Astrocytoma: A Hormone-Sensitive Tumor?
Abstract
:1. Glioma
1.1. Etiology
1.2. Classification
1.3. Current Treatment
1.4. Evolution of Worldwide Incidence/Survival
2. Gender Differences in Astrocytoma: The Hypothesis of Steroid Hormones
2.1. Steroid Biosynthesis
2.2. Steroid Functions in Normal Brain
2.3. Clinical Data: The Female Hormone Paradox
2.3.1. Contraceptive Pills and Hormone Replacement Therapy: The Two Facets of Exogenous Hormones
2.3.2. Hormone Burst During Pregnancy: A Trigger Toward Disease Progression?
2.4. Animal and In Vitro Studies
2.4.1. Exogenous Estrogen Exposure: A Promising Track to Modulate Tumor Hallmarks
2.4.2. The Pro-Tumoral Role of Aromatase
2.4.3. Exogenous Progesterone Exposure: A Dose-Dependent Modulation of Malignancy
2.4.4. Exogenous Androgen Exposure: High Levels and Increased Malignancy
2.4.5. Exogenous Glucocorticoids Exposure: Still Incomplete and Debated Data
3. Steroid Receptors and Downstream Signaling
3.1. Estrogen Receptors, Complex and Interconnected Signaling Pathways
3.1.1. Focus on ERβ5, an Ambivalent Receptor
3.1.2. Focus on ERβ1, a Tumor Suppressor?
3.2. Progesterone Receptors: The PR-A Isoform
3.3. Androgen Receptors
3.4. Glucocorticoid Receptors: Multiple Isoforms but Limited Data
4. Conclusions and Future Prospects
5. Data Source Extraction and Management
Author Contributions
Funding
Conflicts of Interest
References
- Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol. 2007, 114, 97–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perry, A.; Wesseling, P. Histologic classification of gliomas. In Handbook of Clinical Neurology; Elsevier: Amsterdam, The Netherlands, 2016; Volume 134, pp. 71–95. [Google Scholar] [CrossRef]
- Tabouret, E.; Network, F.P.; Nguyen, A.T.; Dehais, C.; Carpentier, C.; Ducray, F.; Idbaih, A.; Mokhtari, K.; Jouvet, A.; Uro-Coste, E.; et al. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort. Acta Neuropathol. 2016, 132, 625–634. [Google Scholar] [CrossRef] [PubMed]
- Komori, T. The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision. Neurol. Medico Chirur. 2017, 57, 301–311. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ye, D.; Guan, K.-L.; Xiong, Y. Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates. Trends Cancer 2018, 4, 151–165. [Google Scholar] [CrossRef] [Green Version]
- Houillier, C.; Wang, X.; Kaloshi, G.; Mokhtari, K.; Guillevin, R.; Laffaire, J.; Paris, S.; Boisselier, B.; Idbaih, A.; Laigle-Donadey, F.; et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 2010, 75, 1560–1566. [Google Scholar] [CrossRef]
- Natsumeda, M.; Igarashi, H.; Nomura, T.; Ogura, R.; Tsukamoto, Y.; Kobayashi, T.; Aoki, H.; Okamoto, K.; Kakita, A.; Takahashi, H.; et al. Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: A study by 3.0-tesla magnetic resonance spectroscopy. Acta Neuropathol. Commun. 2014, 2, 158. [Google Scholar] [CrossRef] [Green Version]
- Tran, A.N.; Lai, A.; Li, S.; Pope, W.B.; Teixeira, S.; Harris, R.J.; Woodworth, D.C.; Nghiemphu, P.L.; Cloughesy, T.F.; Ellingson, B.M. Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro Oncol. 2014, 16, 414–420. [Google Scholar] [CrossRef]
- Monga, V.; Jones, K.; Chang, S. Clinical Relevance of Molecular Markers in Gliomas. Rev. Méd. Clín. Condes 2017, 28, 343–351. [Google Scholar] [CrossRef]
- Esteller, M.; Garcia-Foncillas, J.; Andion, E.; Goodman, S.N.; Hidalgo, O.F.; Vanaclocha, V.; Baylin, S.B.; Herman, J.G. Inactivation of the DNA-Repair GeneMGMTand the Clinical Response of Gliomas to Alkylating Agents. N. Engl. J. Med. 2000, 343, 1350–1354. [Google Scholar] [CrossRef]
- Chen, R.; Smith-Cohn, M.; Cohen, A.L.; Colman, H. Glioma Subclassifications and Their Clinical Significance. Neurotherapeutics 2017, 14, 284–297. [Google Scholar] [CrossRef] [Green Version]
- Lee, E.; Yong, R.L.; Paddison, P.; Zhu, J. Comparison of glioblastoma (GBM) molecular classification methods. Semin. Cancer Biol. 2018, 53, 201–211. [Google Scholar] [CrossRef] [PubMed]
- Mellinghoff, I.K.; Ellingson, B.M.; Touat, M.; Maher, E.; De La Fuente, M.I.; Holdhoff, M.; Cote, G.M.; Burris, H.; Janku, F.; Young, R.J.; et al. Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma. J. Clin. Oncol. 2020, 38, 3398–3406. [Google Scholar] [CrossRef] [PubMed]
- Golub, D.; Iyengar, N.; Dogra, S.; Wong, T.; Bready, D.; Tang, K.; Modrek, A.S.; Placantonakis, D.G. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Front. Oncol. 2019, 9, 417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Feigin, V.L.; Nichols, E.; Alam, T.; Bannick, M.S.; Beghi, E.; Blake, N.; Culpepper, W.J.; Dorsey, E.R.; Elbaz, A.; Ellenbogen, R.G.; et al. Global, regional, and national burden of neurological disorders, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019, 18, 459–480. [Google Scholar] [CrossRef] [Green Version]
- Leece, R.; Xu, J.; Ostrom, Q.T.; Chen, Y.; Kruchko, C.; Barnholtz-Sloan, J.S. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 2017, 19, 1553–1564. [Google Scholar] [CrossRef]
- Sant, M.; Minicozzi, P.; Lagorio, S.; Johannesen, T.B.; Marcos-Gragera, R.; Francisci, S.; the EUROCARE Working Group. Survival of European patients with central nervous system tumors. Int. J. Cancer 2011, 131, 173–185. [Google Scholar] [CrossRef]
- Hemminki, K.; Ji, J.; Brandt, A.; Mousavi, S.M.; Sundquist, K. The Swedish Family-Cancer Database 2009: Prospects for histology-specific and immigrant studies. Int. J. Cancer 2010, 126, 2259–2267. [Google Scholar] [CrossRef]
- Hemminki, K.; Li, X. Cancer risks in second-generation immigrants to Sweden. Int. J. Cancer 2002, 99, 229–237. [Google Scholar] [CrossRef]
- Patel, A.P.; Fisher, J.L.; Nichols, E.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; Abraha, H.N.; Agius, D.; Alahdab, F.; Alam, T.; et al. Global, regional, and national burden of brain and other CNS cancer, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019, 18, 376–393. [Google Scholar] [CrossRef] [Green Version]
- Dubrow, R.; Darefsky, A.S. Demographic variation in incidence of adult glioma by subtype, United States, 1992–2007. BMC Cancer 2011, 11, 325. [Google Scholar] [CrossRef] [Green Version]
- Cohen, A.; Modan, B. Some epidemiologic aspects of neoplastic diseases in Israeli immigrant population. III. Brain tumors. Cancer 1968, 22, 1323–1328. [Google Scholar] [CrossRef]
- Ostrom, M.Q.T.; Gittleman, M.H.; Xu, B.J.; Kromer, M.C.; Wolinsky, P.Y.; Kruchko, B.C.; Barnholtz-Sloan, P.J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Neuro Oncol. 2016, 18, v1–v75. [Google Scholar] [CrossRef] [Green Version]
- Yang, W.; Warrington, N.M.; Taylor, S.J.; Whitmire, P.; Carrasco, E.; Singleton, K.W.; Wu, N.; Lathia, J.D.; Berens, M.E.; Kim, A.H.; et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci. Transl. Med. 2019, 11, eaao5253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baldi, I.; Gruber, A.; Alioum, A.; Berteaud, E.; LeBailly, P.; Huchet, A.; Tourdias, T.; Kantor, G.; Maire, J.P.; Vital, A.; et al. Descriptive epidemiology of CNS tumors in France: Results from the Gironde Registry for the period 2000–2007. Neuro Oncol. 2011, 13, 1370–1378. [Google Scholar] [CrossRef] [PubMed]
- Kabat, G.C.; Etgen, A.M.; Rohan, T.E. Do Steroid Hormones Play a Role in the Etiology of Glioma? Cancer Epidemiol. Biomark. Prev. 2010, 19, 2421–2427. [Google Scholar] [CrossRef] [Green Version]
- Gittleman, H.; Cioffi, G.; Vecchione-Koval, T.; Ostrom, Q.T.; Kruchko, C.; Osorio, D.S.; Finlay, J.L.; Barnholtz-Sloan, J.S. Descriptive epidemiology of germ cell tumors of the central nervous system diagnosed in the United States from 2006 to 2015. J. Neuro Oncol. 2019, 143, 251–260. [Google Scholar] [CrossRef]
- Ostrom, Q.T.; Gittleman, H.; Stetson, L.; Virk, S.M.; Barnholtz-Sloan, J.S. Epidemiology of Gliomas. Cancer Treat Res 2015, 163, 1–14. [Google Scholar] [CrossRef]
- Josso, N.; Rey, R. La cellule de Sertoli, une cellule endocrine. Médecine/Sciences 1995, 11, 537. [Google Scholar] [CrossRef] [Green Version]
- Carreau, S.; Bois, C.; Zanatta, L.; Silva, F.; Bouraima-Lelong, H.; Delalande, C. Estrogen signaling in testicular cells. Life Sci. 2011, 89, 584–587. [Google Scholar] [CrossRef]
- Bennink, H.J.T.C.; Holinka, C.F.; Diczfalusy, E. Estetrol review: Profile and potential clinical applications. Climacteric 2008, 11, 47–58. [Google Scholar] [CrossRef]
- Samavat, H.; Kurzer, M.S. Estrogen metabolism and breast cancer. Cancer Lett. 2015, 356, 231–243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Banks, W.A. Brain Meets Body: The Blood-Brain Barrier as an Endocrine Interface. Endocrinology 2012, 153, 4111–4119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Frye, C.A. Steroids, reproductive endocrine function, and affect. A review. Minerva Ginecol. 2009, 61, 541–562. [Google Scholar] [PubMed]
- Cui, J.; Shen, Y.; Li, R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol. Med. 2013, 19, 197–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Azcoitia, I.; Yagüe, J.G.; García-Segura, L.M. Estradiol synthesis within the human brain. Neuroscience 2011, 191, 139–147. [Google Scholar] [CrossRef]
- Rossetti, M.F.; Cambiasso, M.J.; Holschbach, M.A.; Cabrera, R. Oestrogens and Progestagens: Synthesis and Action in the Brain. J. Neuroendocr. 2016, 28. [Google Scholar] [CrossRef]
- Jellinck, P.H.; Hahn, E.F.; Norton, B.I.; Fishman, J. Catechol Estrogen Formation and Metabolism in Brain Tissue: Comparison of Tritium Release from Different Positions in Ring A of the Steroid. Endocrinology 1984, 115, 1850–1856. [Google Scholar] [CrossRef]
- He, Z.; Zhang, S.S.; Meng, Q.; Li, S.; Zhu, H.H.; Raquil, M.-A.; Alderson, N.; Zhang, H.; Wu, J.; Rui, L.; et al. Shp2 Controls Female Body Weight and Energy Balance by Integrating Leptin and Estrogen Signals. Mol. Cell. Biol. 2012, 32, 1867–1878. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Kang, Y.; Wei, L.; Liu, W.; Tian, Y.; Chen, B.; Lin, X.; Li, Y.; Feng, G.-S.; Lu, Z. Tyrosine Phosphatase Shp2 Mediates the Estrogen Biological Action in Breast Cancer via Interaction with the Estrogen Extranuclear Receptor. PLoS ONE 2014, 9, e102847. [Google Scholar] [CrossRef] [Green Version]
- Rettberg, J.R.; Yao, J.; Brinton, R.D. Estrogen: A master regulator of bioenergetic systems in the brain and body. Front. Neuroendocr. 2014, 35, 8–30. [Google Scholar] [CrossRef] [Green Version]
- Barakat, R.; Oakley, O.; Kim, H.; Jin, J.; Ko, C.J. Extra-gonadal sites of estrogen biosynthesis and function. BMB Rep. 2016, 49, 488–496. [Google Scholar] [CrossRef]
- González-Orozco, J.C.; Camacho-Arroyo, I. Progesterone Actions During Central Nervous System Development. Front. Neurosci. 2019, 13, 503. [Google Scholar] [CrossRef] [Green Version]
- Nguyen, T.-V. Developmental effects of androgens in the human brain. J. Neuroendocr. 2018, 30, e12486. [Google Scholar] [CrossRef]
- Farinetti, A.; Tomasi, S.; Foglio, B.; Ferraris, A.; Ponti, G.; Gotti, S.; Peretto, P.; Panzica, G. Testosterone and estradiol differentially affect cell proliferation in the subventricular zone of young adult gonadectomized male and female rats. Neuroscisence 2015, 286, 162–170. [Google Scholar] [CrossRef] [Green Version]
- Diotel, N.; Charlier, T.D.; D’Hellencourt, C.L.; Couret, D.; Trudeau, V.L.; Nicolau, J.C.; Meilhac, O.; Kah, O.; Pellegrini, E. Steroid Transport, Local Synthesis, and Signaling within the Brain: Roles in Neurogenesis, Neuroprotection, and Sexual Behaviors. Front. Neurosci. 2018, 12, 84. [Google Scholar] [CrossRef] [Green Version]
- Carson, R.; Monaghan-Nichols, A.P.; DeFranco, D.B.; Rudine, A.C. Effects of antenatal glucocorticoids on the developing brain. Steroids 2016, 114, 25–32. [Google Scholar] [CrossRef] [Green Version]
- Fietta, P.; Fietta, P. Glucocorticoids and brain functions. Riv. Biol. 2008, 100, 403–418. [Google Scholar]
- Koenig, J.I.; Kirkpatrick, B.; Lee, P. Glucocorticoid Hormones and Early Brain Development in Schizophrenia. Neuropsychopharmacology 2002, 27, 309–318. [Google Scholar] [CrossRef]
- Cowppli-Bony, A.; Bouvier, G.; Rué, M.; Loiseau, H.; Vital, A.; LeBailly, P.; Fabbro-Peray, P.; Baldi, I. Brain tumors and hormonal factors: Review of the epidemiological literature. Cancer Causes Control 2011, 22, 697–714. [Google Scholar] [CrossRef]
- Felini, M.J.; Olshan, A.F.; Schroeder, J.C.; Carozza, S.E.; Miike, R.; Rice, T.; Wrensch, M. Reproductive factors and hormone use and risk of adult gliomas. Cancer Causes Control 2008, 20, 87–96. [Google Scholar] [CrossRef] [Green Version]
- Lan, Y.-L.; Wang, X.; Lou, J.-C.; Ma, B.-B.; Xing, J.-S.; Zou, S.; Zhang, B. Update on the effect of exogenous hormone use on glioma risk in women: A meta-analysis of case-control and cohort studies. J. Neuro Oncol. 2017, 137, 357–365. [Google Scholar] [CrossRef]
- Benson, V.S.; for the Million Women Study Collaborators; Pirie, K.; Green, J.; Casabonne, D.; Beral, V. Lifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort. Br. J. Cancer 2008, 99, 185–190. [Google Scholar] [CrossRef]
- Kabat, G.C.; Park, Y.; Hollenbeck, A.R.; Schatzkin, A.; Rohan, T.E. Reproductive factors and exogenous hormone use and risk of adult glioma in women in the NIH-AARP Diet and Health Study. Int. J. Cancer 2010, 128, 944–950. [Google Scholar] [CrossRef]
- Andersen, L.; Friis, S.; Hallas, J.; Ravn, P.; Kristensen, B.W.; Gaist, D. Hormonal contraceptive use and risk of glioma among younger women: A nationwide case-control study. Br. J. Clin. Pharmacol. 2015, 79, 677–684. [Google Scholar] [CrossRef] [Green Version]
- Forster, M.-T.; Baumgarten, P.; Gessler, F.; Maurer, G.; Senft, C.; Hattingen, E.; Seifert, V.; Harter, P.N.; Franz, K. Influence of pregnancy on glioma patients. Acta Neurochir. 2019, 161, 535–543. [Google Scholar] [CrossRef]
- Pallud, J.; Mandonnet, E.; Deroulers, C.; Fontaine, D.; Badoual, M.; Capelle, L.; Guillet-May, F.; Page, P.; Peruzzi, P.; Jouanneau, E.; et al. Pregnancy increases the growth rates of WHO grade II gliomas. Ann. Neurol. 2009, 67, 398–404. [Google Scholar] [CrossRef]
- Peeters, S.M.; Pagès, M.; Gauchotte, G.; Miquel, C.; Cartalat-Carel, S.; Guillamo, J.-S.; Capelle, L.; Delattre, J.-Y.; Beauchesne, P.; Debouverie, M.; et al. Interactions between glioma and pregnancy: Insight from a 52-case multicenter series. J. Neurosurg. 2018, 128, 3–13. [Google Scholar] [CrossRef] [Green Version]
- Van Westrhenen, A.; Senders, J.T.; Martin, E.; DiRisio, A.C.; Broekman, M.L.D. Clinical challenges of glioma and pregnancy: A systematic review. J. Neuro Oncol. 2018, 139, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Barone, T.A.; Gorski, J.W.; Greenberg, S.J.; Plunkett, R. Estrogen increases survival in an orthotopic model of glioblastoma. J. Neuro Oncol. 2009, 95, 37–48. [Google Scholar] [CrossRef]
- Altiok, N.; Ersoz, M.; Koyuturk, M. Estradiol induces JNK-dependent apoptosis in glioblastoma cells. Oncol. Lett. 2011, 2, 1281–1285. [Google Scholar] [CrossRef]
- Bishop, J.; Simpkins, J.W. Estradiol Treatment Increases Viability of Glioma and Neuroblastoma Cells in Vitro. Mol. Cell. Neurosci. 1994, 5, 303–308. [Google Scholar] [CrossRef]
- Castracani, C.C.; Longhitano, L.; Distefano, A.; Anfuso, D.; Kalampoka, S.; La Spina, E.; Astuto, M.; Avola, R.; Caruso, M.; Nicolosi, D.; et al. Role of 17β-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells. J. Oncol. 2020, 2020, 2314693. [Google Scholar] [CrossRef]
- Wan, S.; Jiang, J.; Zheng, C.; Wang, N.; Zhai, X.; Fei, X.; Wu, R.; Jiang, X. Estrogen nuclear receptors affect cell migration by altering sublocalization of AQP2 in glioma cell lines. Cell Death Discov. 2018, 4, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Moinfar, Z.; Dambach, H.; Schoenebeck, B.; Förster, E.; Prochnow, N.; Faustmann, P.M. Estradiol Receptors Regulate Differential Connexin 43 Expression in F98 and C6 Glioma Cell Lines. PLoS ONE 2016, 11, e0150007. [Google Scholar] [CrossRef] [Green Version]
- Chamaon, K.; Stojek, J.; Kanakis, D.; Braeuninger, S.; Kirches, E.; Krause, G.; Mawrin, C.; Dietzmann, K. Micromolar concentrations of 2-methoxyestradiol kill glioma cells by an apoptotic mechanism, without destroying their microtubule cytoskeleton. J. Neuro Oncol. 2005, 72, 11–16. [Google Scholar] [CrossRef]
- Lis, A.; Ciesielski, M.J.; Barone, T.A.; Scott, B.E.; Fenstermaker, R.A.; Plunkett, R.J. 2-Methoxyestradiol inhibits proliferation of normal and neoplastic glial cells, and induces cell death, in vitro. Cancer Lett. 2004, 213, 57–65. [Google Scholar] [CrossRef]
- Jiménez, J.M.D.; Arellano, A.C.; Santerre, A.; Suárez, S.O.; Sánchez, H.S.; Romero, I.F.; López-Elizalde, R.; Venegas, M.A.; Netel, B.; Valdovinos, B.D.L.T. Aromatase and estrogen receptor alpha mRNA expression as prognostic biomarkers in patients with astrocytomas. J. Neuro Oncol. 2014, 119, 275–284. [Google Scholar] [CrossRef]
- Yague, J.G.; Garcia-Segura, L.M.; Azcoitia, I. Selective transcriptional regulation of aromatase gene by vitamin D, dexamethasone, and mifepristone in human glioma cells. Endocrine 2009, 35, 252–261. [Google Scholar] [CrossRef] [Green Version]
- Gonzalez, A.; Martínez-Campa, C.; Mediavilla, M.D.; Alonso-González, C.; Sanchez-Barcelo, E.J.; Cos, S. Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells. Br. J. Cancer 2007, 97, 755–760. [Google Scholar] [CrossRef] [Green Version]
- Tivnan, A.; Heilinger, T.; Ramsey, J.M.; O’Connor, G.; Pokorny, J.L.; Sarkaria, J.N.; Stringer, B.W.; Day, B.W.; Boyd, A.W.; Kim, E.L.; et al. Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells. Oncotarget 2017, 8, 16605–16620. [Google Scholar] [CrossRef]
- Dave, N.; Chow, L.M.; Gudelsky, G.A.; LaSance, K.; Qi, X.; Desai, P. Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas. Mol. Cancer Ther. 2015, 14, 857–864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Atif, F.; Patel, N.R.; Yousuf, S.; Stein, N.G. The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells. PLoS ONE 2015, 10, e0131441. [Google Scholar] [CrossRef] [PubMed]
- Atif, F.; Yousuf, S.; Stein, D.G. Anti-tumor effects of progesterone in human glioblastoma multiforme: Role of PI3K/Akt/mTOR signaling. J. Steroid Biochem. Mol. Biol. 2015, 146, 62–73. [Google Scholar] [CrossRef] [PubMed]
- Atif, F.; Yousuf, S.; Espinosa-Garcia, C.; Sergeeva, E.; Stein, D.G. Progesterone Treatment Attenuates Glycolytic Metabolism and Induces Senescence in Glioblastoma. Sci. Rep. 2019, 9, 1–12. [Google Scholar] [CrossRef]
- Altinoz, M.A.; Ucal, Y.; Yilmaz, M.C.; Kiris, I.; Ozisik, O.; Sezerman, U.; Ozpinar, A.; Elmacı, I. Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity. Cancer Med. 2020, 9, 5767–5780. [Google Scholar] [CrossRef]
- Gutiérrez-Rodríguez, A.; Hansberg-Pastor, V.; Camacho-Arroyo, I. Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells. BioMed Res. Int. 2017, 2017, 1295087. [Google Scholar] [CrossRef]
- González-Agüero, G.; Gutiérrez, A.A.; González-Espinosa, D.; Solano, J.D.; Morales, R.; González-Arenas, A.; Cabrera-Muñoz, E.; Camacho-Arroyo, I. Progesterone effects on cell growth of U373 and D54 human astrocytoma cell lines. Endocrine 2007, 32, 129–135. [Google Scholar] [CrossRef]
- Piña-Medina, A.G.; Hansberg-Pastor, V.; González-Arenas, A.; Cerbón, M.; Camacho-Arroyo, I. Progesterone promotes cell migration, invasion and cofilin activation in human astrocytoma cells. Steroids 2016, 105, 19–25. [Google Scholar] [CrossRef]
- Germán-Castelán, L.; Manjarrez-Marmolejo, J.; González-Arenas, A.; Camacho-Arroyo, I. Intracellular Progesterone Receptor Mediates the Increase in Glioblastoma Growth Induced by Progesterone in the Rat Brain. Arch. Med Res. 2016, 47, 419–426. [Google Scholar] [CrossRef]
- Germán-Castelán, L.; Manjarrez-Marmolejo, J.; González-Arenas, A.; González-Morán, M.G.; Camacho-Arroyo, I. Progesterone Induces the Growth and Infiltration of Human Astrocytoma Cells Implanted in the Cerebral Cortex of the Rat. BioMed Res. Int. 2014, 2014, 393174. [Google Scholar] [CrossRef]
- Yu, X.; Jiang, Y.; Wei, W.; Cong, P.; Ding, Y.; Xiang, L.; Wu, K. Androgen receptor signaling regulates growth of glioblastoma multiforme in men. Tumor Biol. 2015, 36, 967–972. [Google Scholar] [CrossRef] [PubMed]
- Weidenfeld, J.; Schiller, H. Metabolism of Steroids by Human Brain Tumors. Clin. Neuropharmacol. 1984, 7, 395–398. [Google Scholar] [CrossRef] [PubMed]
- Bunevicius, A.; Tamašauskas, Š.; Deltuva, V.P.; Tamasauskas, A.; Sliauzys, A.; Bunevicius, R. Digit ratio (2D:4D) in primary brain tumor patients: A case-control study. Early Hum. Dev. 2016, 103, 205–208. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Z.; Cohn, M.J. Developmental basis of sexually dimorphic digit ratios. Proc. Natl. Acad. Sci. USA 2011, 108, 16289–16294. [Google Scholar] [CrossRef] [Green Version]
- Rodríguez-Lozano, D.C.; Velázquez-Vázquez, D.E.; Del Moral-Morales, A.; Camacho-Arroyo, I. Dihydrotestosterone Induces Proliferation, Migration, and Invasion of Human Glioblastoma Cell Lines. OncoTargets Ther. 2020, 13, 8813–8823. [Google Scholar] [CrossRef]
- Rodríguez-Lozano, D.C.; Piña-Medina, A.G.; Hansberg-Pastor, V.; Bello-Alvarez, C.; Camacho-Arroyo, I. Testosterone Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Androgen Receptor Activation. Front. Endocrinol. 2019, 10, 16. [Google Scholar] [CrossRef] [Green Version]
- Hopewell, J.W. The Effects of Castration on the Induction of Experimental Gliomas in Male Rats. Br. J. Cancer 1970, 24, 187–190. [Google Scholar] [CrossRef] [Green Version]
- Yang, W.-B.; Chuang, J.-Y.; Ko, C.-Y.; Chang, W.-C.; Hsu, T.-I. Dehydroepiandrosterone Induces Temozolomide Resistance Through Modulating Phosphorylation and Acetylation of Sp1 in Glioblastoma. Mol. Neurobiol. 2018, 56, 2301–2313. [Google Scholar] [CrossRef]
- Loria, R.M.; Graf, M.R. 17α-androstenediol-mediated oncophagy of tumor cells by different mechanisms is determined by the target tumor. Ann. N. Y. Acad. Sci. 2012, 1262, 127–133. [Google Scholar] [CrossRef]
- Cenciarini, M.; Valentino, M.; Belia, S.; Sforna, L.; Rosa, P.; Ronchetti, S.; D’Adamo, M.C.; Pessia, M. Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies. Front. Mol. Neurosci. 2019, 12, 65. [Google Scholar] [CrossRef]
- Kostaras, X.; Cusano, F.; Kline, G.; Roa, W.; Easaw, J. Use of dexamethasone in patients with high-grade glioma: A clinical practice guideline. Curr. Oncol. 2014, 21, 493–503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dubinski, D.; Won, S.-Y.; Gessler, F.; Quick-Weller, J.; Behmanesh, B.; Bernatz, S.; Forster, M.-T.; Franz, K.; Plate, K.-H.; Seifert, V.; et al. Dexamethasone-induced leukocytosis is associated with poor survival in newly diagnosed glioblastoma. J. Neuro Oncol. 2018, 137, 503–510. [Google Scholar] [CrossRef] [PubMed]
- Dubinski, D.; Hattingen, E.; Senft, C.; Seifert, V.; Peters, K.G.; Reiss, Y.; Devraj, K.; Plate, K.H. Controversial roles for dexamethasone in glioblastoma—Opportunities for novel vascular targeting therapies. Br. J. Pharmacol. 2019, 39, 1460–1468. [Google Scholar] [CrossRef] [PubMed]
- Nakatani, Y.; Amano, T.; Takeda, H. Corticosterone Inhibits the Proliferation of C6 Glioma Cells via the Translocation of Unphosphorylated Glucocorticoid Receptor. Biol. Pharm. Bull. 2016, 39, 1121–1129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Puzianowska-Kuznicka, M.; Pawlik-Pachucka, E.; Owczarz, M.; Budzińska, M.; Polosak, J. Small-Molecule Hormones: Molecular Mechanisms of Action. Int. J. Endocrinol. 2013, 2013, 601246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tata, J.R. One hundred years of hormones. EMBO Rep. 2005, 6, 490–496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thiebaut, C.; Konan, H.-P.; Guerquin, M.-J.; Chesnel, A.; Livera, G.; Le Romancer, M.; Dumond, H. The Role of ERα36 in Development and Tumor Malignancy. Int. J. Mol. Sci. 2020, 21, 4116. [Google Scholar] [CrossRef]
- Zhu, Y.; Luo, J. Regulation of androgen receptor variants in prostate cancer. Asian J. Urol. 2020, 7, 251–257. [Google Scholar] [CrossRef]
- Toran-Allerand, C.D. Estrogen and the Brain: Beyond ER-α, ER-β, and 17β-Estradiol. Ann. N. Y. Acad. Sci. 2005, 1052, 136–144. [Google Scholar] [CrossRef]
- Toran-Allerand, C.D.; Guan, X.; MacLusky, N.J.; Horvath, T.L.; Diano, S.; Singh, M.; Connolly, E.S.; Nethrapalli, I.S.; Tinnikov, A.A. ER-X: A Novel, Plasma Membrane-Associated, Putative Estrogen Receptor That Is Regulated during Development and after Ischemic Brain Injury. J. Neurosci. 2002, 22, 8391–8401. [Google Scholar] [CrossRef]
- Weiser, M.J.; Foradori, C.D.; Handa, R.J. Estrogen receptor beta in the brain: From form to function. Brain Res. Rev. 2008, 57, 309–320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tavares, C.B.; Gomes-Braga, F.D.C.S.; Sousa, E.B.; Borges, U.S.; Escórcio-Dourado, C.S.; Da Silva-Sampaio, J.P.; Da Silva, B.B. Evaluation of estrogen receptor expression in low-grade and high-grade astrocytomas. Rev. Assoc. Méd. Bras. 2018, 64, 1129–1133. [Google Scholar] [CrossRef] [Green Version]
- Liu, Y.; Huang, L.; Guan, X.; Li, H.; Zhang, Q.-Q.; Han, C.; Wang, Y.-J.; Wang, C.; Zhang, Y.; Qu, C.; et al. ER-α36, a novel variant of ERα, is involved in the regulation of Tamoxifen-sensitivity of glioblastoma cells. Steroids 2016, 111, 127–133. [Google Scholar] [CrossRef] [PubMed]
- Qu, C.; Ma, J.; Zhang, Y.; Han, C.; Huang, L.; Shen, L.; Li, H.; Wang, X.; Liu, J.; Zou, W. Estrogen receptor variant ER-α36 promotes tamoxifen agonist activity in glioblastoma cells. Cancer Sci. 2019, 110, 221–234. [Google Scholar] [CrossRef] [PubMed]
- Liu, C.; Zhang, Y.; Zhang, K.; Bian, C.; Zhao, Y.; Zhang, J. Expression of estrogen receptors, androgen receptor and steroid receptor coactivator-3 is negatively correlated to the differentiation of astrocytic tumors. Cancer Epidemiol. 2014, 38, 291–297. [Google Scholar] [CrossRef] [PubMed]
- Batistatou, A.; Kyzas, P.A.; Goussia, A.; Arkoumani, E.; Voulgaris, S.; Polyzoidis, K.; Agnantis, N.J.; Stefanou, D. Estrogen receptor beta (ERβ) protein expression correlates with BAG-1 and prognosis in brain glial tumours. J. Neuro-Oncol. 2005, 77, 17–23. [Google Scholar] [CrossRef]
- Sareddy, G.R.; Li, X.; Liu, J.; Viswanadhapalli, S.; Garcia, L.; Gruslova, A.; Cavazos, D.; Garcia, M.; Strom, A.M.; Gustafsson, J.-A.; et al. Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma. Sci. Rep. 2016, 6, 24185. [Google Scholar] [CrossRef]
- Cao, L.; Qu, D.; Wang, H.; Zhang, S.; Jia, C.; Shi, Z.; Wang, Z.-R.; Zhang, J.; Ma, J. Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor β- and p53-Mediated Apoptosis. Int. J. Mol. Sci. 2016, 17, 1928. [Google Scholar] [CrossRef] [Green Version]
- Huang, R.-P.; Hossain, M.Z.; Sehgal, A.; Boynton, A.L. Reduced connexin43 expression in high-grade human brain glioma cells. J. Surg. Oncol. 1999, 70, 21–24. [Google Scholar] [CrossRef]
- Liu, J.; Sareddy, G.R.; Zhou, M.; Viswanadhapalli, S.; Li, X.; Lai, Z.; Tekmal, R.R.; Brenner, A.J.; Vadlamudi, R.K. Differential effects of estrogen receptor beta isoforms on glioblastoma progression. Cancer Res. 2018, 78, 3176–3189. [Google Scholar] [CrossRef] [Green Version]
- Li, W.; Winters, A.; Poteet, E.; Ryou, M.-G.; Lin, S.; Hao, S.; Wu, Z.; Yuan, F.; Hatanpaa, K.J.; Simpkins, J.W.; et al. Involvement of estrogen receptor β5 in the progression of glioma. Brain Res. 2013, 1503, 97–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, M.; Sareddy, G.R.; Li, M.; Liu, J.; Luo, Y.; Venkata, P.P.; Viswanadhapalli, S.; Tekmal, R.R.; Brenner, A.; Vadlamudi, R.K. Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways. Sci. Rep. 2019, 9, 6124. [Google Scholar] [CrossRef] [PubMed]
- Proietti, C.J.; Izzo, F.; Flaqué, M.C.D.; Russo, R.C.; Venturutti, L.; Mercogliano, M.F.; De Martino, M.; Pineda, V.; Muñoz, S.; Guzmán, P.; et al. Heregulin Co-opts PR Transcriptional Action Via Stat3 Role as a Coregulator to Drive Cancer Growth. Mol. Endocrinol. 2015, 29, 1468–1485. [Google Scholar] [CrossRef] [PubMed]
- Boonyaratanakornkit, V.; McGowan, E.M.; Sherman, L.; Mancini, M.A.; Cheskis, B.J.; Edwards, D.P. The Role of Extranuclear Signaling Actions of Progesterone Receptor in Mediating Progesterone Regulation of Gene Expression and the Cell Cycle. Mol. Endocrinol. 2007, 21, 359–375. [Google Scholar] [CrossRef] [Green Version]
- Pang, Y.; Dong, J.; Thomas, P. Characterization, Neurosteroid Binding and Brain Distribution of Human Membrane Progesterone Receptors δ and ϵ (mPRδ and mPRϵ) and mPRδ Involvement in Neurosteroid Inhibition of Apoptosis. Endocrinology 2013, 154, 283–295. [Google Scholar] [CrossRef] [Green Version]
- Singh, M.; Su, C.; Ng, S. Non-genomic mechanisms of progesterone action in the brain. Front. Neurosci. 2013, 7, 159. [Google Scholar] [CrossRef] [Green Version]
- Cabrera-Muñoz, E.; González-Arenas, A.; Saqui-Salces, M.; Camacho-Arroyo, I.; Larrea, F.; García-Becerra, R.; Camacho-Arroyo, I. Regulation of progesterone receptor isoforms content in human astrocytoma cell lines. J. Steroid Biochem. Mol. Biol. 2009, 113, 80–84. [Google Scholar] [CrossRef]
- Hernández-Hernández, O.T.; González-García, T.K.; Camacho-Arroyo, I. Progesterone receptor and SRC-1 participate in the regulation of VEGF, EGFR and Cyclin D1 expression in human astrocytoma cell lines. J. Steroid Biochem. Mol. Biol. 2012, 132, 127–134. [Google Scholar] [CrossRef]
- González-Agüero, G.; Ondarza, R.; Gamboa-Domínguez, A.; Cerbón, M.A.; Camacho-Arroyo, I. Progesterone receptor isoforms expression pattern in human astrocytomas. Brain Res. Bull. 2001, 56, 43–48. [Google Scholar] [CrossRef]
- Inoue, T.; Akahira, J.-I.; Suzuki, T.; Darnel, A.D.; Kaneko, C.; Takahashi, K.; Hatori, M.; Shirane, R.; Kumabe, T.; Kurokawa, Y.; et al. Progesterone Production and Actions in the Human Central Nervous System and Neurogenic Tumors. J. Clin. Endocrinol. Metab. 2002, 87, 5325–5331. [Google Scholar] [CrossRef] [Green Version]
- Hu, C.; Fang, D.; Xu, H.; Wang, Q.; Xia, H. The androgen receptor expression and association with patient’s survival in different cancers. Genomics 2020, 112, 1926–1940. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Liu, Y.; Cao, J.-M. G Protein-Coupled Receptors: Extranuclear Mediators for the Non-Genomic Actions of Steroids. Int. J. Mol. Sci. 2014, 15, 15412–15425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kraemer, W.J.; Ratamess, N.A.; Hymer, W.C.; Nindl, B.C.; Fragala, M.S. Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth with Exercise. Front. Endocrinol. 2020, 11, 33. [Google Scholar] [CrossRef] [PubMed]
- Chung, Y.G.; Kim, H.K.; Lee, H.K.; Lee, K.C. Expression of androgen receptors in astrocytoma. J. Korean Med. Sci. 1996, 11, 517–521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bao, D.; Cheng, C.; Lan, X.; Xing, R.; Chen, Z.; Zhao, H.; Sun, J.; Wang, Y.; Niu, C.; Zhang, B.; et al. Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting protein expression. Oncotarget 2017, 8, 23142–23154. [Google Scholar] [CrossRef] [Green Version]
- Zalcman, N.; Canello, T.; Ovadia, H.; Charbit, H.; Zelikovitch, B.; Mordechai, A.; Fellig, Y.; Rabani, S.; Shahar, T.; Lossos, A.; et al. Androgen receptor: A potential therapeutic target for glioblastoma. Oncotarget 2018, 9, 19980–19993. [Google Scholar] [CrossRef] [Green Version]
- Kikuchi, H.; Uchida, C.; Hattori, T.; Isobe, T.; Hiramatsu, Y.; Kitagawa, K.; Oda, T.; Konno, H.; Kitagawa, M. ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells. Carcinog. 2007, 28, 1752–1758. [Google Scholar] [CrossRef] [Green Version]
- Sakurai, K.; Reon, B.J.; Anaya, J.; Dutta, A. The lncRNA DRAIC/PCAT29 Locus Constitutes a Tumor-Suppressive Nexus. Mol. Cancer Res. 2015, 13, 828–838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Madalena, K.M.; Lerch, J.K. The Effect of Glucocorticoid and Glucocorticoid Receptor Interactions on Brain, Spinal Cord, and Glial Cell Plasticity. Neural Plast. 2017, 2017, 8640970. [Google Scholar] [CrossRef] [Green Version]
- Meijer, O.; Buurstede, J.C.; Schaaf, M.J.M. Corticosteroid Receptors in the Brain: Transcriptional Mechanisms for Specificity and Context-Dependent Effects. Cell. Mol. Neurobiol. 2018, 39, 539–549. [Google Scholar] [CrossRef] [Green Version]
- DeRijk, R.H.; Schaaf, M.; Stam, F.J.; Swaab, D.F.; Ravid, R.; Vreugdenhil, E.; Cidlowski, J.A.; de Kloet, E.R.; Lucassen, P.J. Very low levels of the glucocorticoid receptor b isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry. Mol. Brain Res. 2003, 116, 17–26. [Google Scholar] [CrossRef]
- Ellemann, K.; Christensen, L.; Gjerris, F.; Briand, P.; Kruse-Larsen, C. Glucocorticoid receptors in glioblastoma multiforme: A new approach to antineoplastic glucocorticoid therapy. Acta Neurochir. 1988, 93, 6–9. [Google Scholar] [CrossRef] [PubMed]
- Poisson, M.; Pertuiset, B.F.; Hauw, J.-J.; Philippon, J.; Moguilewsky, M.; Philibert, D. Steroid hormone receptors in human meningiomas, gliomas and brain metastases. J. Neuro-Oncol. 1983, 1, 179–189. [Google Scholar] [CrossRef]
- Minchenko, D.; Riabovol, O.; Tsymbal, D.; Ratushna, O.; Minchenko, D. Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells. Endocr. Regul. 2016, 50, 127–136. [Google Scholar] [CrossRef] [Green Version]
- Riabovol, O.O.; Tsymbal, D.O.; Minchenko, D.O.; Lebid-Biletska, K.M.; Sliusar, M.Y.; Rudnytska, O.V.; Minchenko, O.H. Effect of glucose deprivation on the expression of genes encoding glucocorticoid receptor and some related factors in ERN1-knockdown U87 glioma cells. Endocr. Regul. 2019, 53, 237–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Q.; Lu, P.-H.; Shi, Z.-F.; Xu, Y.-J.; Xiang, J.; Wang, Y.-X.; Deng, L.-X.; Xie, P.; Yin, Y.; Zhang, B.; et al. Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation. Mol. Neurobiol. 2014, 52, 1106–1118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yin, Y.; Zhang, X.; Li, Z.; Deng, L.; Jiao, G.; Zhang, B.; Xie, P.; Mu, H.; Qiao, W.; Zou, J. Glucocorticoid receptor β regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/TCF transcriptional activity. Neurobiol. Dis. 2013, 59, 165–176. [Google Scholar] [CrossRef]
Histologic Class | Grade | 50% Overall Survival (years) | Mean Age at Diagnosis | |
---|---|---|---|---|
Low-grade glioma | Astrocytoma | II | 4–10 | 42 |
Oligodendroglioma | II | 8–20 | 43 | |
Oligoastrocytoma | II | 5–12 | 44 | |
High-grade glioma | Anaplastic astrocytoma | III | 2–5 | 57 |
Anaplastic oligodendroglioma | III | 2–10 | 61 | |
Anaplastic oligoastrocytoma | III | 2–8 | 52 | |
High-grade glioma | Glioblastoma | IV | 1–2 | 45–75 |
Histologic Class | Molecular Subtype | Grade | 50% Overall Survival (years) | Mean Age at Diagnosis | ||
---|---|---|---|---|---|---|
IDH1 | 1p/19q | Other Genetic Alteration (Not Required for Diagnosis) | ||||
Oligodendroglioma | mut | codel | TERT mut | II/III | >15/10 | 35–45 |
Diffuse astrocytoma | mut | wt | ATRX mut, p53 mut | II/III | 11/9 | 35–45 |
Diffuse astrocytoma | wt | wt | p53 mut, PTEN mut, PIK3, EGFR amplification, CDKN2A/B deletion, CDK4, BRAF, ATRX mut | II/III | 5/2–3 | 45–50 |
Glioblastoma | mut | wt | p53 mut | IV | 2.5 | 50–60 |
wt | wt | PTEN mut, EGFR amplification | IV | 1.5 | 50–60 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Hirtz, A.; Rech, F.; Dubois-Pot-Schneider, H.; Dumond, H. Astrocytoma: A Hormone-Sensitive Tumor? Int. J. Mol. Sci. 2020, 21, 9114. https://doi.org/10.3390/ijms21239114
Hirtz A, Rech F, Dubois-Pot-Schneider H, Dumond H. Astrocytoma: A Hormone-Sensitive Tumor? International Journal of Molecular Sciences. 2020; 21(23):9114. https://doi.org/10.3390/ijms21239114
Chicago/Turabian StyleHirtz, Alex, Fabien Rech, Hélène Dubois-Pot-Schneider, and Hélène Dumond. 2020. "Astrocytoma: A Hormone-Sensitive Tumor?" International Journal of Molecular Sciences 21, no. 23: 9114. https://doi.org/10.3390/ijms21239114