New Anti-Cancer Strategies in Testicular Germ Cell Tumors

Author(s): Paolo Chieffi*, Marco De Martino, Francesco Esposito.

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 1 , 2019

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Abstract:

Background: The most common solid malignancy of young men aged 20 to 34 years is testicular germ cell tumor. In addition, the incidence of these tumors has significantly increased throughout the last years. Testicular germ cell tumors are classified into seminoma and nonseminoma germ cell tumors, which take in yolk sac tumor, embryonal cell carcinoma, choriocarcinoma, and teratoma. There are noteworthy differences about therapy and prognosis of seminomas and nonseminoma germ cell tumors, even though both share characteristics of the primordial germ cells.

Objectives: The study is focused on different molecular mechanisms strongly involved in testicular germ cell line tumors underlying new strategies to treat this human neoplasia.

Methods: Bibliographic data from peer-reviewed research, patent and clinical trial literature, and around eighty papers and patents have been included in this review.

Results: Our study reveals that several biomarkers are usefully utilized to discriminate among different histotypes. Moreover, we found new patents regarding testicular germ cell tumor treatments such as the expression of claudin 6, monoclonal antibody (Brentuximab Vedotin), immune checkpoint blockade (ICB) with the FDA-approved drugs pembrolizumab and nivolumab or the oncolytic virus Pelareorep, the combination of selective inhibitors of Aurora kinase.

Conclusion: Finally, the pathogenesis of testicular germ cell tumor needs to be deeply understood so that it will improve data on stem cells, tumorigenesis and disease tumor management by more selective treatment.

Keywords: Aurora B, GPR30, HMGA, PATZ1, seminomas, testicular germ cells tumors.

[1]
Chieffi P. Molecular targets for the treatment of testicular germ cell tumors. Mini Rev Med Chem 2007; 7: 755-9.
[2]
Chieffi P, Franco R, Portella G. Molecular and cell biology of testicular germ cell tumors. Int Rev Cell Mol Biol 2009; 278: 277-308.
[3]
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol 2016; 70: 93-105.
[4]
Chieffi P, Chieffi S, Franco R, Sinisi A. Recent advances in the biology of germ cell tumors: Implications for the diagnosis and treatment. J Endocrinol Invest 2012; 35: 1015-20.
[5]
Chieffi P, Chieffi S. Molecular biomarkers as potential targets for therapeutic strategies in human testicular germ cell tumours: An overview. J Cell Physiol 2013; 22: 1641-6.
[6]
Chieffi P, Chieffi S. An up-date on newly discovered immunohistochemical biomarkers for the diagnosis of human testicular germ cell tumors. Histol Histopathol 2014; 29: 999-1006.
[7]
Chieffi P. An overview on predictivebiomarkers of testicu- largermcelltumors. J Cell Physiol 2017; 232: 276-80.
[8]
Chieffi P. Potential new anticancermolecular targets for the treatment of human testicularseminomas. Mini Rev Med Chem 2011; 11: 1075-81.
[9]
Shelley MD, Burgon K, Mason MD. Treatment of testicular germ-cell cancer: A cochrane evidence-based systematic review. Cancer Treat Rev 2002; 28: 237-53.
[10]
Perrotti M, Ankem M, Bancilla A, deCarvalho V, Amenta P, Weiss R. Prospective metastatic risk assignment in clinical stage I nonseminomatous germ cell testis cancer: a single institution pilot study. Urol Oncol 2004; 22: 174-7.
[11]
Chieffi P, Battista S, Barchi M, Di Agostino S, Pierantoni G, Fedele M, et al. HMGA1 and HMGA2 proteinexpression in mouse spermatogenesis. Oncogene 2002; 21: 3644-50.
[12]
Franco R, Esposito F, Fedele M, Liguori G, Pierantoni G, Botti G, et al. Detection of high mobility group proteins A1 and A2 represents a valid diagnostic marker in post-puberal testicular germ cell tumours. J Pathol 2008; 214: 58-64.
[13]
Esposito F, Tornincasa M, Chieffi P, De Martino I, Pierantoni G, Fusco A. High mobility group A1 (HMGA1) proteins regulate p53-mediated transcription of Bcl-2 gene. Cancer Res 2010; 70: 5379-88.
[14]
Federico A, Forzati F, Esposito F, Arra C, Palma G, Barbieri A, et al. HMGA1/HMGA2 double knock-out mice display a “superpygmy” phenotype. Biol Open 2014; 3(5): 372-8.
[15]
Pero R, Lembo F, Di Vizio D, Boccia A, Chieffi P, Fedele M, et al. RNF4 is a growthinhibitorexpressed in germcells and lost in human testicular tumours. Am J Pathol 2001; 159: 1225-30.
[16]
Pero R, Lembo F, Chieffi P, Del Pozzo G, Fedele M, Fusco A, et al. Translationalregulation of a novel testis-specific RNF4 transcript. Mol Reprod Dev 2003; 66: 1-7.
[17]
Fedele M, Franco R, Salvatore G, Paronetto MP, Barbagallo F, Pero R, et al. PATZ1 gene has a critical role in the spermatogenesis and testiculartumours. J Pathol 2008; 215: 39-47.
[18]
Esposito F, Boscia F, Franco R, Tornincasa M, Fusco A, Kitazawa S, et al. Down-regulation of estrogen receptor-β associates with transcriptional coregulator PATZ1 delocalization in human testicular seminomas. J Pathol 2011; 224: 110-20.
[19]
Esposito F, Boscia F, Gigantino V, Tornincasa M, Fusco A, Franco R, et al. The high mobility group A1-oestrogen receptor β nuclear interaction is impaired in human testicular seminomas. J Cell Physiol 2012; 227: 3749-55.
[20]
Di Agostino S, Fedele M, Chieffi P, Fusco A, Rossi P, Geremia R, et al. Phosphorylation of high mobility group protein A2 by Nek kinase during the first meiotic division in mouse spermatocytes. Mol Biol Cell 2004; 15: 1224-32.
[21]
Barbagallo F, Paronetto MP, Franco R, Chieffi P, Dolci S, Fry AM, et al. Increased expression and nuclear localization of the centrosomal kinase NEK2 in human testicular seminomas. J Pathol 2009; 217: 431-41.
[22]
Naro C, Barbagallo F, Chieffi P, Bourgeois CF, Paronetto MP, Sette C. The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival. Nucleic Acids Res 2014; 42: 3218-27.
[23]
Chieffi P, Chieffi S. An up-date on the molecular biomarkers as potential therapeutic targets in human testicular germ cell tumours. Open Androl J 2013; 5: 6-9.
[24]
Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW. OCT4 spliced variants are differentially expressed in human pluripotent and non-pluripotent cells. Stem Cells 2008; 26: 3068-74.
[25]
Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell BR. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 2003; 17: 126-40.
[26]
Yamaguchi S, Kimura H, Tada M, Nakatsuji N, Tada T. Nanog expression in mouse germ cell development. Gene Expr Patterns 2005; 5: 639-46.
[27]
Voutsadakis IA. The chemosensitivity of testicular germ cell tumors. Cell Oncol 2014; 37: 79-94.
[28]
Cao D, Allan RW, Cheng L, Peng Y, Guo CC, Dahiya N, et al. RNA-binding protein LIN28 is a marker for testicular germ cell tumors. Hum Pathol 2011; 42: 710-8.
[29]
Hart AH, Hartley L, Parker K, Ibrahim M, Looijenga LH, Pauchnik M, et al. The pluripotency homeobox gene NANOG is expressed in human germ cell tumors. Cancer 2005; 104: 2092-8.
[30]
de Jong J, Stoop H, Gillis AJ, van Gurp RJ, van de Geijn GJ, Boer M, et al. Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. J Pathol 2008; 215: 21-30.
[31]
Kim I, Saunders TL, Morrison SJ. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 2007; 130: 470-83.
[32]
Vicini E, Loiarro M, Di Agostino S, Corallini S, Capolunghi F, Carsetti R, et al. 17-β-Estradiol elicits genomic and non-genomic responses in mouse male germ cells. J Cell Physiol 2006; 206: 238-45.
[33]
Staibano S, Franco R, Mezza E, Chieffi P, Sinisi A, Pasquali D, et al. Loss of oestrogen receptor beta, high PCNA and P53 expression and aneuploidy as markers of worse prognosis in ovarian granulosa cell tumours. Histopathology 2003; 43: 254-62.
[34]
Chieffi P, Colucci D’Amato GL, Staibano S, Franco R, Tramontano D. Estradiol-induced mitogen-activated protein kinase (extracellular signal-regulated kinase 1 and 2) activity in the frog (Rana esculenta) testis. J Endocrinol 2000; 167: 77-84.
[35]
Franco R, Boscia F, Gigantino V, Marra L, Esposito F, Ferrara D, et al. GPR30 is over-expressed in post puberal testicular germ cell tumors. Cancer Biol Ther 2011; 11: 609-13.
[36]
Boscia F, Passaro C, Gigantino V, Perdonà S, Franco R, Portella G, et al. High levels of GPR30 protein in human testicular carcinoma in situ and seminomas correlate with low levels of estrogen receptor-beta and indicate a switch in estrogen responsiveness. J Cell Physiol 2015; 230: 1290-7.
[37]
Chieffi P, Franco R, Fulgione D, Staibano S. PCNA in the testis of the frog, Rana esculenta: A molecular marker of the mitotic testicular epithelium proliferation. Gen Comp Endocrinol 2000; 119: 11-6.
[38]
Staibano S, Ilardi G, Leone V, Luise C, Merolla F, Esposito F, et al. Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors. BMC Cancer 2013; 13: 433-9.
[39]
Sestakova Z, Kalavska K, Hurbanova L, Jurkovicova D, Gursky J, Chovanec M, et al. The prognostic value of DNA damage level in peripheral blood lymphocytes of chemotherapy-naïve patients with germ cell cancer. Oncotarget 2016; 7: 75996-6005.
[40]
Shiokawa M, Masutani M, Fujihara H, Ueki K, Nishikawa R, Sugimura T, et al. Genetic alteration of Poly (ADP-ribose) polymerase-1 in human germ cell tumors. Jpn J Clin Oncol 2005; 35: 97-102.
[41]
Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, et al. PARP expression in germ cell tumours. J Clin Pathol 2013; 66: 607-12.
[42]
Usanova S, Piée-Staffa A, Sied U, Thomale J, Schneider A, Kaina B, et al. Cisplatin sensitivity of testis tumour cells is due to deficiency in inter strand-crosslink repair and low ERCC1-XPF expression. Mol Cancer 2010; 9: 248.
[43]
Pauls K, Schorle H, Jeske W, Brehm R, Steger K, Wernert N, et al. Spatial expression of germ cell markers during maturation of human fetal male gonads: An immune histo chemical study. Hum Reprod 2006; 21: 397-404.
[44]
Tsuchiya N, Mishina M, Narita J, Kumazawa T, Inoue T, Horikawa Y, et al. Association of XRCC1 gene polymorphisms with the susceptibility and chromosomal aberration of testicular germ cell tumors. Int J Oncol 2006; 28: 1217-23.
[45]
Litchfield K, Summersgill B, Yost S, Broderick P, Nsengimana J, Eeles R, et al. Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat Commun 2015; 6: 5973-81.
[46]
Chen YT, Chiu R, Lee P, Beneck D, Jin B, Old LJ. Chromosome X-encoded cancer/testis antigens show distinctive expression patterns in developing gonads and in testicular seminoma. Hum Reprod 2011; 26: 3232-43.
[47]
Ferlin A, Pengo M, Pizzol D, Carraro U, Frigo AC, Foresta C. Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function. Endocr Relat Cancer 2012; 19: 101-8.
[48]
Mayer F, Stoop H, Sen S, Bokemeyer C, Oosterhuis JW, Looijenga LHJ. Aneuploidy of human testicular germ cell tumors is associated with amplification of centrosomes. Oncogene 2003; 22: 3859-66.
[49]
Chieffi P, Troncone G, Caleo A, Libertini S, Linardopoulos S, Tramontano D, et al. Aurora B expression in normal testis and seminomas. J Endocrinol 2004; 181: 263-70.
[50]
Esposito F, Libertini S, Franco R, Abagnale A, Marra L, Portella G, et al. Aurora B expression in post-puberal testicular germ cell tumours. J Cell Physiol 2009; 221: 435-9.
[51]
Portella G, Passaro C, Chieffi P, Aurora B. A new prognostic marker and therapeutic target in cancer. Curr Med Chem 2011; 18: 482-96.
[52]
Marra L, Cantile M, Scognamiglio G, Marra L, Perdonà S, La Manti E, et al. Deregulation of HOXB13 expression in urinary bladder cancer progression. Curr Med Chem 2013; 20: 833-9.
[53]
Franco R, Zappavigna S, Gigantino V, Luce A, Cantile M, Cerrone M, et al. Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/ invasion. J Exp Clin Cancer Res 2014; 33: 48-57.
[54]
Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4: 927-36.
[55]
Gavriilidis P, Giakoustidis A, Giakoustidis D. Aurora kinases and potential medical applications of Aurora kinase inhibitors: A review. J Clin Med Res 2015; 7: 742-51.
[56]
Forzati F, De Martino M, Esposito F, Sepe R, Pellecchia S, Malapelle U, et al. miR-155 is positively regulated by CBX7 in mouse embryonic fibroblasts and colon carcinomas, and targets the KRAS oncogene. BMC Cancer 2017; 17(1): 170-8.
[57]
Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, et al. Dicer is essential for mouse development. Nat Genet 2003; 35: 215-7.
[58]
Maatouk DM, Loveland KL, McManus MT, Moore K, Harfe BD. Dicer1 is required for differentiation of the mouse male germline. Biol Reprod 2008; 79: 696-703.
[59]
Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 2006; 124: 1169-81.
[60]
Langroudi L, Jamshidi-Adegani F, Shafiee A, Rad SM, Keramati F, Azadmanesh K, et al. MiR-371-373 cluster acts as a tumor- suppressor-miR and promotes cell cycle arrest in unrestricted somatic stem cells. Tumour Biol 2015; 36: 7765-74.
[61]
Özata DM, Li X, Lee L, Liu J, Warsito D, Hajeri P, et al. Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors. Cell Death Dis 2017; 8: e2759.
[62]
Kedde M, Strasser MJ, Boldajipour B, Oude Vrielink JA, Slanchev K, le Sage C, et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 2007; 131: 1273-86.
[63]
Linger R, Dudakia D, Huddart R, Tucker K, Friedlander M, Phillips KA, et al. Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors. Genes Chrom Cancer 2008; 47: 247-52.
[64]
Rijlaarsdam MA, van Agthoven T, Gillis AJM, Patel S, Hayashibara K, Lee KY, et al. Identification of known and novel germ cell cancer-specific (embryonic) miRs in serum by high-throughput profiling. Andrology 2015; 3: 85-91.
[65]
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010; 465(7301): 1033-8.
[66]
Esposito F, De Martino M, Petti MG, Forzati F, Tornincasa M, Federico A, et al. HMGA1 pseudogenes as candidate proto-oncogenic competitive endogenous RNAs. Oncotarget 2014; 5(18): 8341-54.
[67]
Esposito F, De Martino M, Forzati F, Fusco A. HMGA1-pseudogene overexpression contributes to cancer progression. Cell Cycle 2014; 13(23): 3636-9.
[68]
Esposito F, De Martino M, D’Angelo D, Mussnich P, Raverot G, Jaffrain-Rea ML, et al. HMGA1-pseudogene expression is induced in human pituitary tumors. Cell Cycle 2015; 14(9): 1471-5.
[69]
De Martino M, Forzati F, Arra C, Fusco A, Esposito F. HMGA1-pseudogenes and cancer. Oncotarget 2016; 7(19): 28724-35.
[70]
De Martino M, Forzati F, Marfella M, Pellecchia S, Arra C, Terracciano L, et al. HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism. Sci Rep 2016; 6: 37622-9.
[71]
De Martino M, Palma G, Azzariti A, Arra C, Fusco A, Esposito F. The HMGA1 pseudogene 7 induces miR-483 and miR-675 upregulation by activating EGR1 through a ceRNA mechanism. Genes (Basel) 2017; 8(11): 52-9.
[72]
Lal-Nag M, Battis M, Santin AD, Morin PJ. Claudin-6: A novel receptor for CPE-mediated cytotoxicity in ovarian cancer. Oncogenesis 2012; 1: e33.
[73]
Micke P, Mattsson JS, Edlund K, Lohr M, Jirström K, Berglund A, et al. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer 2014; 135(9): 2206-14.
[74]
Sahin U, Tureci O, Koslowski M, Walter K, Kreuzberg M, Luxen S. Cancer therapy using CLDN6 target-directed antibodies in vivo. WO2012003956 (2012)
[75]
Senter PD, Doronina S, Toki BE. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease. US8906376 (2010)
[76]
Morris D, Thompson BG, Matthew C. Coffey. Reovirus clearance of RAS-mediated neoplastic cells from mixed cellular compositions. US13408478 (2012)
[77]
Ecsedy JA, Shyu WC, Chakravarty A, Kleinfield RW, Le KN, Venkatakrishnan K. Methods of treating cancer using aurora kinase inhibitors. US20160193224 (2016)


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Article Details

VOLUME: 14
ISSUE: 1
Year: 2019
Page: [53 - 59]
Pages: 7
DOI: 10.2174/1574892814666190111120023

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