{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:58:24Z","timestamp":1788872304788,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,7,9]],"date-time":"2014-07-09T00:00:00Z","timestamp":1404864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"crossref","award":["R93-A8990"],"award-info":[{"award-number":["R93-A8990"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001732","name":"Danish National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:p>The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti\u2010tumor barrier can be breached by defects in DDR factors, such as the ATM\u2010Chk2\u2010p53 pathway, thereby allowing tumor progression. The DDR barrier is strongly activated in brain tumors, particularly gliomas, due to oxidative damage and replication stress. Here, we took advantage of rare human primary intracranial germ cell tumors (PIGCTs), to address the roles of cell\u2010intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in\u00a0vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens and 20 glioblastomas, revealed the following: i) The overall DDR signaling (\u03b3H2AX) and activation of the ATM\u2010Chk2\u2010p53 pathway were very low among the PIGCTs, reminiscent of TGCTs, and contrasting sharply with strong DDR activation in glioblastomas; ii) Except for one case of embryonal carcinoma, there were no clear aberrations in the ATM\u2010Chk2\u2010p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and\/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather than the brain tumors with which they share the tissue environment. Hence cell\u2010intrinsic factors and cell of origin dictate the extent of DDR barrier activation and also the ensuing pressure to select for DDR defects. Our data provide conceptually important insights into the role of DNA damage checkpoints in intracranial tumorigenesis, with implications for the differential biological responses of diverse tumor types to endogenous stress as well as to genotoxic treatments such as ionizing radiation or chemotherapy.<\/jats:p>","DOI":"10.1016\/j.molonc.2014.07.001","type":"journal-article","created":{"date-parts":[[2014,7,9]],"date-time":"2014-07-09T01:15:14Z","timestamp":1404868514000},"page":"1667-1678","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: Implications for the anti\u2010tumor barrier concept and treatment"],"prefix":"10.1002","volume":"8","author":[{"given":"Jirina","family":"Bartkova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina E.","family":"Hoei-Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Krizova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Hamerlik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels E.","family":"Skakkeb\u00e6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Rajpert-De Meyts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Bartek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,7,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711690106"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210881"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0808-887"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1493"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.4.6.1742"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204746"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.249"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03482"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210553"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1353"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0463.2003.1110129.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2007.00772.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05268"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12625"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2233"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05327"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.76"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008360523160"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03485"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1140735"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1487"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1948"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100520"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4154"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03097"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2013.13"},{"key":"e_1_2_7_29_1","first-page":"4990","article-title":"DNA damage-activated kinase Chk2 is independent of proliferation or differentiation, yet correlates with tissue biology","volume":"61","author":"Lukas C.","year":"2001","journal-title":"Cancer Res."},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPH.0000000000000125"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2007.00793.x"},{"key":"e_1_2_7_32_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1034\/j.1600-0463.2003.11101301.x","article-title":"The emerging phenotype of the testicular carcinoma in situ germ cell","volume":"111","author":"Rajpert-De Meyts E.","year":"2003","journal-title":"APMIS"},{"key":"e_1_2_7_33_1","unstructured":"2000 IARC Press (International Agency for Research on Cancer) M.K. 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