight-or-flight response [1,2]. Tumors of chromaffin cells (pheochromocytomas) are often present with classic symptoms of hypertension, headache, and syncope with an incidence rate of 0.04 to 0.95 per 100,000 [3,4,5]. Within the cortex, three distinct zones are present, the zona glomerulosa, zona fasciculata, and zona reticularis; these zones are responsible for manufacturing steroid-based mineralocorticoids, glucocorticoids, and androgens, respectively [6]. Broadly, tumors of the adrenal cortex may be divided into adenomas and carcinomas [7].
Adrenocortical adenoma (ACA) is a benign neoplasm originating from the secretory cells of the adrenal gland, with an incidence of 425 per 100,000 and accounting for 33% to 96% of aberrant adrenal incidentalomas, although this may be an underestimate [8,9,10]. While 85% of ACAs are non-secretory, a subset of ACA may be associated with autonomous glucocorticoid and mineralocorticoid stimulation, and rarely androgen secretion [8,11]. The most common clinical presentation for ACA is autonomous cortisol secretion (Cushing’s syndrome), which presents with symptoms of hypertension, insulin resistance, and obesity, and is associated with increased mortality [7]. Cushing’s occurs in 3.8% to 6.6% of patients with ACA, with a 14.3% risk of developing Cushing’s if the adenoma is >2.4 cm, compared to 3.8% for those <2.4 cm [12,13].
ACC is a malignant neoplasm originating from the adrenal cortex [14]. In contrast to the relatively high prevalence of ACA, ACCs may be classified as an ultra-rare disorder, with an incidence of 0.72 to 1.02 per million people/year [15,16,17,18,19]. The prognosis for patients with ACC is poor, with a median 5 year survival rate of 22% and a 10 year survival rate of <5%, accounting for 0.2% of all cancer deaths [14,20]. In 40 to 60 percent of cases, patients with ACC present a chief complaint associated with hormone excess, such as Cushing’s syndrome, gynecomastia, or virilization in women [21,22]. The most common hormonal findings are excess cortisol alone, cortisol paired with androgens, androgens alone, or cortisol paired with an additional cortical hormone, and very rarely mineralocorticoid or estrogen excess [21].
A key identifying feature of ACC which differentiates it from secretory ACA is the identification of secretion from two adrenal zones [7]. ACC is often an aggressive and rapidly proliferative disease. While more than 90% of ACC presents >4 cm, ACC only makes up 10–50% of adrenal masses >4 cm [23,24,25,26,27]. Due to their size, approximately 30% of ACC presents with symptoms associated with tumor mass, such as abdominal or flank pain [23]. The most common sites of metastasis are the liver and lungs, followed by peritoneum, bone, and brain, with half of all patients developing metastasis to multiple organs or sites [28,29].
While ACC is rare, there is an increased prevalence of ACC in cancer predisposition syndromes. The Li Fraumeni syndrome (LFS) is a syndrome resulting from an autosomal dominant variant in the TP53 gene—a gene coding for the tumor suppressor p53—which drastically predisposes toward malignancy [30]. Among patients with LFS, between three and ten percent present with ACC, suggesting a strong influence of germline TP53 mutation on ACC risk [31,32]. Similarly, the low penetrance alleles of TP53 have been implicated in a high incidence of childhood ACC, with TP53 being the underlying genetic cause in 50–80% of childhood ACC [33,34]. In Brazil, a familial low-penetrance (9.9%) TP53 variant (R337H) contributes to increased ACC development, resulting in the incidence of ACC being nearly 3 to 4 times the global rate at 0.29 to 0.42 per 100,000 [35].
In addition to TP53 variants, ACC is associated with other syndromes. In the case of Beckwith–Weidemann syndrome (BWS)—the most common congenital growth disorder (11p15.5)—resultant tumors may occur within the adrenal cortex, with ACC accounting for 5–15% of tumors in children with BWS [36,37,38]. ACC is also at an increased prevalence in patients with Lynch syndrome, Werner syndrome, and congenital adrenal hyperplasia [39]. Overall, understanding the connection between ACCs and other hereditary diseases has been vital in elucidating the mechanisms of tumorigenesis. However, due to its rarity and poor prognosis, the development of new models of ACC is essential if we are to further explore routes of early diagnosis and therapeutic intervention.
Current preclinical research models for ACC are limited. There are currently 12 available ACC cell lines (8 human, 4 murine) originating from human ACC (see Table 1) and 6 widely reported primary cultures of human ACC (see Table 2) [40]. Cell culture is often in the form of monolayer or suspension, both of which are relatively cost-efficient and provide relatively reproducible results due to their culture in ideal conditions [41]. Despite their value, neither method adequately replicates the tumor microenvironment (TME). Monolayers have demonstrated impaired cytoskeletal activity and lack cellular diversity, while suspensions do not possess adequate extracellular support [41]. Pre-clinical mouse models of ACC, which more closely capture the tumor microenvironment, have been generated; however, they are also limited. Cell line-derived xenografts (CDXs) are established using cell culture that is subcutaneously administered to immunocompromised mice for localized propagation and in vivo tumor growth [42]. Patient-derived xenografts (PDXs) are generated using tumor fragments from human tissue collected during surgical resection and then directly implanted into immunocompromised mice and are further propagated across generational passages [42]. Both CDXs and PDXs present the ability to observe in vivo human tumor progression; however, there are limitations. CDXs present with atypical histologic findings and poorer chromosomal maintenance when compared to PDXs. PDXs are limited by the supply of viable grafts, complex passaging techniques, and issues associated with clinically relevant dosing [42,43]. There are multiple transgenic mouse models as well, which focus on the manipulation of different growth factors and signaling molecules to produce an ACC-like phenotype. While there are many models present, transgenic mouse models are usually limited to one or two genetic modifications that might only partially recapitulate the heterogeneity of human disease.
This review summarizes the currently used cell line and xenograft models of ACC, which have provided valuable insights into the pathogenesis and natural history of human ACCs. We focused especially on elaborating the details of more in vitro models than current mouse models, although all types of models are included for the completeness of the survey. Newer and more accurate models of ACC are critical to furthering the early detection and targeted treatment of this disease, and a holistic understanding of current models and their advantages and deficiencies is the first step to designing better ones.

2. Results

2.1. Cell Lines

Cell lines are summarized in Table 1. Notable primary cultures are summarized in Table 2. The earliest derived ACC cell line for continuous culture was Y-1, initially transplanted from an Itgal−/− mouse line, and noted for their continuous production of progesterone derivates from cholesterol [44]. The other major mouse lines, ATC1 and ATC7, were generated from tumors in transgenic mice with SV40-Tag added under the AKR1B7 promoter. The ATC1 and ATC7 lines have been mostly used in basic endocrine research toward understanding the patterning of and hormonal crosstalk within the adrenal cortex. They have also been used for some therapeutic target discovery, focusing on HOX genes with them [66,67,68].
For decades, the only continuous ACC cell lines available were SW-13 and H295, the latter of which is notable for its sustained steroid secretion even after decades of culture [49,56]. On the other hand, the current consensus is that SW-13, which never produced steroids in culture, is probably derived from a small cell lung cancer metastasis to the adrenal gland, and hence it has fallen out of use in modeling ACC [69,70]. While many more cell lines have been introduced in recent years, H295R remains the most available and heavily used line in current preclinical research [71,72]. In recent years, perhaps not surprising due to its age and passage number, the reproducibility of results across different clones of H295R has been called into question, emphasizing the need not only for new models, but also for avoiding overpassaging models [55]. The ACC HAC15 cell line, first reported in 2008, was later shown to be a subclone of H295R, which had presumably contaminated the attempted culture of a new line [70,73]. Other concerns with H295R cells include their lack of response to ACTH stimulation, which has been attributed to their low expression of its receptor, the melanocortin 2 receptor (MC2R). To remedy this, Nanba et al. used lentiviral particles to introduce the open reading frame of a protein necessary for the surface trafficking of MC2R, the MC2R accessory protein, into H295R cells, generating a strain termed H295RA with the inducible production of 11-deoxycortisol, cortisol, and androstenedione [74].
Excitingly, several more ACC lines have been reported in the last few years, including MUC-1 cell lines in 2016, and CU-ACC1 and CU-ACC2 in 2018 (all three with companion PDX lines for comparison) [55,56]. Recent work has also depended much on primary culture, with more than 40 primary ACC cultures isolated in the last seven years [75,76]. While these cultures have been shared extensively, only the ACC115m clone has been sufficiently immortalized for use as a cell line (now reported as TVBF-7) [40,65]. Hence, H295R remains the only widely available ACC cell line in repositories. Quantitative measures (such as RNA sequencing) of how cell type and function changes in and between models such as tissue culture and PDX vs. in primary tumors are improving, although detailed breakdowns of what changes in particular are present have not yet been developed [56].
Warde et al. recently showed that mitotane sensitivity correlates with intracellular lipid content; while MUC-1 and H295R cells store similar amounts of intracellular lipid droplets, MUC-1 (mitotane resistant) cells are rich in triacylglycerols, whereas H295R (mitotane sensitive) cells are rich in cholesterol esters [77]. Lipid content as measured by Hounsfield units is used in some diagnostic algorithms for ACC; however, these results show that further distinguishing the particular lipids involved may provide more useful clinical information [78,79]. Further investigation of lipid compositions of cell lines may be valuable and can potentially inform the inclusion of such analysis in the future analyses of biopsy and surgical samples to inform the precise treatment of ACC. Recent investigations have also shown crosstalk between adipose stem cells and H295R cells, reinforcing the importance of local lipid metabolism in ACC [80].

2.2. Xenografts

While patient-derived xenografts (PDXs) of samples acquired directly from biopsy or surgery into immunodeficient mice are typically recognized as the gold standard for human cancer models, limited PDXs of ACC are available [81,82]. Hence, here, we have included cell line-derived xenograft (CDX) models, which are summarized in Table 3, while PDXs are summarized in Table 4.
The first PDX model was generated from a pediatric patient with ACC and was reported in 2013. No separate cell line of this model has been established [91]. Since then, three new models have been developed, which have companion cell lines [55,56]. Further work has investigated the behavior of one of these models, CU-ACC2-M2B, in a humanized mouse model to better understand the efficacy of checkpoint inhibitor immunotherapy [56,93].
Modern ACC PDX lines not only retain significant molecular similarity (as confirmed by IHC) to their primaries, but also recapitulate the differences between those primaries and some of the heterogeneity of the disease [56,93].

2.3. 3D Models

Refer to Table 5: Two primary ACC 3D models (one spheroid, one organoid) have been reportedly recently [94,95]. Prior to 2022, 3D models of ACC consisted only of spheroids generated from H295R and SW-13 cells, primarily used in drug-screening protocols [96,97]. One additional H295R-derived spheroid model was also developed last year [98]. As with cell lines, newer models are increasingly moving toward larger-scale biobank models that will enhance the heterogeneity of models available for future research, although these models are not yet publicly available [95].
In addition, a transwell model of ACC co-culture with adipose stem cells showed evidence of crosstalk and worsened disease phenotype induced by the adipose stem cells [80]. Beyond the lipid microenvironment specifics of endocrine cells, co-culture experiments are increasingly important for understanding metastasis and immune response or lack thereof, the latter of which is critical for better improving immunotherapy outcomes.
3D models are particularly promising in the complex microenvironment of the adrenal cortex as an opportunity to better recapitulate tissue zonation. Recent experiments have also looked at interactions between ATC7 cells and human monocytes, showing that activation of intra-adrenal immune cells may play a role in stimulating steroidogenesis or proliferation [66].
A 2022 work by Bornstein et al. on standardized 3D culture techniques has yielded promising results in both replicating H295R and MUC-1 data and establishing additional primary cultures of ACC successfully. Bornstein et al. also worked with bovine and porcine adrenal organoids, but this work was focused primarily on normal tissue working toward transplantation rather than disease. Notably, this comparative work on porcine and bovine organoids also made progress toward the co-culture of medullary and cortical tissue [94].
Although not yet peer reviewed, Dedhia et al. released promising organoid models of ACC, studying metastasis through matrix metalloproteinase experiments in organoids and microfluidic models [99].

2.4. Genetically Engineered Mouse Models

While this review will not go into extensive detail about current mouse models, they are summarized here for completeness, and presented in Table 6. A more thorough review which particularly focused on them was recently published by Basham et al. [100]. Relatively many models have been developed to understand adrenocortical neoplasia as opposed to other neuroendocrine, as summarized in Table 5 [101]. Early models mostly focused on the role of IGF2 [102,103]. While it has been confirmed to be involved in the development and progression of tumors, it is no longer seen as likely to be a driver of oncogenesis itself [104,105,106]. Although no longer a central focus of transgenic models, a study continues on elucidating the mechanism of IGF2’s role in adrenocortical neoplasia. Pereira et al. showed that its effects on H295R cells could preferentially be inhibited by mTOR pathway inhibition vs. MEK/MAPK/ERK pathway inhibition [103].
Other recent work has focused more on CTNNB1, APC, WNT, ZNRF3, and TP53 [107]. Val and coauthors recently showed evidence that phagocytic macrophages may be involved in the relatively higher prevalence of ACC in women via a conditional ZNRF3 KO model [108].
Table
Table 6. Genetically engineered mouse models of neuroendocrine neoplasia.
Table 6. Genetically engineered mouse models of neuroendocrine neoplasia.
Model NameType 1Type 2Gene (Promoter)YearReference
P540scc-SV40ACCtransgenicSV40-TAg (CYP11A1)1994[109]
FG-TagNEPC, ACTtransgenicSV40-TAg (HBG)1996[110,111,112]
PEPCK-IGF-IIACCtransgenicIGF2 (PEPCK)1999[102]
Nr5a1+/−ACTKONR5A12000[113]
AdTAgACCtransgenicSV40-TAg (AKR1B7)2000[54,114,115]
YAC-TRACTtransgenicNR5A1 (YAC)2007[116]
FAdE-SF1Pediatric ACTtransgenicNR5A1 (FAdE)2009[117]
ACDacd/acd::p53+/−ACCKOACD, TP532009[118]
APC KOACCTS KOAPC2012[104]
Adlgf2ACCtransgenicIGF2 (AKR1B7)2012[105]
H19ADMDACCtransgenicAPC, IGF2/H19-ICR (NR5A1)2012[104]
Apc+/−ACCKOAPC2014[119]
RNF43−/−-TS KORNF432019[120]
ZNRF−/− CTNNB1+/−adrenal hyperplasiaTS KOZNRF3, CTNNB12019[120]
ZNRF−/−-TS KOZNRF32019[120]
p53-LOF (ASCre/+::Trp53flox/flox), PCreAS/+-TS transgenicTP532020[121]
βcat-GOF (ASCre/+::Ctnnbflox(ex3)/+), BCreAS/+-TS transgenicCTNNB12020[121]
p53-LOF/βcat-GOF (ASCre/+::Trp53flox/flox::Ctnnbflox(ex3)/+), BPCreAS/+ACCTS transgenicTP53, CTNNB12020[121]
Znrf3flox/flox SF1-CrehighACCTS KOZNRF32022[108]
1 ACC: adrenocortical carcinoma, NEPC: neuroendocrine prostate cancer. 2 KO: Knockout, TS: Tissue-specific.

3. Discussion

In comparison with ACC explants, several features are important to consider, including genetics, hormone secretion, and growth patterns. We summarize below a synthesis of the processes used for verifying the ACC115m primary culture, associated TVBF-7 cell line, and Bornstein et al.’s spheroid models as a paradigm for an appropriate analysis and confirmation of samples [55,58,94].
To verify the authenticity of primary cultures, cell lines, and xenografts, it is valuable to perform short tandem repeat (STR) profiling in comparison to primary samples. Numerous cases of contamination across cell lines and the overgrowth of lymphocytes or other cells instead of intended tumor cells have reinforced the necessity of such verification.
In characterizing any sample ACC cells, exome sequencing of at least driver- (TP53, MEN1, PRKAR1A, CTNNB1, APC, ZNRF3, IGF2, EGFR, RB1, BRCA1, BRCA2, RET, GNAS and PTEN) and steroidogenesis-related (CYP11A1, CYP17A1, HSD3B2, HSD17B4, CYP21A2, CYP11B1, CYP11B2, MC2R, AT1R) genes should be performed, if not more comprehensive sequencing. Hormone secretion of cortisol, aldosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and 17-hydroxyprogesterone should ideally also be screened by mass spectrometry. For primary tissue samples, xenografts, and organoids, immunostaining should be performed for Ki-67 and for the endocrine-specific markers SF1, EGFR, and 3β-hydroxysteroid dehydrogenase.
It is also important for appropriate positive and negative controls to be used in analyzing the secretion and stimulation of endocrine cells, as many popular forms of media, such as Nu-serum, contain hormones such as testosterone [122]. Researchers should ensure that their measurements compare to an appropriate baseline (i.e., of complete media before culture of cells) and use appropriate controls.
In trying to convert less aggressive phenotypes to lines suitable for in vitro study, transgenic models with such genes as SV40-TAg are often used, and ACC models such as ATC1 and ATC7 use this technique. However, we urge caution with such approaches as they may no longer resemble their original less aggressive phenotype. Instead, we encourage more complex culture models that better recapitulate the original environment, such as the standardized spheroid model of Bornstein et al. reported above or other 3D systems. Such systems are also valuable in analyzing the co-culture of ACC with other cell types such as adipose cells or lymphocytes, which are essential to understanding the lipid and immune microenvironment of ACC. As standardized 3D culture systems become a reality, ideally, co-culture techniques will also become more refined and widespread in understanding ACC.

4. Conclusions

Adrenocortical carcinoma is an aggressive orphan malignancy with limited therapeutic options. Its rarity has slowed clinical research advances. As a result, preclinical models are doubly important in understanding ACC’s pathogenesis and potential treatment. Since the development of the first ACC model systems (mouse and human cell lines) in the 1960s and 1970s, much of the research has focused on the use of those now widely available systems. However, many novel systems of various types have been developed since. In particular, biobanking and standardized protocols have led to the generation of more patient-derived models in recent years. Unfortunately, only a few of these have reached wider usage and public availability such as in biobanks and mouse repositories. While there is a critical demand for new ACC model systems, it is just as important that existing model systems are shared and cross-validated across different research groups and between one another.
Using a variety of models is essential to capture the heterogeneity of clinical disease and to compensate for the flaws that different model systems have. No single model system can perfectly recapitulate disease, but the use of multiple models with complementary strengths will bring us closer to that understanding. Moving fast in research is sometimes essential, and simpler in vitro systems (such as monolayer and spheroid culture) perform this admirably. Slower and more relevant in vivo data using mouse or other xenograft models provide some information about how ACC interacts with the rest of the body, but an orthotopic model would be better for showing these interactions than existing flank models. More complicated in vitro systems that incorporate the 3D organization of cells or larger organoid structures can help to bridge the gap between the former simpler and the latter more complex models. In addition, human ACC tumor-bearing immunocompromised mice are useful for the exploration of potential therapeutic approaches, including chemotherapy, targeted therapy, or a combination of these modalities. To accelerate ACC immunotherapy, there is also an urgent need to develop rapid syngeneic mouse models rather than genetically engineered mouse models with slow tumor development.
The concerted application of existing models and the development of new ones to fill gaps will improve preclinical understanding and empower future clinical research on ACC. In particular, the major gaps in current ACC preclinical models are a comparison across newer model systems and the development of better in vitro model systems for organoid or more complex 3D cultures.

Author Contributions

Conceptualization, J.d.R. and A.J.H.S.; data curation, A.J.H.S. and S.J.H.; writing—original draft preparation, A.J.H.S., S.J.H. and J.d.R.; writing—review and editing, A.J.H.S., S.K., J.d.R., Y.A., N.R., N.-Y.S., C.D.H., N.N., K.K.-V., E.K.B., J.M.H. and Y.P.; supervision, J.d.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by intramural funding from the National Cancer Institute.

Acknowledgments

We would like to acknowledge the support of Diana Varghese and Kimia Saleh-Anaraki in the early development of this project.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dutt, M.; Wehrle, C.J.; Jialal, I. Physiology, Adrenal Gland. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  2. Tischler, A.S.; Pacak, K.; Eisenhofer, G. The Adrenal Medulla and Extra-Adrenal Paraganglia: Then and Now. Endocr. Pathol. 2014, 25, 49–58. [Google Scholar] [CrossRef] [PubMed]
  3. Beard, C.M.; Sheps, S.G.; Kurland, L.T.; Carney, J.A.; Lie, J.T. Occurrence of Pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin. Proc. 1983, 58, 802–804. [Google Scholar] [PubMed]
  4. Guerrero, M.A.; Schreinemakers, J.M.J.; Vriens, M.R.; Suh, I.; Hwang, J.; Shen, W.T.; Gosnell, J.; Clark, O.H.; Duh, Q.-Y. Clinical Spectrum of Pheochromocytoma. J. Am. Coll. Surg. 2009, 209, 727–732. [Google Scholar] [CrossRef] [PubMed]
  5. Al Subhi, A.R.; Boyle, V.; Elston, M.S. Systematic Review: Incidence of Pheochromocytoma and Paraganglioma over 70 Years. J. Endocr. Soc. 2022, 6, bvac105. [Google Scholar] [CrossRef]
  6. Willenberg, H.S.; Bornstein, S.R. Adrenal Cortex; Development, Anatomy, Physiology. In Endotext; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Hershman, J.M., Hofland, J., Kalra, S., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000. [Google Scholar]
  7. Sherlock, M.; Scarsbrook, A.; Abbas, A.; Fraser, S.; Limumpornpetch, P.; Dineen, R.; Stewart, P.M. Adrenal Incidentaloma. Endocr. Rev. 2020, 41, 775–820. [Google Scholar] [CrossRef]
  8. Mantero, F.; Terzolo, M.; Arnaldi, G.; Osella, G.; Masini, A.M.; Alı̀, A.; Giovagnetti, M.; Opocher, G.; Angeli, A. A Survey on Adrenal Incidentaloma in Italy1. J. Clin. Endocrinol. Metab. 2000, 85, 637–644. [Google Scholar] [CrossRef]
  9. Russell, R.P.; Masi, A.T.; Richter, E.D. Adrenal Cortical Adenomas and Hypertension. A Clinical Pathologic Analysis of 690 Cases with Matched Controls and a Review of the Literature. Medicine 1972, 51, 211–225. [Google Scholar] [CrossRef]
  10. Terzolo, M.; Stigliano, A.; Chiodini, I.; Loli, P.; Furlani, L.; Arnaldi, G.; Reimondo, G.; Pia, A.; Toscano, V.; Zini, M.; et al. AME Position Statement on Adrenal Incidentaloma. Eur. J. Endocrinol. 2011, 164, 851–870. [Google Scholar] [CrossRef]
  11. Mahmood, E.; Anastasopoulou, C. Adrenal Adenoma. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  12. Barzon, L.; Fallo, F.; Sonino, N.; Boscaro, M. Development of Overt Cushing’s Syndrome in Patients with Adrenal Incidentaloma. Eur. J. Endocrinol. 2002, 146, 61–66. [Google Scholar] [CrossRef]
  13. Morelli, V.; Reimondo, G.; Giordano, R.; Della Casa, S.; Policola, C.; Palmieri, S.; Salcuni, A.S.; Dolci, A.; Mendola, M.; Arosio, M.; et al. Long-Term Follow-Up in Adrenal Incidentalomas: An Italian Multicenter Study. J. Clin. Endocrinol. Metab. 2014, 99, 827–834. [Google Scholar] [CrossRef]
  14. Angelousi, A.; Kassi, E.; Kaltsas, G.A. Adrenocortical Carcinoma. In Endotext; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Hershman, J.M., Hofland, J., Kalra, S., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000. [Google Scholar]
  15. Wajchenberg, B.L.; Albergaria Pereira, M.A.; Medonca, B.B.; Latronico, A.C.; Carneiro, P.C.; Ferreira Alves, V.A.; Zerbini, M.C.N.; Liberman, B.; Gomes, G.C.; Kirschner, M.A. Adrenocortical carcinoma. Cancer 2000, 88, 711–736. [Google Scholar] [CrossRef]
  16. Allolio, B.; Fassnacht, M. Clinical Review: Adrenocortical Carcinoma: Clinical Update. J. Clin. Endocrinol. Metab. 2006, 91, 2027–2037. [Google Scholar] [CrossRef]
  17. Sharma, E.; Dahal, S.; Sharma, P.; Bhandari, A.; Gupta, V.; Amgai, B.; Dahal, S. The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study. J. Clin. Med. Res. 2018, 10, 636–640. [Google Scholar] [CrossRef] [PubMed]
  18. Kebebew, E.; Reiff, E.; Duh, Q.-Y.; Clark, O.H.; McMillan, A. Extent of Disease at Presentation and Outcome for Adrenocortical Carcinoma: Have We Made Progress? World J. Surg. 2006, 30, 872–878. [Google Scholar] [CrossRef]
  19. Kerkhofs, T.M.A.; Verhoeven, R.H.A.; Van der Zwan, J.M.; Dieleman, J.; Kerstens, M.N.; Links, T.P.; Van de Poll-Franse, L.V.; Haak, H.R. Adrenocortical Carcinoma: A Population-Based Study on Incidence and Survival in the Netherlands since 1993. Eur. J. Cancer 2013, 49, 2579–2586. [Google Scholar] [CrossRef]
  20. Luton, J.P.; Cerdas, S.; Billaud, L.; Thomas, G.; Guilhaume, B.; Bertagna, X.; Laudat, M.H.; Louvel, A.; Chapuis, Y.; Blondeau, P. Clinical Features of Adrenocortical Carcinoma, Prognostic Factors, and the Effect of Mitotane Therapy. N. Engl. J. Med. 1990, 322, 1195–1201. [Google Scholar] [CrossRef]
  21. Koschker, A.-C.; Fassnacht, M.; Hahner, S.; Weismann, D.; Allolio, B. Adrenocortical Carcinoma—Improving Patient Care by Establishing New Structures. Exp. Clin. Endocrinol. Diabetes 2006, 114, 45–51. [Google Scholar] [CrossRef]
  22. Fassnacht, M.; Allolio, B. Clinical Management of Adrenocortical Carcinoma. Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 273–289. [Google Scholar] [CrossRef]
  23. Henley, D.J.; van Heerden, J.A.; Grant, C.S.; Carney, J.A.; Carpenter, P.C. Adrenal Cortical Carcinoma—A Continuing Challenge. Surgery 1983, 94, 926–931. [Google Scholar] [PubMed]
  24. Mantero, F.; Arnaldi, G. Management Approaches to Adrenal Incidentalomas: A View from Ancona, Italy. Endocrinol. Metab. Clin. N. Am. 2000, 29, 107–125. [Google Scholar] [CrossRef]
  25. Libé, R. Adrenocortical Carcinoma (ACC): Diagnosis, Prognosis, and Treatment. Front. Cell Dev. Biol. 2015, 3, 45. [Google Scholar] [CrossRef] [PubMed]
  26. Wang, C.; Sun, Y.; Wu, H.; Zhao, D.; Chen, J. Distinguishing Adrenal Cortical Carcinomas and Adenomas: A Study of Clinicopathological Features and Biomarkers. Histopathology 2014, 64, 567–576. [Google Scholar] [CrossRef]
  27. Sturgeon, C.; Shen, W.T.; Clark, O.H.; Duh, Q.-Y.; Kebebew, E. Risk Assessment in 457 Adrenal Cortical Carcinomas: How Much Does Tumor Size Predict the Likelihood of Malignancy? J. Am. Coll. Surg. 2006, 202, 423–430. [Google Scholar] [CrossRef] [PubMed]
  28. Lam, K.-Y.; Lo, C.-Y. Metastatic Tumours of the Adrenal Glands: A 30-Year Experience in a Teaching Hospital. Clin. Endocrinol. 2002, 56, 95–101. [Google Scholar] [CrossRef] [PubMed]
  29. Lutz, A.; Stojkovic, M.; Schmidt, M.; Arlt, W.; Allolio, B.; Reincke, M. Adrenocortical Function in Patients with Macrometastases of the Adrenal Gland. Eur. J. Endocrinol. 2000, 143, 91–97. [Google Scholar] [CrossRef]
  30. Batalini, F.; Peacock, E.G.; Stobie, L.; Robertson, A.; Garber, J.; Weitzel, J.N.; Tung, N.M. Li-Fraumeni Syndrome: Not a Straightforward Diagnosis Anymore-the Interpretation of Pathogenic Variants of Low Allele Frequency and the Differences between Germline PVs, Mosaicism, and Clonal Hematopoiesis. Breast Cancer Res. 2019, 21, 107. [Google Scholar] [CrossRef]
  31. Li, F.P.; Fraumeni, J.F.; Mulvihill, J.J.; Blattner, W.A.; Dreyfus, M.G.; Tucker, M.A.; Miller, R.W. A Cancer Family Syndrome in Twenty-Four Kindreds. Cancer Res. 1988, 48, 5358–5362. [Google Scholar]
  32. Bougeard, G.; Sesboüé, R.; Baert-Desurmont, S.; Vasseur, S.; Martin, C.; Tinat, J.; Brugières, L.; Chompret, A.; de Paillerets, B.B.; Stoppa-Lyonnet, D.; et al. Molecular Basis of the Li-Fraumeni Syndrome: An Update from the French LFS Families. J. Med. Genet. 2008, 45, 535–538. [Google Scholar] [CrossRef]
  33. Varley, J.M.; McGown, G.; Thorncroft, M.; James, L.A.; Margison, G.P.; Forster, G.; Evans, D.G.R.; Harris, M.; Kelsey, A.M.; Birch, J.M. Are There Low-Penetrance TP53 Alleles? Evidence from Childhood Adrenocortical Tumors. Am. J. Hum. Genet. 1999, 65, 995–1006. [Google Scholar] [CrossRef]
  34. Rodriguez-Galindo, C.; Figueiredo, B.C.; Zambetti, G.P.; Ribeiro, R.C. Biology, Clinical Characteristics, and Management of Adrenocortical Tumors in Children. Pediatr. Blood Cancer 2005, 45, 265–273. [Google Scholar] [CrossRef]
  35. Costa, T.E.J.; Gerber, V.K.Q.; Ibañez, H.C.; Melanda, V.S.; Parise, I.Z.S.; Watanabe, F.M.; Pianovski, M.A.D.; Fiori, C.M.C.M.; Fabro, A.L.M.R.; da Silva, D.B.; et al. Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil. Cancers 2019, 11, 1804. [Google Scholar] [CrossRef] [PubMed]
  36. Lapunzina, P. Risk of Tumorigenesis in Overgrowth Syndromes: A Comprehensive Review. Am. J. Med. Genet. Part C Semin. Med. Genet. 2005, 137C, 53–71. [Google Scholar] [CrossRef] [PubMed]
  37. Wiedemann, H.-R. Tumours and Hemihypertrophy Associated with Wiedemann-Beckwith Syndrome. Eur. J. Pediatr. 1983, 141, 129. [Google Scholar] [CrossRef]
  38. Manor, J.; Lalani, S.R. Overgrowth Syndromes—Evaluation, Diagnosis, and Management. Front. Pediatr. 2020, 8, 574857. [Google Scholar] [CrossRef] [PubMed]
  39. Else, T.; Kim, A.C.; Sabolch, A.; Raymond, V.M.; Kandathil, A.; Caoili, E.M.; Jolly, S.; Miller, B.S.; Giordano, T.J.; Hammer, G.D. Adrenocortical Carcinoma. Endocr. Rev. 2014, 35, 282–326. [Google Scholar] [CrossRef]
  40. Sigala, S.; Rossini, E.; Abate, A.; Tamburello, M.; Bornstein, S.R.; Hantel, C. An Update on Adrenocortical Cell Lines of Human Origin. Endocrine 2022, 77, 432–437. [Google Scholar] [CrossRef]
  41. Jubelin, C.; Muñoz-Garcia, J.; Griscom, L.; Cochonneau, D.; Ollivier, E.; Heymann, M.-F.; Vallette, F.M.; Oliver, L.; Heymann, D. Three-Dimensional in Vitro Culture Models in Oncology Research. Cell Biosci. 2022, 12, 155. [Google Scholar] [CrossRef]
  42. Rosfjord, E.; Lucas, J.; Li, G.; Gerber, H.-P. Advances in Patient-Derived Tumor Xenografts: From Target Identification to Predicting Clinical Response Rates in Oncology. Biochem. Pharm. 2014, 91, 135–143. [Google Scholar] [CrossRef]
  43. Tentler, J.J.; Tan, A.C.; Weekes, C.D.; Jimeno, A.; Leong, S.; Pitts, T.M.; Arcaroli, J.J.; Messersmith, W.A.; Eckhardt, S.G. Patient-Derived Tumour Xenografts as Models for Oncology Drug Development. Nat. Rev. Clin. Oncol. 2012, 9, 338–350. [Google Scholar] [CrossRef]
  44. Schimmer, B.P. [52] Adrenocortical Y1 Cells. In Methods in Enzymology; Cell Culture; Academic Press: New York, NY, USA, 1979; Volume 58, pp. 570–574. [Google Scholar]
  45. Szyf, M.; Milstone, D.S.; Schimmer, B.P.; Parker, K.L.; Seidman, J.G. Cis Modification of the Steroid 21-Hydroxylase Gene Prevents Its Expression in the Y1 Mouse Adrenocortical Tumor Cell Line. Mol. Endocrinol. 1990, 4, 1144–1152. [Google Scholar] [CrossRef]
  46. Yasumura, Y.; Buonassisi, V.; Sato, G. Clonal Analysis of Differentiated Function in Animal Cell Cultures: I. Possible Correlated Maintenance of Differentiated Function and the Diploid Karyotype1. Cancer Res. 1966, 26, 529–535. [Google Scholar] [PubMed]
  47. Tissier, F.; Cavard, C.; Groussin, L.; Perlemoine, K.; Fumey, G.; Hagneré, A.-M.; René-Corail, F.; Jullian, E.; Gicquel, C.; Bertagna, X.; et al. Mutations of Beta-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in Both Benign and Malignant Adrenocortical Tumors. Cancer Res. 2005, 65, 7622–7627. [Google Scholar] [CrossRef]
  48. Gaujoux, S.; Hantel, C.; Launay, P.; Bonnet, S.; Perlemoine, K.; Lefèvre, L.; Guillaud-Bataille, M.; Beuschlein, F.; Tissier, F.; Bertherat, J.; et al. Silencing Mutated β-Catenin Inhibits Cell Proliferation and Stimulates Apoptosis in the Adrenocortical Cancer Cell Line H295R. PLoS ONE 2013, 8, e55743. [Google Scholar] [CrossRef] [PubMed]
  49. Gazdar, A.F.; Oie, H.K.; Shackleton, C.H.; Chen, T.R.; Triche, T.J.; Myers, C.E.; Chrousos, G.P.; Brennan, M.F.; Stein, C.A.; La Rocca, R.V. Establishment and Characterization of a Human Adrenocortical Carcinoma Cell Line that Expresses Multiple Pathways of Steroid Biosynthesis. Cancer Res. 1990, 50, 5488–5496. [Google Scholar] [PubMed]
  50. Rahman, N.A.; Kiiveri, S.; Siltanen, S.; Levallet, J.; Kero, J.; Lensu, T.; Wilson, D.B.; Heikinheimo, M.T.; Huhtaniemi, I.T. Adrenocortical Tumorigenesis in Transgenic Mice: The Role of Luteinizing Hormone Receptor and Transcription Factors GATA-4 and GATA-61. Reprod. Biol. 2001, 1, 5–9. [Google Scholar]
  51. Schteingart, D.E.; Giordano, T.J.; Benitez, R.S.; Burdick, M.D.; Starkman, M.N.; Arenberg, D.A.; Strieter, R.M. Overexpression of CXC Chemokines by an Adrenocortical Carcinoma: A Novel Clinical Syndrome. J. Clin. Endocrinol. Metab. 2001, 86, 3968–3974. [Google Scholar] [CrossRef]
  52. Ueno, M.; Nakashima, J.; Akita, M.; Ban, S.-I.; Nakanoma, T.; Iida, M.; Deguchi, N. Characterization of a Newly Established Cell Line Derived from Human Adrenocortical Carcinoma. Int. J. Urol. 2001, 8, 17–22. [Google Scholar] [CrossRef]
  53. Ragazzon, B.; Lefrançois-Martinez, A.M.; Val, P.; Tournaire, C.; Berger, M.; Gachancard-Bouya, J.L.; Bègue, R.J.; Veyssière, G.; Martinez, A. ACTH and PRL Sensitivity of Highly Differentiated Cell Lines Obtained by Adrenocortical Targeted Oncogenesis. Endocr. Res. 2004, 30, 945–950. [Google Scholar] [CrossRef]
  54. Ragazzon, B.; Lefrançois-Martinez, A.-M.; Val, P.; Sahut-Barnola, I.; Tournaire, C.; Chambon, C.; Gachancard-Bouya, J.-L.; Begue, R.-J.; Veyssière, G.; Martinez, A. Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis. Endocrinology 2006, 147, 1805–1818. [Google Scholar] [CrossRef]
  55. Hantel, C.; Shapiro, I.; Poli, G.; Chiapponi, C.; Bidlingmaier, M.; Reincke, M.; Luconi, M.; Jung, S.; Beuschlein, F. Targeting Heterogeneity of Adrenocortical Carcinoma: Evaluation and Extension of Preclinical Tumor Models to Improve Clinical Translation. Oncotarget 2016, 7, 79292–79304. [Google Scholar] [CrossRef]
  56. Kiseljak-Vassiliades, K.; Zhang, Y.; Bagby, S.M.; Kar, A.; Pozdeyev, N.; Xu, M.; Gowan, K.; Sharma, V.; Raeburn, C.D.; Albuja-Cruz, M.; et al. Development of New Preclinical Models to Advance Adrenocortical Carcinoma Research. Endocr. Relat. Cancer 2018, 25, 437–451. [Google Scholar] [CrossRef] [PubMed]
  57. Landwehr, L.-S.; Schreiner, J.; Appenzeller, S.; Kircher, S.; Herterich, S.; Sbiera, S.; Fassnacht, M.; Kroiss, M.; Weigand, I. A Novel Patient-Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH Mutation and High Tumour Mutational Burden. Eur. J. Endocrinol. 2021, 184, 823–835. [Google Scholar] [CrossRef] [PubMed]
  58. Sigala, S.; Bothou, C.; Penton, D.; Abate, A.; Peitzsch, M.; Cosentini, D.; Tiberio, G.A.M.; Bornstein, S.R.; Berruti, A.; Hantel, C. A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma. Cells 2022, 11, 1439. [Google Scholar] [CrossRef] [PubMed]
  59. Almeida, M.Q.; Fragoso, M.C.B.V.; Lotfi, C.F.P.; Santos, M.G.; Nishi, M.Y.; Costa, M.H.S.; Lerario, A.M.; Maciel, C.C.; Mattos, G.E.; Jorge, A.A.L.; et al. Expression of Insulin-Like Growth Factor-II and Its Receptor in Pediatric and Adult Adrenocortical Tumors. J. Clin. Endocrinol. Metab. 2008, 93, 3524–3531. [Google Scholar] [CrossRef]
  60. França, M.M.; Ferraz-de-Souza, B.; Santos, M.G.; Lerario, A.M.; Fragoso, M.C.B.V.; Latronico, A.C.; Kuick, R.D.; Hammer, G.D.; Lotfi, C.F.P. POD-1 Binding to the E-Box Sequence Inhibits SF-1 and StAR Expression in Human Adrenocortical Tumor Cells. Mol. Cell. Endocrinol. 2013, 371, 140–147. [Google Scholar] [CrossRef]
  61. Gara, S.K.; Wang, Y.; Patel, D.; Liu-Chittenden, Y.; Jain, M.; Boufraqech, M.; Zhang, L.; Meltzer, P.S.; Kebebew, E. Integrated Genome-Wide Analysis of Genomic Changes and Gene Regulation in Human Adrenocortical Tissue Samples. Nucleic Acids Res. 2015, 43, 9327–9339. [Google Scholar] [CrossRef]
  62. Nilubol, N.; Boufraqech, M.; Zhang, L.; Gaskins, K.; Shen, M.; Zhang, Y.-Q.; Gara, S.K.; Austin, C.P.; Kebebew, E. Synergistic Combination of Flavopiridol and Carfilzomib Targets Commonly Dysregulated Pathways in Adrenocortical Carcinoma and Has Biomarkers of Response. Oncotarget 2018, 9, 33030–33042. [Google Scholar] [CrossRef]
  63. Fragni, M.; Palma Lopez, L.P.; Rossini, E.; Abate, A.; Cosentini, D.; Salvi, V.; Vezzoli, S.; Poliani, P.L.; Bosisio, D.; Hantel, C.; et al. In Vitro Cytotoxicity of Cabazitaxel in Adrenocortical Carcinoma Cell Lines and Human Adrenocortical Carcinoma Primary Cell Cultures☆. Mol. Cell. Endocrinol. 2019, 498, 110585. [Google Scholar] [CrossRef]
  64. Abate, A.; Rossini, E.; Bonini, S.A.; Fragni, M.; Cosentini, D.; Tiberio, G.A.M.; Benetti, D.; Hantel, C.; Laganà, M.; Grisanti, S.; et al. Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells. Cancers 2020, 12, 928. [Google Scholar] [CrossRef]
  65. Rossini, E.; Tamburello, M.; Abate, A.; Beretta, S.; Fragni, M.; Cominelli, M.; Cosentini, D.; Hantel, C.; Bono, F.; Grisanti, S.; et al. Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer. Front. Endocrinol. 2021, 12, 669426. [Google Scholar] [CrossRef]
  66. Fudulu, D.P.; Horn, G.; Hazell, G.; Lefrançois-Martinez, A.-M.; Martinez, A.; Angelini, G.D.; Lightman, S.L.; Spiga, F. Co-Culture of Monocytes and Zona Fasciculata Adrenal Cells: An in Vitro Model to Study the Immune-Adrenal Cross-Talk. Mol. Cell. Endocrinol. 2021, 526, 111195. [Google Scholar] [CrossRef] [PubMed]
  67. Hazell, G.; Horn, G.; Lightman, S.L.; Spiga, F. Dynamics of ACTH-Mediated Regulation of Gene Transcription in ATC1 and ATC7 Adrenal Zona Fasciculata Cell Lines. Endocrinology 2019, 160, 587–604. [Google Scholar] [CrossRef] [PubMed]
  68. Francis, J.C.; Gardiner, J.R.; Renaud, Y.; Chauhan, R.; Weinstein, Y.; Gomez-Sanchez, C.; Lefrançois-Martinez, A.-M.; Bertherat, J.; Val, P.; Swain, A. HOX Genes Promote Cell Proliferation and Are Potential Therapeutic Targets in Adrenocortical Tumours. Br. J. Cancer 2021, 124, 805–816. [Google Scholar] [CrossRef] [PubMed]
  69. Leibovitz, A.; McCombs, W.M.; Johnston, D.; McCoy, C.E.; Stinson, J.C. New Human Cancer Cell Culture Lines. I. SW-13, Small-Cell Carcinoma of the Adrenal Cortex. J. Natl. Cancer Inst. 1973, 51, 691–697. [Google Scholar]
  70. Wang, T.; Rainey, W.E. Human Adrenocortical Carcinoma Cell Lines. Mol. Cell. Endocrinol. 2012, 351, 58–65. [Google Scholar] [CrossRef]
  71. Laha, D.; Grant, R.R.C.; Mishra, P.; Boufraqech, M.; Shen, M.; Zhang, Y.-Q.; Hall, M.D.; Quezado, M.; De Melo, M.S.; Del Rivero, J.; et al. Preclinical Assessment of Synergistic Efficacy of MELK and CDK Inhibitors in Adrenocortical Cancer. J. Exp. Clin. Cancer Res. 2022, 41, 282. [Google Scholar] [CrossRef]
  72. Avena, P.; De Luca, A.; Chimento, A.; Nocito, M.C.; Sculco, S.; La Padula, D.; Zavaglia, L.; Giulietti, M.; Hantel, C.; Sirianni, R.; et al. Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression. Cancers 2022, 14, 3885. [Google Scholar] [CrossRef]
  73. Parmar, J.; Key, R.E.; Rainey, W.E. Development of an Adrenocorticotropin-Responsive Human Adrenocortical Carcinoma Cell Line. J. Clin. Endocrinol. Metab. 2008, 93, 4542–4546. [Google Scholar] [CrossRef]
  74. Nanba, K.; Chen, A.X.; Turcu, A.F.; Rainey, W.E. H295R Expression of Melanocortin 2 Receptor Accessory Protein Results in ACTH Responsiveness. J. Mol. Endocrinol. 2016, 56, 69–76. [Google Scholar] [CrossRef]
  75. Creemers, S.G.; van Koetsveld, P.M.; van den Dungen, E.S.R.; Korpershoek, E.; van Kemenade, F.J.; Franssen, G.J.H.; de Herder, W.W.; Feelders, R.A.; Hofland, L.J. Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene. J. Clin. Endocrinol. Metab. 2016, 101, 4574–4584. [Google Scholar] [CrossRef]
  76. van Koetsveld, P.M.; Creemers, S.G.; Dogan, F.; Franssen, G.J.H.; de Herder, W.W.; Feelders, R.A.; Hofland, L.J. The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures. J. Clin. Endocrinol. Metab. 2020, 105, 407–417. [Google Scholar] [CrossRef] [PubMed]
  77. Warde, K.M.; Lim, Y.J.; Ribes Martinez, E.; Beuschlein, F.; O’Shea, P.; Hantel, C.; Dennedy, M.C. Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma. Endocrinology 2022, 163, bqac102. [Google Scholar] [CrossRef] [PubMed]
  78. Yalon, T.; Yalon, M.; Assaf, D.; Lenartowicz, K.; Foster, T.; Lyden, M.; Dy, B.; Bancos, I.; McKenzie, T. Differentiating between Adrenocortical Carcinoma and Lipid-Poor Cortical Adenoma: A Novel Cross-Sectional Imaging-Based Score. Surgery 2023, 173, 35–42. [Google Scholar] [CrossRef] [PubMed]
  79. Kahramangil, B.; Kose, E.; Remer, E.M.; Reynolds, J.P.; Stein, R.; Rini, B.; Siperstein, A.; Berber, E. A Modern Assessment of Cancer Risk in Adrenal Incidentalomas: Analysis of 2219 Patients. Ann. Surg. 2022, 275, e238. [Google Scholar] [CrossRef] [PubMed]
  80. Armignacco, R.; Cantini, G.; Poli, G.; Guasti, D.; Nesi, G.; Romagnoli, P.; Mannelli, M.; Luconi, M. The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model. Cancers 2019, 11, 1931. [Google Scholar] [CrossRef]
  81. Detjen, K.; Hammerich, L.; Özdirik, B.; Demir, M.; Wiedenmann, B.; Tacke, F.; Jann, H.; Roderburg, C. Models of Gastroenteropancreatic Neuroendocrine Neoplasms: Current Status and Future Directions. Neuroendocrinology 2021, 111, 217–236. [Google Scholar] [CrossRef]
  82. Tsumura, R.; Koga, Y.; Hamada, A.; Kuwata, T.; Sasaki, H.; Doi, T.; Aikawa, K.; Ohashi, A.; Katano, I.; Ikarashi, Y.; et al. Report of the Use of Patient-Derived Xenograft Models in the Development of Anticancer Drugs in Japan. Cancer Sci. 2020, 111, 3386–3394. [Google Scholar] [CrossRef] [PubMed]
  83. Doghman, M.; Wakil, A.E.; Cardinaud, B.; Thomas, E.; Wang, J.; Zhao, W.; Peralta-Del Valle, M.H.C.; Figueiredo, B.C.; Zambetti, G.P.; Lalli, E. Regulation of Insulin-like Growth Factor–Mammalian Target of Rapamycin Signaling by MicroRNA in Childhood Adrenocortical Tumors. Cancer Res. 2010, 70, 4666–4675. [Google Scholar] [CrossRef]
  84. Doghman, M.; Lalli, E. Efficacy of the Novel Dual PI3-Kinase/MTOR Inhibitor NVP-BEZ235 in a Preclinical Model of Adrenocortical Carcinoma. Mol. Cell. Endocrinol. 2012, 364, 101–104. [Google Scholar] [CrossRef]
  85. Doghman, M.; Lalli, E. Lack of Long-Lasting Effects of Mitotane Adjuvant Therapy in a Mouse Xenograft Model of Adrenocortical Carcinoma. Mol. Cell. Endocrinol. 2013, 381, 66–69. [Google Scholar] [CrossRef]
  86. Nagy, Z.; Baghy, K.; Hunyadi-Gulyás, É.; Micsik, T.; Nyírő, G.; Rácz, G.; Butz, H.; Perge, P.; Kovalszky, I.; Medzihradszky, K.F.; et al. Evaluation of 9-Cis Retinoic Acid and Mitotane as Antitumoral Agents in an Adrenocortical Xenograft Model. Am. J. Cancer Res. 2015, 5, 3645–3658. [Google Scholar] [PubMed]
  87. Hantel, C.; Ozimek, A.; Lira, R.; Ragazzon, B.; Jäckel, C.; Frantsev, R.; Reincke, M.; Bertherat, J.; Mussack, T.; Beuschlein, F. TNF Alpha Signaling Is Associated with Therapeutic Responsiveness to Vascular Disrupting Agents in Endocrine Tumors. Mol. Cell. Endocrinol. 2016, 423, 87–95. [Google Scholar] [CrossRef] [PubMed]
  88. Cerquetti, L.; Bucci, B.; Carpinelli, G.; Lardo, P.; Proietti, A.; Saporito, R.; Rindi, G.; Petrangeli, E.; Toscano, V.; Stigliano, A. Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study. Cancers 2019, 11, 1768. [Google Scholar] [CrossRef] [PubMed]
  89. Nadella, K.; Faucz, F.R.; Stratakis, C.A. C-KIT Oncogene Expression in PRKAR1A-Mutant Adrenal Cortex. Endocr. Relat. Cancer 2020, 27, 591–599. [Google Scholar] [CrossRef]
  90. Hantel, C.; Beuschlein, F. Xenograft Models for Adrenocortical Carcinoma. Mol. Cell. Endocrinol. 2016, 421, 28–33. [Google Scholar] [CrossRef]
  91. Pinto, E.M.; Morton, C.; Rodriguez-Galindo, C.; McGregor, L.; Davidoff, A.M.; Mercer, K.; Debelenko, L.V.; Billups, C.; Ribeiro, R.C.; Zambetti, G.P. Establishment and Characterization of the First Pediatric Adrenocortical Carcinoma Xenograft Model Identifies Topotecan as a Potential Chemotherapeutic Agent. Clin. Cancer Res. 2013, 19, 1740–1747. [Google Scholar] [CrossRef]
  92. Kar, A.; Zhang, Y.; Yacob, B.; Tompkins, K.; Bagby, S.; Leong, S.; Pitts, T.; Wierman, M.; Kiseljak-Vassiliades, K. SUN-337 Anti-Tumorigenic Effects Of The Maternal Leucine Zipper Kinase (MELK) Inhibitor, OTSSP167, In Pre-Clinical In Vivo Models Of Adrenocortical Carcinomas (ACC). J. Endocr. Soc. 2019, 3, SUN-337. [Google Scholar] [CrossRef]
  93. Lang, J.; Capasso, A.; Jordan, K.R.; French, J.D.; Kar, A.; Bagby, S.M.; Barbee, J.; Yacob, B.W.; Head, L.S.; Tompkins, K.D.; et al. Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment. J. Clin. Endocrinol. Metab. 2020, 105, dgz014. [Google Scholar] [CrossRef]
  94. Bornstein, S.; Shapiro, I.; Malyukov, M.; Züllig, R.; Luca, E.; Gelfgat, E.; Beuschlein, F.; Nölting, S.; Berruti, A.; Sigala, S.; et al. Innovative Multidimensional Models in a High-Throughput-Format for Different Cell Types of Endocrine Origin. Cell Death Dis. 2022, 13, 648. [Google Scholar] [CrossRef]
  95. Baregamian, N.; Sekhar, K.R.; Krystofiak, E.S.; Vinogradova, M.; Thomas, G.; Mannoh, E.; Solórzano, C.C.; Kiernan, C.M.; Mahadevan-Jansen, A.; Abumrad, N.; et al. Engineering Functional 3-Dimensional Patient-Derived Endocrine Organoids for Broad Multiplatform Applications. Surgery 2023, 173, 67–75. [Google Scholar] [CrossRef]
  96. Nilubol, N.; Zhang, L.; Shen, M.; Zhang, Y.-Q.; He, M.; Austin, C.P.; Kebebew, E. Four Clinically Utilized Drugs Were Identified and Validated for Treatment of Adrenocortical Cancer Using Quantitative High-Throughput Screening. J. Transl. Med. 2012, 10, 198. [Google Scholar] [CrossRef] [PubMed]
  97. Cerquetti, L.; Bucci, B.; Raffa, S.; Amendola, D.; Maggio, R.; Lardo, P.; Petrangeli, E.; Torrisi, M.R.; Toscano, V.; Pugliese, G.; et al. Effects of Sorafenib, a Tyrosin Kinase Inhibitor, on Adrenocortical Cancer. Front. Endocrinol. 2021, 12, 667798. [Google Scholar] [CrossRef] [PubMed]
  98. Langer, C.; Köll-Weber, M.; Holzer, M.; Hantel, C.; Süss, R. Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids. Pharmaceutics 2022, 14, 1891. [Google Scholar] [CrossRef] [PubMed]
  99. Dedhia, P.H.; Sivakumar, H.; Rodriguez, M.A.; Nairon, K.G.; Zent, J.M.; Zheng, X.; Jones, K.; Popova, L.; Leight, J.L.; Skardal, A. A 3D Adrenocortical Carcinoma Tumor Platform for Preclinical Modeling of Drug Response and Matrix Metalloproteinase Activity. bioRxiv 2023. [Google Scholar] [CrossRef]
  100. Basham, K.J.; Hung, H.A.; Lerario, A.M.; Hammer, G.D. Mouse Models of Adrenocortical Tumors. Mol. Cell. Endocrinol. 2016, 421, 82–97. [Google Scholar] [CrossRef]
  101. Gahete, M.D.; Jiménez-Vacas, J.M.; Alors-Pérez, E.; Herrero-Aguayo, V.; Fuentes-Fayos, A.C.; Pedraza-Arévalo, S.; Castaño, J.P.; Luque, R.M. Mouse Models of Endocrine Tumors. J. Endocrinol. 2019, 240, R73–R96. [Google Scholar] [CrossRef]
  102. Weber, M.M.; Fottner, C.; Schmidt, P.; Brodowski, K.M.H.; Gittner, K.; Lahm, H.; Engelhardt, D.; Wolf, E. Postnatal Overexpression of Insulin-Like Growth Factor II in Transgenic Mice Is Associated with Adrenocortical Hyperplasia and Enhanced Steroidogenesis*. Endocrinology 1999, 140, 1537–1543. [Google Scholar] [CrossRef]
  103. Pereira, S.S.; Monteiro, M.P.; Costa, M.M.; Moreira, Â.; Alves, M.G.; Oliveira, P.F.; Jarak, I.; Pignatelli, D. IGF2 Role in Adrenocortical Carcinoma Biology. Endocrine 2019, 66, 326–337. [Google Scholar] [CrossRef]
  104. Heaton, J.H.; Wood, M.A.; Kim, A.C.; Lima, L.O.; Barlaskar, F.M.; Almeida, M.Q.; Fragoso, M.C.B.V.; Kuick, R.; Lerario, A.M.; Simon, D.P.; et al. Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and β-Catenin. Am. J. Pathol. 2012, 181, 1017–1033. [Google Scholar] [CrossRef]
  105. Drelon, C.; Berthon, A.; Ragazzon, B.; Tissier, F.; Bandiera, R.; Sahut-Barnola, I.; de Joussineau, C.; Batisse-Lignier, M.; Lefrançois-Martinez, A.-M.; Bertherat, J.; et al. Analysis of the Role of Igf2 in Adrenal Tumour Development in Transgenic Mouse Models. PLoS ONE 2012, 7, e44171. [Google Scholar] [CrossRef]
  106. Kar, A.; Wierman, M.E.; Kiseljak-Vassiliades, K. Update on In-Vivo Preclinical Research Models in Adrenocortical Carcinoma. Curr. Opin. Endocrinol. Diabetes Obes. 2020, 27, 170–176. [Google Scholar] [CrossRef] [PubMed]
  107. Berthon, A.; Sahut-Barnola, I.; Lambert-Langlais, S.; de Joussineau, C.; Damon-Soubeyrand, C.; Louiset, E.; Taketo, M.M.; Tissier, F.; Bertherat, J.; Lefrançois-Martinez, A.-M.; et al. Constitutive β-Catenin Activation Induces Adrenal Hyperplasia and Promotes Adrenal Cancer Development. Hum. Mol. Genet. 2010, 19, 1561–1576. [Google Scholar] [CrossRef] [PubMed]
  108. Wilmouth, J.J.; Olabe, J.; Garcia-Garcia, D.; Lucas, C.; Guiton, R.; Roucher-Boulez, F.; Dufour, D.; Damon-Soubeyrand, C.; Sahut-Barnola, I.; Pointud, J.-C.; et al. Sexually Dimorphic Activation of Innate Antitumor Immunity Prevents Adrenocortical Carcinoma Development. Sci. Adv. 2022, 8, eadd0422. [Google Scholar] [CrossRef] [PubMed]
  109. Mellon, S.H.; Miller, W.L.; Bair, S.R.; Moore, C.C.; Vigne, J.L.; Weiner, R.I. Steroidogenic Adrenocortical Cell Lines Produced by Genetically Targeted Tumorigenesis in Transgenic Mice. Mol. Endocrinol. 1994, 8, 97–108. [Google Scholar] [CrossRef] [PubMed]
  110. Perez-Stable, C.; Altman, N.H.; Brown, J.; Harbison, M.; Cray, C.; Roos, B.A. Prostate, Adrenocortical, and Brown Adipose Tumors in Fetal Globin/T Antigen Transgenic Mice. Lab. Investig. 1996, 74, 363–373. [Google Scholar] [PubMed]
  111. Perez-Stable, C.; Altman, N.H.; Mehta, P.P.; Deftos, L.J.; Roos, B.A. Prostate Cancer Progression, Metastasis, and Gene Expression in Transgenic Mice. Cancer Res. 1997, 57, 900–906. [Google Scholar]
  112. Reiner, T.; de las Pozas, A.; Parrondo, R.; Perez-Stable, C. Progression of Prostate Cancer from a Subset of P63-Positive Basal Epithelial Cells in FG/Tag Transgenic Mice. Mol. Cancer Res. 2007, 5, 1171–1179. [Google Scholar] [CrossRef]
  113. Bland, M.L.; Jamieson, C.A.M.; Akana, S.F.; Bornstein, S.R.; Eisenhofer, G.; Dallman, M.F.; Ingraham, H.A. Haploinsufficiency of Steroidogenic Factor-1 in Mice Disrupts Adrenal Development Leading to an Impaired Stress Response. Proc. Natl. Acad. Sci. USA 2000, 97, 14488–14493. [Google Scholar] [CrossRef]
  114. Sahut-Barnola, I.; Lefrancois-Martinez, A.M.; Jean, C.; Veyssiere, G.; Martinez, A. Adrenal Tumorigenesis Targeted by the Corticotropin-Regulated Promoter of the Aldo-Keto Reductase AKR1B7 Gene in Transgenic Mice. Endocr. Res. 2000, 26, 885–898. [Google Scholar] [CrossRef]
  115. Batisse-Lignier, M.; Sahut-Barnola, I.; Tissier, F.; Dumontet, T.; Mathieu, M.; Drelon, C.; Pointud, J.-C.; Damon-Soubeyrand, C.; Marceau, G.; Kemeny, J.-L.; et al. P53/Rb Inhibition Induces Metastatic Adrenocortical Carcinomas in a Preclinical Transgenic Model. Oncogene 2017, 36, 4445–4456. [Google Scholar] [CrossRef]
  116. Doghman, M.; Karpova, T.; Rodrigues, G.A.; Arhatte, M.; De Moura, J.; Cavalli, L.R.; Virolle, V.; Barbry, P.; Zambetti, G.P.; Figueiredo, B.C.; et al. Increased Steroidogenic Factor-1 Dosage Triggers Adrenocortical Cell Proliferation and Cancer. Mol. Endocrinol. 2007, 21, 2968–2987. [Google Scholar] [CrossRef] [PubMed]
  117. Zubair, M.; Oka, S.; Parker, K.L.; Morohashi, K. Transgenic Expression of Ad4BP/SF-1 in Fetal Adrenal Progenitor Cells Leads to Ectopic Adrenal Formation. Mol. Endocrinol. 2009, 23, 1657–1667. [Google Scholar] [CrossRef] [PubMed]
  118. Else, T.; Trovato, A.; Kim, A.C.; Wu, Y.; Ferguson, D.O.; Kuick, R.D.; Lucas, P.C.; Hammer, G.D. Genetic P53 Deficiency Partially Rescues the Adrenocortical Dysplasia Phenotype at the Expense of Increased Tumorigenesis. Cancer Cell 2009, 15, 465–476. [Google Scholar] [CrossRef] [PubMed]
  119. Assié, G.; Letouzé, E.; Fassnacht, M.; Jouinot, A.; Luscap, W.; Barreau, O.; Omeiri, H.; Rodriguez, S.; Perlemoine, K.; René-Corail, F.; et al. Integrated Genomic Characterization of Adrenocortical Carcinoma. Nat. Genet. 2014, 46, 607–612. [Google Scholar] [CrossRef]
  120. Basham, K.J.; Rodriguez, S.; Turcu, A.F.; Lerario, A.M.; Logan, C.Y.; Rysztak, M.R.; Gomez-Sanchez, C.E.; Breault, D.T.; Koo, B.-K.; Clevers, H.; et al. A ZNRF3-Dependent Wnt/β-Catenin Signaling Gradient Is Required for Adrenal Homeostasis. Genes Dev. 2019, 33, 209–220. [Google Scholar] [CrossRef]
  121. Borges, K.S.; Pignatti, E.; Leng, S.; Kariyawasam, D.; Ruiz-Babot, G.; Ramalho, F.S.; Taketo, M.M.; Carlone, D.L.; Breault, D.T. Wnt/β-Catenin Activation Cooperates with Loss of P53 to Cause Adrenocortical Carcinoma in Mice. Oncogene 2020, 39, 5282–5291. [Google Scholar] [CrossRef]
  122. Strajhar, P.; Tonoli, D.; Jeanneret, F.; Imhof, R.M.; Malagnino, V.; Patt, M.; Kratschmar, D.V.; Boccard, J.; Rudaz, S.; Odermatt, A. Steroid Profiling in H295R Cells to Identify Chemicals Potentially Disrupting the Production of Adrenal Steroids. Toxicology 2017, 381, 51–63. [Google Scholar] [CrossRef]
Table
Table 1. Adrenocortical carcinoma-derived cell lines.
Table 1. Adrenocortical carcinoma-derived cell lines.
StudyCell LineSourceRepositoryRef. No. 1NotesYearReference
Yasumura, 1966Y-1mouseATCC48Produces 20α- and 11β-20α-hydroxyprogesterone in culture, cannot produce corticosterone due to lack of CYP21 expression [44,45]. 1966[46]
Gazdar, 1990H295RprimaryATCC 2717Has an activating S45P CTNNB1 mutation [47,48]. Limited response to ACTH stimulation, although compensatory variant has been generated (see text). 1980[49]
Rahman, 2001Calpha1mouse-1Generated by introduction of SV40-TAg expression under INHA promoter, ACC developed only by mice which were gonadectomized prepubertally. Limited use.2001[50]
Schteingart, 2001RL-251primary-6Limited response to ACTH stimulation. Secretion of IL-8 and angiogenic factors.2001[51]
Ueno, 2001ACT-1primary-1Expression of 3β-hydroxysteroid dehydrogenase. Significant chromosomal abnormalities, modal number 61.2001[52]
Ragazzon, 2004ATC1mouse-8Generated by introduction of SV40-Tag expression under AKR1B7 promoter. Zona fasciculata phenotype. ACTH responsive, corticosterone production positive.2004[53]
Ragazzon, 2006ATC7mouse-8As ATC1.2006[54]
Hantel, 2016MUC-1PDX-33Nuclear expression of SF1, cytoplasmic expression of 3β-hydroxysteroid dehydrogenase. Cortisol production positive.2016[55]
Kiseljak-Vassiliades, 2018CU-ACC1PDX-6G34R CTNNB1 mutation. Cortisol and corticosterone production positive, aldosterone production negative (although primary tumor was aldosterone-secreting, metastases from which line is derived were not). ACTH unresponsive.2018[56]
Kiseljak-Vassiliades, 2018CU-ACC2PDX-6G245S TP53 mutation. ACTH unresponsive. Minor cortisol secretion. Deletion of MSH2 exons 1–6. 2018[56]
Landwehr, 2021JIL-2266primary-1Hemizygous mutations in MUTYH and TP53. Insignificant hormone secretion. High mutational burden relative to most ACC.2021[57]
Sigala, 2022TVBF-7primary-2Q247* APC mutation (nonsense). Derived from primary culture ACC115m (Table 2). Significant expression of MC2R compared to H295R, but limited responsiveness to ACTH stimulation.2022[58]
1 Determined as number of non-reviewed, non-conference references on PubMed or PubMed Central. 2 Parent cell line NCI-H295 is only available from BCRC; H295R is the most widely used subclone.
Table
Table 2. Adrenocortical carcinoma-derived primary cultures.
Table 2. Adrenocortical carcinoma-derived primary cultures.
StudyCultureSourceRepositoryRef. No. 1NotesYearReference
Almeida, 2008Almeida pediatricprimary-1Survived to eight passages.2008[59]
França, 2013ACC-T36primary-6Demonstrated that forced expression of TCF21 reduced expression of SF1.2013[60]
Gara, 2015BD140Aprimary-7Generated at Phoenix Translational Genomics Research Institute, limited information available in publication.2015[61,62]
Fragni, 2019Fragni seriesprimary-2Six unique reported cultures.2019[63]
Abate, 2020ACC24-Iprimary-1Metastasis derived. Previously treated with EDP + M.2020[64]
Rossini, 2021ACC115mprimary-3Lymph node metastasis derived. Primary non-secretory. Survived continuous culture as TVBF-7 cell line (Table 1).2021[65]
1 Determined as number of non-reviewed, non-conference references on PubMed or PubMed Central.
Table
Table 3. Cell line-derived xenografts.
Table 3. Cell line-derived xenografts.
CDX LineHostSourceNotesYearReference
RL-251 (Schteingart, 2001)SCIDRL-251Seeded cells produced detectable circulating IL-8 and ENA-78 in xenografted mice.2001[51]
Doghman, 2010NOD/SCID/γcnullH295RShowed miRNAs miR-99a and miR-100 coordinately regulate expression of mTOR in ACC.2010[83]
Doghman, 2012NOD/SCID/γcnullH295RShowed dual inhibitor of PI3K/mTOR reduced ACC xenograft growth.2012[84]
Doghman, 2013NOD/SCID/γcnullH295RShowed that mitotane does not inhibit the growth of H295R xenografts long-term even with sustained therapeutic levels.2013[85]
Nagy, 2015BALB/c SCIDH295RShowed mitotane inhibits xenografted tumor growth.2015[86]
Hantel, 2016NMRI nu/nuH295RIdentified TNFAIP3/A20 overexpression as mechanism of TNFα inhibition resistance in xenografted ACC.2016[87]
Nilubol, 2018Nuþ/NuþH295R, BD140A, SW-13Showed combination of flavopiridol and carfilzomib inhibits xenografted tumor growth.2018[62]
Cerquetti, 2019nu/nu Forkhead miceH295R, SW13Showed radiosensitizing effect of mitotane to inhibit tumor growth in full-body irradiation of xenografted mice.2019[88]
Nadella, 2020nu/nuH295RShowed c-KIT inhibitor inhibits xenografted tumor growth.2020[89]
Laha, 2022Nuþ/NuþH295R, SW-13High-throughput drug screening identifying combination inhibition of MELK and CDK as potential therapeutic target.2022[71]
Table
Table 4. Primary tumor-derived xenografts.
Table 4. Primary tumor-derived xenografts.
StudyPDX LineHostNotesYearReference
Pinto, 2013SJ-ACC3CB17 scid−/−First (pediatric) ACC PDX. Primary-derived. Treatment naïve at establishment. Successfully reseeded into multiple different lines [90]. 2013[91]
Hantel, 2016MUC-1NMRI nu/nuFirst adult ACC PDX. Neck metastasis derived; originally treated with EDP + M 1. 2016[55]
Kiseljak-Vassiliades, 2018CU-ACC1nu/nuPerinephric metastasis derived. Treatment naïve at establishment. Androgen-secreting primary.2018[56]
Kiseljak-Vassiliades, 2018CU-ACC2nu/nuLiver metastasis derived, post-mitotane, SBRT 2, and embolization. 2018[56]
Kar, 2019CU-ACC9nu/nuPrimary-derived. Cortisol-secreting primary. Originally treated with EDP + M 1.2019[92]
Lang, 2020CU-ACC2-M2BBRGSCU-ACC2 variant in humanized mouse model for immunotherapy studies.2020[93]
1 EDP + M: Etoposide, doxorubicin, cisplatin, and mitotane. 2 SBRT: Stereotactic body radiation therapy.
Table
Table 5. Adrenocortical carcinoma-derived 3D models.
Table 5. Adrenocortical carcinoma-derived 3D models.
3D Model LineTypeSourceNotesYearReference
Nilubol, 2012spheroidH295R, SW3Bortezomib, ouabain, methotrexate, and pyrimethamine showed inhibitory activity against spheroids and monolayers.2012[96]
Armignacco, 2019transwellH295RCo-culture of H295R monolayer above an adipose stem cell monolayer leads to reprogramming of both cell types, leading to more aggressive disease phenotype.2019[80]
Cerquetti, 2021spheroidH295RSorafenib inhibited growth and caused disaggregation of tumor spheroids.2021[8]
Fudulu, 2021transwellATC7Co-culture of ATC7 monolayer below human monocytes to study immune interactions and cross-talk, showing that IL-6 release by monocytes may modulate steroidogenesis.2021[66]
Langer, 2022spheroidH295RAlbumin-stabilized carrier nanoparticles efficiently delivered higher doses of mitotane to spheroids than are possible in aqueous solution.2022[98]
ACC15m (Bornstein, 2022)spheroidprimaryLymph node met-derived. Treatment history unpublished. No hormone secretion.2022[94]
Laha, 2022aggregateH295R, SW-3High-throughput drug screening identifying combination inhibition of MELK and CDK as potential therapeutic target.2022[71]
Bornstein, 2022spheroidprimary, MUC-, H295RStandardized spheroid generation in a custom 24-well plate format. Proof-of-concept for generation and pharmacological testing of not only malignant but also benign hyperplasia derived spheroids.2022[94]
Baregamian, 2023organoidprimaryThree ACC and five benign adrenal neoplasia established in continuous organoid culture. Hormone secretion reduced after second passage.2023[95]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Sedlack, A.J.H.; Hatfield, S.J.; Kumar, S.; Arakawa, Y.; Roper, N.; Sun, N.-Y.; Nilubol, N.; Kiseljak-Vassiliades, K.; Hoang, C.D.; Bergsland, E.K.; et al. Preclinical Models of Adrenocortical Cancer. Cancers 2023, 15, 2873. https://doi.org/10.3390/cancers15112873

AMA Style

Sedlack AJH, Hatfield SJ, Kumar S, Arakawa Y, Roper N, Sun N-Y, Nilubol N, Kiseljak-Vassiliades K, Hoang CD, Bergsland EK, et al. Preclinical Models of Adrenocortical Cancer. Cancers. 2023; 15(11):2873. https://doi.org/10.3390/cancers15112873

Chicago/Turabian Style

Sedlack, Andrew J. H., Samual J. Hatfield, Suresh Kumar, Yasuhiro Arakawa, Nitin Roper, Nai-Yun Sun, Naris Nilubol, Katja Kiseljak-Vassiliades, Chuong D. Hoang, Emily K. Bergsland, and et al. 2023. "Preclinical Models of Adrenocortical Cancer" Cancers 15, no. 11: 2873. https://doi.org/10.3390/cancers15112873

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop