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Horm Metab Res 2024; 56(01): 51-64
DOI: 10.1055/a-2204-4549
Review

Animal and Cell Culture Models of PPGLs – Achievements and Limitations

Bhargavi Karna
1   Institute for Diabetes and Cancer, Helmholtz Center Munich – German Research Center for Environmental Health, Neuherberg, Germany
,
Natalia Simona Pellegata
1   Institute for Diabetes and Cancer, Helmholtz Center Munich – German Research Center for Environmental Health, Neuherberg, Germany
2   Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
,
Hermine Mohr
1   Institute for Diabetes and Cancer, Helmholtz Center Munich – German Research Center for Environmental Health, Neuherberg, Germany
› Author Affiliations Funding Information Deutsche Forschungsgemeinschaft (CRC/Transregio 205 “The Adrenal: Central Relay in Health and Disease”, project number 314061271).
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Abstract

Research on rare tumors heavily relies on suitable models for basic and translational research. Paragangliomas (PPGL) are rare neuroendocrine tumors (NET), developing from adrenal (pheochromocytoma, PCC) or extra-adrenal (PGL) chromaffin cells, with an annual incidence of 2–8 cases per million. While most PPGL cases exhibit slow growth and are primarily treated with surgery, limited systemic treatment options are available for unresectable or metastatic tumors. Scarcity of appropriate models has hindered PPGL research, preventing the translation of omics knowledge into drug and therapy development. Human PPGL cell lines are not available, and few animal models accurately replicate the disease’s genetic and phenotypic characteristics. This review provides an overview of laboratory models for PPGLs, spanning cellular, tissue, organ, and organism levels. We discuss their features, advantages, and potential contributions to diagnostics and therapeutics. Interestingly, it appears that in the PPGL field, disease models already successfully implemented in other cancers have not been fully explored.

Key words

pheochromocytoma  - paraganglioma - PDX - SDHx - neuroendocrine tumor


Publication History

Received: 18 June 2023

Accepted after revision: 27 October 2023

Article published online:
03 January 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Cascón A, Calsina B, Monteagudo M. et al. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol 2023; 70: e220167
    CrossrefPubMedGoogle Scholar
  • 2 Fishbein L, Leshchiner I, Walter V. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 2017; 31: 181-193
    CrossrefPubMedGoogle Scholar
  • 3 Otis M, Campbell S, Payet MD. et al. Expression of extracellular matrix proteins and integrins in rat adrenal gland: importance for ACTH-associated functions. J Endocrinol 2007; 193: 331-347
    CrossrefPubMedGoogle Scholar
  • 4 Jansky S, Sharma AK, Körber V. et al. Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma. Nat Genet 2021; 53: 683-693
    CrossrefPubMedGoogle Scholar
  • 5 Zethoven M, Martelotto L, Pattison A. et al. Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment. Nat Commun 2022; 13: 6262
    CrossrefPubMedGoogle Scholar
  • 6 Richter S, D’Antongiovanni V, Martinelli S. et al. Primary fibroblast co-culture stimulates growth and metabolism in Sdhb-impaired mouse pheochromocytoma MTT cells. Cell Tissue Res 2018; 374: 473-485
    CrossrefPubMedGoogle Scholar
  • 7 Takahashi K. Pheochromocytoma and paraganglioma: challenges and opportunities in 2021. Intern Med 2021; 60: 7413-7421
    CrossrefPubMedGoogle Scholar
  • 8 Sanford T, Gomella PT, Siddiqui R. et al. Long term outcomes for patients with von Hippel-Lindau and pheochromocytoma: defining the role of active surveillance. Urol Oncol- Semin ORI 2021; 39: 134.e1-134.e8
    CrossrefPubMedGoogle Scholar
  • 9 Michałowska I, Ćwikła J, Michalski W. et al. Growth rate of paragangliomas related to germline mutations of the SDHx genes. Endocr Pract 2017; 23: 342-352
    CrossrefPubMedGoogle Scholar
  • 10 Pamporaki C, Prodanov T, Meuter L. et al. Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma. Eur J Cancer 2022; 169: 32-41
    CrossrefPubMedGoogle Scholar
  • 11 Furlan A, Dyachuk V, Kastriti ME. et al. Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. J Sci 2017; 357: eaal3753
    PubMedGoogle Scholar
  • 12 Brazda P, Ruiz-Moreno C, Megchelenbrink WL. et al. Extensive patient-to-patient single nucleus transcriptome heterogeneity in pheochromocytomas and paragangliomas. Front Oncol 2022; 12: 965168
    CrossrefPubMedGoogle Scholar
  • 13 Bradley HC, Belfer S. Autolysis of adrenal gland tissue. J Biol Chem 1938; 124: 331-338
    CrossrefPubMedGoogle Scholar
  • 14 Sedlack AJH, Saleh-Anaraki K, Kumar S. et al. Preclinical models of neuroendocrine neoplasia. Cancers 2022; 14: 5646
    CrossrefPubMedGoogle Scholar
  • 15 Bayley JP, Rebel HG, Scheurwater K. et al. Long-term in vitro 2D-culture of SDHB and SDHD-related human paragangliomas and pheochromocytomas. PLoS One 2022; 17: e0274478
    CrossrefPubMedGoogle Scholar
  • 16 Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 1976; 73: 2424-2428
    CrossrefPubMedGoogle Scholar
  • 17 Bayley JP, Devilee P. Advances in paraganglioma–pheochromocytoma cell lines and xenografts. Endocr Relat Cancer 2020; 27: R433-R450
    CrossrefPubMedGoogle Scholar
  • 18 Warren S, Hurst EE, Brown CE. et al. Anastomotic sarcoma of irradiated parabiont rats. Cancer Res 1972; 32: 983-987
    PubMedGoogle Scholar
  • 19 Chua P, Lim WK. Optimisation of a PC12 cell-based in vitro stroke model for screening neuroprotective agents. Sci Rep 2021; 11: 8096
    CrossrefPubMedGoogle Scholar
  • 20 Hopewell R, Ziff EB. The nerve growth factor-responsive PC12 cell line does not express the Myc dimerization partner Max. Mol Cell Biol 1995; 15: 3470-3478
    CrossrefPubMedGoogle Scholar
  • 21 Burnichon N, Cascón A, Schiavi F. et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 2012; 18: 2828-2837
    CrossrefPubMedGoogle Scholar
  • 22 Flynn A, Benn D, Clifton-Bligh R. et al. The genomic landscape of phaeochromocytoma. J Pathol 2015; 236: 78-89
    CrossrefPubMedGoogle Scholar
  • 23 Powers JF, Cochran B, Baleja JD. et al. A xenograft and cell line model of SDH-deficient pheochromocytoma derived from Sdhb+/− rats. Endocr Relat Cancer 2020; 27: 337-354
    CrossrefPubMedGoogle Scholar
  • 24 Dixon DN, Loxley RA, Barron A. et al. Comparative studies of PC12 and mouse Pheochromocytoma-derived rodent cell lines as models for the study of neuroendocrine systems. In Vitro Cell Dev Biol Anim 2005; 41: 197-206
    CrossrefPubMedGoogle Scholar
  • 25 Powers JF, Evinger MJ, Tsokas P. et al. Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice. Cell Tissue Res 2000; 302: 309-320
    CrossrefPubMedGoogle Scholar
  • 26 Zografos GN, Vasiliadis GK, Zagouri F. et al. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends. World J Surg Oncol 2010; 8: 1-4
    CrossrefPubMedGoogle Scholar
  • 27 Powers JF, Evinger MJ, Zhi J. et al. Pheochromocytomas in Nf1 knockout mice express a neural progenitor gene expression profile. J Neurosci 2007; 147: 928-937
    CrossrefPubMedGoogle Scholar
  • 28 Powers JF, Schelling K, Brachold JM. et al. High-level expression of receptor tyrosine kinase ret and responsiveness to ret-activating ligands in pheochromocytoma cell lines from neurofibromatosis knockout mice. Mol Cell Neurosci 2002; 20: 382-389
    CrossrefPubMedGoogle Scholar
  • 29 Nölting S, Grossman AB. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr Pathol 2012; 23: 21-33
    CrossrefPubMedGoogle Scholar
  • 30 Nölting S, Giubellino A, Tayem Y. et al. Combination of 13-cis retinoic acid and lovastatin: marked antitumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice. Endocrinology 2014; 155: 2377-2390
    CrossrefPubMedGoogle Scholar
  • 31 Martiniova L, Lai EW, Thomasson D. et al. Animal model of metastatic pheochromocytoma: evaluation by MRI and PET. Endocr Regul 2009; 43: 59-64
    PubMedGoogle Scholar
  • 32 Ullrich M, Bergmann R, Peitzsch M. et al. In vivo fluorescence imaging and urinary monoamines as surrogate biomarkers of disease progression in a mouse model of pheochromocytoma. Endocrinology 2014; 155: 4149-4156
    CrossrefPubMedGoogle Scholar
  • 33 Rapizzi E, Fucci R, Giannoni E. et al. Role of microenvironment on neuroblastoma SK-N-AS SDHB-silenced cell metabolism and function. Endocr Relat Cancer 2015; 22: 409-417
    CrossrefPubMedGoogle Scholar
  • 34 Ohta S, Lai EW, Morris JC. et al. MicroCT for high-resolution imaging of ectopic pheochromocytoma tumors in the liver of nude mice. Int J Cancer 2006; 119: 2236-2241
    CrossrefPubMedGoogle Scholar
  • 35 Martiniova L, Perera SM, Brouwers FM. et al. Increased uptake of [123I]meta-iodobenzylguanidine, [18F]fluorodopamine, and [3H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors. Endocr Relat Cancer 2011; 18: 143-157
    CrossrefPubMedGoogle Scholar
  • 36 Fankhauser M, Bechmann N, Lauseker M. et al. Synergistic highly potent targeted drug combinations in different pheochromocytoma models including human tumor cultures. Endocrinology 2019; 160: 2600-2617
    PubMedGoogle Scholar
  • 37 Nölting S, Garcia E, Alusi G. et al. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. J Mol Endocrinol 2012; 49: 79-96
    CrossrefPubMedGoogle Scholar
  • 38 Watts D, Bechmann N, Meneses A. et al. HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla. J Mol Med 2021; 99: 1655-1666
    CrossrefPubMedGoogle Scholar
  • 39 Leinhäuser I, Richter A, Lee M. et al. Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma. Oncotarget. 2015; 6: 39111-39126
    CrossrefPubMedGoogle Scholar
  • 40 Mellid S, Gil E, Letón R. et al. Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne) 2023; 13: 1070074
    CrossrefPubMedGoogle Scholar
  • 41 Jagannathan L, Cuddapah S, Costa M. Oxidative stress under ambient and physiological oxygen tension in tissue culture. Curr Pharmacol Rep 2016; 2: 64-72
    CrossrefPubMedGoogle Scholar
  • 42 Pfragner R, Behmel A, Smith DP. et al. First continuous human pheochromocytoma cell line: KNA Biological, cytogenetic and molecular characterization of KNA cells. J Neurocytol 1998; 27: 175-186
    CrossrefPubMedGoogle Scholar
  • 43 Venihaki M, Gravanis A, Margioris AN. KAT45 human pheochromocytoma cell line : A new model for the in vitro study of neuro-immuno-hormonal interactions. Ann N Y Acad Sci 1998; 840: 425-433
    CrossrefPubMedGoogle Scholar
  • 44 Stuschke M, Budach V, Stüben G. et al. Heterogeneity in the fractionation sensitivities of human tumor cell lines: Studies in a three-dimensional model system. Int J Radiat 1995; 32: 395-408
    PubMedGoogle Scholar
  • 45 Letouzé E, Martinelli C, Loriot C. et al. Sdh mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013; 23: 739-752
    CrossrefPubMedGoogle Scholar
  • 46 Fankhauser M, Bechmann N, Lauseker M. et al. Synergistic highly potent targeted drug combinations in different pheochromocytoma models including human tumor cultures. Endocrinology 2019; 160: 2600-2617
    CrossrefPubMedGoogle Scholar
  • 47 Lussey-Lepoutre C, Hollinshead KE, Ludwig C. et al. Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat Commun 2015; 6: 8784
    CrossrefPubMedGoogle Scholar
  • 48 Loriot C, Domingues M, Berger A. et al. Deciphering the molecular basis of invasiveness in Sdhb -deficient cells. Oncotarget 2015; 6: 32955-32965
    CrossrefPubMedGoogle Scholar
  • 49 Moog S, Salgues B, Braik-Djellas Y. et al. Preclinical evaluation of targeted therapies in Sdhb-mutated tumors. Endocr Relat Cancer 2022; 29: 375-388
    CrossrefPubMedGoogle Scholar
  • 50 Ghayee HK, Bhagwandin VJ, Stastny V. et al. Progenitor cell line (hpheo1) derived from a human pheochromocytoma tumor. PLoS One 2013; 8: e65624
    CrossrefPubMedGoogle Scholar
  • 51 Kastriti ME, Kameneva P, Kamenev D. et al. Schwann cell precursors generate the majority of chromaffin cells in zuckerkandl organ and some sympathetic neurons in paraganglia. Front Mol Neurosci 2019; 12: 6
    CrossrefPubMedGoogle Scholar
  • 52 Abu-Bonsrah KD, Zhang D, Bjorksten AR. et al. Generation of adrenal chromaffin-like cells from human pluripotent stem cells. Stem Cell Rep 2018; 10: 134-150
    CrossrefPubMedGoogle Scholar
  • 53 Marin Navarro A, Susanto E, Falk A. et al. Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies. Cell Death Discov 2018; 4: 7
    CrossrefPubMedGoogle Scholar
  • 54 Papapetrou EP. Patient-derived induced pluripotent stem cells in cancer research and precision oncology. Nat Med 2016; 22: 1392-1401
    CrossrefPubMedGoogle Scholar
  • 55 Mizrachi Y, Naranjo JR, Levi BZ. et al. PC12 cells differentiate into chromaffin cell-like phenotype in coculture with adrenal medullary endothelial cells. Proc Natl Acad Sci U S A 1990; 87: 6161-6165
    CrossrefPubMedGoogle Scholar
  • 56 Santana MM, Chung KF, Vukicevic V. et al. Isolation, characterization, and differentiation of progenitor cells from human adult adrenal medulla. Stem Cells Transl Med 2012; 1: 783-791
    CrossrefPubMedGoogle Scholar
  • 57 Wang K, Schütze I, Gulde S. et al. Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. Endocr Relat Cancer 2022; 29: 285-306
    CrossrefPubMedGoogle Scholar
  • 58 Bayley JP, Rebel HG, Scheurwater K. et al. Long-term in vitro 2D-culture of SDHB and SDHD-related human paragangliomas and pheochromocytomas. PLoS One 2022; 17: e0274478
    CrossrefPubMedGoogle Scholar
  • 59 Xu R, Zhou X, Wang S. et al. Tumor organoid models in precision medicine and investigating cancer-stromal interactions. Pharmacol Ther 2021; 218: 107668
    CrossrefPubMedGoogle Scholar
  • 60 Bechmann N, Poser I, Seifert V. et al. Impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or presence of Hif2α in pheochromocytoma cells. Cancers 2019; 11: 594
    CrossrefPubMedGoogle Scholar
  • 61 Seifert V, Richter S, Bechmann N. et al. HIF2alpha-associated pseudohypoxia promotes radioresistance in pheochromocytoma: insights from 3D models. Cancers 2021; 13: 385
    CrossrefPubMedGoogle Scholar
  • 62 Martinelli S, Riverso M, Mello T. et al. SDHB and SDHD silenced pheochromocytoma spheroids respond differently to tumour microenvironment and their aggressiveness is inhibited by impairing stroma metabolism. Mol Cell Endocrinol 2022; 547: 111594
    CrossrefPubMedGoogle Scholar
  • 63 Nguyen HTL, Soragni A. Patient-derived tumor organoid rings for histologic characterization and high-throughput screening. STAR Protoc 2020; 1: 100056
    CrossrefPubMedGoogle Scholar
  • 64 Petrovic J, Walsh PL, Thornley KT. et al. Real-time monitoring of chemical transmission in slices of the murine adrenal gland. Endocrinology 2010; 151: 1773-1783
    CrossrefPubMedGoogle Scholar
  • 65 Chan S, Smith C. Low frequency stimulation of mouse adrenal slices reveals a clathrin-independent, protein kinase c-mediated endocytic mechanism. J Physiol 2003; 553: 707-717
    CrossrefPubMedGoogle Scholar
  • 66 De Nardi F, Lefort C, Bréard D. et al. Monitoring the secretory behavior of the rat adrenal medulla by high-performance liquid chromatography-based catecholamine assay from slice supernatants. Front Endocrinol (Lausanne) 2017; 8: 248
    CrossrefPubMedGoogle Scholar
  • 67 Takács-Vellai K, Farkas Z, Ősz F. et al. Model systems in SDHx-related pheochromocytoma/paraganglioma. Cancer and Metastasis Rev 2021; 40: 1177-1201
    CrossrefPubMedGoogle Scholar
  • 68 Yi-Wen L. Interrenal Organogenesis in the Zebrafish Model. Organogenesis 2007; 3: 44-48
    CrossrefPubMedGoogle Scholar
  • 69 van Rooijen E, Santhakumar K, Logister I. et al. A zebrafish model for VHL and hypoxia signaling. Methods Cell Biol 2011; 105: 163-190
    CrossrefPubMedGoogle Scholar
  • 70 Dona M, Waaijers S, Richter S. et al. Loss of sdhb in zebrafish larvae recapitulates human paraganglioma characteristics. Endocr Relat Cancer 2021; 28: 65-77
    CrossrefPubMedGoogle Scholar
  • 71 Dona M, Lamers M, Rohde S. et al. Targeting the redox balance pathway using ascorbic acid in Sdhb zebrafish mutant larvae. Cancers 2021; 13: 5124
    CrossrefPubMedGoogle Scholar
  • 72 Piruat JI, Pintado CO, Ortega-Sáenz P. et al. The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia. Mol Cell Biol 2004; 24: 10933-10940
    CrossrefPubMedGoogle Scholar
  • 73 Bayley JP, van Minderhout I, Hogendoorn PC. et al. Sdhd and Sdhd/H19 knockout mice do not develop paraganglioma or pheochromocytoma. PLoS One 2009; 4: e7987
    CrossrefPubMedGoogle Scholar
  • 74 Maher LJ, Smith EH, Rueter EM. et al. Mouse models of human familial paraganglioma. IntechOpen.com 2011; DOI: 10.5772/25346.
    CrossrefPubMedGoogle Scholar
  • 75 Lepoutre-Lussey C, Thibault C, Buffet A. et al. From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma. Mol Cell Endocrinol 2016; 421: 40-48
    CrossrefPubMedGoogle Scholar
  • 76 Armstrong N, Storey CM, Noll SE. et al. SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas. Cell Rep 2022; 38: 110453
    CrossrefPubMedGoogle Scholar
  • 77 Wang H, Cui J, Yang C. et al. A transgenic mouse model of Pacak–Zhuang syndrome with an Epas1 gain-of-function mutation. Cancers 2019; 11: 667
    CrossrefPubMedGoogle Scholar
  • 78 Gnarra JR, Ward JM, Porter FD. et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A 1997; 94: 9102-9107
    CrossrefPubMedGoogle Scholar
  • 79 Jacks T, Shih TS, Schmitt EM. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 1994; 7: 353-361
    CrossrefPubMedGoogle Scholar
  • 80 Smith-Hicks CL, Sizer KC, Powers JF. et al. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO J 2000; 19: 612-622
    CrossrefPubMedGoogle Scholar
  • 81 Chao RC, Pyzel U, Fridlyand J. et al. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell 2005; 8: 337-348
    CrossrefPubMedGoogle Scholar
  • 82 Engelmann D, Koczan D, Ricken P. et al. Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance. Endocr Relat Cancer 2009; 16: 211-224
    CrossrefPubMedGoogle Scholar
  • 83 Schulz N, Propst F, Rosenberg MP. et al. Pheochromocytomas and C-cell thyroid neoplasms in transgenic c-mos mice: a model for the human multiple endocrine neoplasia type 2 syndrome. Cancer Res 1992; 52: 450-455
    PubMedGoogle Scholar
  • 84 van Veelen W, Klompmaker R, Gloerich M. et al. P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. Int J Cancer 2009; 124: 339-345
    CrossrefPubMedGoogle Scholar
  • 85 Reilly KM. The effects of genetic background of mouse models of cancer: friend or foe?. Cold Spring Harb Protoc 2016; pdb-top076273
    PubMedGoogle Scholar
  • 86 Giubellino A, Woldemichael GM, Sourbier C. et al. Characterization of two mouse models of metastatic pheochromocytoma using bioluminescence imaging. Cancer Lett 2012; 316: 46-52
    CrossrefPubMedGoogle Scholar
  • 87 Mohr H, Foscarini A, Steiger K. et al. Imaging pheochromocytoma in small animals: preclinical models to improve diagnosis and treatment. EJNMMI Res 2021; 11: 1-14
    CrossrefPubMedGoogle Scholar
  • 88 Pang Y, Yang C, Schovanek J. et al. Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway. Oncotarget 2017; 8: 22313-22324
    CrossrefPubMedGoogle Scholar
  • 89 Denorme M, Yon L, Roux C. et al. Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model. Cancer Lett 2014; 352: 236-244
    CrossrefPubMedGoogle Scholar
  • 90 Zielke A, Bresalier RS, Allan E. et al. A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytomaxenografts to nude mice and establishment of metastases-derived PC12 variants. Clin Exp Metastasis 1998; 16: 341-352
    CrossrefPubMedGoogle Scholar
  • 91 Gross DJ, Reibstein I, Weiss L. et al. The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice. Clin Cancer Res 1999; 5: 3669-3675
    PubMedGoogle Scholar
  • 92 Powers JF, Pacak K, Tischler AS. Pathology of human pheochromocytoma and paraganglioma xenografts in NSG Mice. Endocr Pathol 2017; 28: 2-6
    CrossrefPubMedGoogle Scholar
  • 93 Verginelli F, Perconti S, Vespa S. et al. Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib. Acta Neuropathol 2018; 135: 779-798
    CrossrefPubMedGoogle Scholar
  • 94 Greim H, Hartwig A, Reuter U. et al. Chemically induced pheochromocytomas in rats: mechanisms and relevance for human risk assessment. Crit Rev Toxicol 2009; 39: 695-718
    CrossrefPubMedGoogle Scholar
  • 95 Tischler AS. Vitamin D3-induced proliferative lesions in the rat adrenal medulla. Toxicol Sci 1999; 51: 9-18
    CrossrefPubMedGoogle Scholar
  • 96 Jochmanova I, Wolf KI, King KS. et al. SDHB-related pheochromocytoma and paraganglioma penetrance and genotype–phenotype correlations. J Cancer Res Clin Oncol 2017; 143: 1421-1435
    CrossrefPubMedGoogle Scholar
  • 97 Pellegata NS, Quintanilla-Martinez L, Siggelkow H. et al. Germ-line mutations in p27 Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 2006; 103: 15558-15563
    CrossrefPubMedGoogle Scholar
  • 98 Mohr H, Ballke S, Bechmann N. et al. Mutation of the cell cycle regulator P27KIP1 drives pseudohypoxic pheochromocytoma development. Cancers 2021; 13: 126
    CrossrefPubMedGoogle Scholar
  • 99 Wiedemann T, Peitzsch M, Qin N. et al. Morphology, biochemistry, and pathophysiology of MENX-related pheochromocytoma recapitulate the clinical features. Endocrinology 2016; 157: 3157-3166
    CrossrefPubMedGoogle Scholar
  • 100 Molatore S, Liyanarachchi S, Irmler M. et al. Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma. Proc Natl Acad Sci U S A 2010; 107: 18493-18498
    CrossrefPubMedGoogle Scholar
  • 101 Miederer M, Molatore S, Marinoni I. et al. Functional imaging of pheochromocytoma with 68 Ga-DOTATOC and 68 C-HED in a genetically defined rat model of multiple endocrine neoplasia. Int J Mol Imaging 2011; 175352 DOI: 10.1155/2011/175352.
    CrossrefPubMedGoogle Scholar
  • 102 Lee M, Marinoni I, Irmler M. et al. Transcriptome analysis of MENX-associated rat pituitary adenomas identifies novel molecular mechanisms involved in the pathogenesis of human pituitary gonadotroph adenomas. Acta Neuropathol 2013; 126: 137-150
    CrossrefPubMedGoogle Scholar
  • 103 Barthez PY, Marks SL, Woo J. et al. Pheochromocytoma in dogs: 61 cases (1984-1995). J Vet Intern 1997; 11: 272-278
    PubMedGoogle Scholar
  • 104 Galac S, Korpershoek E. Pheochromocytomas and paragangliomas in humans and dogs. Vet Comp Oncol 2017; 15: 1158-1170
    CrossrefPubMedGoogle Scholar
  • 105 Korpershoek E, Dieduksman DA, Grinwis GC. et al. Molecular alterations in dog pheochromocytomas and paragangliomas. Cancers 2019; 11: 607
    CrossrefPubMedGoogle Scholar
  • 106 Enright D, Dickerson VM, Grimes JA. et al. Short- and long-term survival after adrenalectomy in 53 dogs with pheochromocytomas with or without alpha-blocker therapy. Vet Surg 2022; 51: 438-446
    CrossrefPubMedGoogle Scholar
  • 107 Tischler AS, Favier J. Progress and challenges in experimental models for pheochromocytoma and paraganglioma. Endocr Relat Cancer 2023; 30: e220405
    PubMedGoogle Scholar
  • 108 Cama A, Verginelli F, Lotti LV. et al. Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling. Acta Neuropathol 2013; 126: 575-594
    CrossrefPubMedGoogle Scholar
  • 109 Florio R, De Lellis L, di Giacomo V. et al. Effects of PPARalpha inhibition in head and neck paraganglioma cells. PLoS One 2017; 12: e0178995
    CrossrefPubMedGoogle Scholar
  • 110 Franklin DS, Godfrey VL, O’Brien DA. et al. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 2000; 20: 6147-6158
    CrossrefPubMedGoogle Scholar
  • 111 Di Cristofano A, De Acetis M, Koff A. et al. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 2001; 27: 222-224
    CrossrefPubMedGoogle Scholar
  • 112 You MJ, Castrillon DH, Bastian BC. et al. Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. Proc Natl Acad Sci 2002; 99: 1455-1460
    CrossrefPubMedGoogle Scholar
  • 113 Nikitin AY, Juárez-Pérez MI, Li S, Huang L. et al. RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/− mice. Proc Natl Acad Sci 1999; 96: 3916-3921
    CrossrefPubMedGoogle Scholar
  • 114 Dannenberg JH, Schuijff L, Dekker M. et al. Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Develop 2004; 18: 2952-2962
    CrossrefPubMedGoogle Scholar
  • 115 Tonks ID, Mould AW, Schroder WA. et al. Dual loss of rb1 and Trp53 in the adrenal medulla leads to spontaneous pheochromocytoma. Neoplasia 2010; 12: 235-243
    CrossrefPubMedGoogle Scholar
  • 116 Lai EW, Rodriguez OC, Aventian M. et al. ErbB-2 Induces Bilateral Adrenal Pheochromocytoma Formation in Mice. Cell Cycle 2007; 6: 1946-1950
    CrossrefPubMedGoogle Scholar
  • 117 Park WJ, Brenner O, Kogot-Levin A. et al. Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr Relat Cancer 2015; 22: 623
    CrossrefPubMedGoogle Scholar
  • 118 Scortegagna M, Ding K, Oktay Y. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat Genet 2003; 35: 331-340
    CrossrefPubMedGoogle Scholar
  • 119 Tian H, Hammer RE, Matsumoto AM. et al. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Develop 1998; 12: 3320-3324
    CrossrefPubMedGoogle Scholar
  • 120 Peng YJ, Nanduri J, Khan SA. et al. Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci 2011; 108: 3065-3070
    CrossrefPubMedGoogle Scholar
  • 121 Macias D, Cowburn AS, Torres-Torrelo H. et al. HIF-2α is essential for carotid body development and function. Elife 2018; 7: e34681
    CrossrefPubMedGoogle Scholar
  • 122 Fielding JW, Hodson EJ, Cheng X. et al. PHD2 inactivation in Type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies. J Physiol 2018; 596: 4393-4412
    CrossrefPubMedGoogle Scholar
  • 123 Ma W, Tessarollo L, Hong SB. et al. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res 2003; 63: 5320-5328
    PubMedGoogle Scholar
  • 124 Macías D, Fernández-Agüera MC, Bonilla-Henao V. et al. Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor-mediated adaptation to hypoxia. EMBO Mol Med 2014; 6: 1577-1592
    CrossrefPubMedGoogle Scholar
  • 125 Eckardt L, Prange-Barczynska M, Hodson EJ. et al. Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma. Endocr Relat Cancer 2021; 28: 757-772
    CrossrefPubMedGoogle Scholar
  • 126 Al Khazal F, Kang S, Holte MN. et al. Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency. FASEB J 2021; 35: e21227
    CrossrefPubMedGoogle Scholar
  • 127 Díaz-Castro B, Pintado CO, García-Flores P. et al. Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction. Mol Cell Biol 2012; 32: 3347-3357
    CrossrefPubMedGoogle Scholar
  • 128 Pollard PJ, Spencer-Dene B, Shukla D. et al. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007; 11: 311-319
    CrossrefPubMedGoogle Scholar