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PMID: 29141221 Published · ppublish English Journal Article

Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer.

Cell reports ·Vol. 21 ·No. 7 ·2017-11-14 ·Pages 1896-1909

Pierpont TM, Lyndaker AM, Anderson CM, Jin Q, Moore ES, Roden JL, Braxton A, Bagepalli L, Kataria N, Hu HZ, Garness J, Cook MS, Capel B, Schlafer DH, Southard T, Weiss RS

Abstract

Testicular germ cell tumors (TGCTs) are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation. The resulting mice developed malignant, metastatic TGCTs composed of teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. Consistent with epidemiological data linking human testicular cancer risk to in utero exposures, embryonic germ cells were susceptible to malignant transformation, whereas adult germ cells underwent apoptosis in response to the same oncogenic events. Treatment of tumor-bearing mice with genotoxic chemotherapy not only prolonged survival and reduced tumor size but also selectively eliminated the OCT4-positive cancer stem cells. We conclude that the chemosensitivity of TGCTs derives from the sensitivity of their cancer stem cells to DNA-damaging chemotherapy.

Keywords
CSCs DDR DNA damage response EC TGCT cancer stem cells chemotherapy embryonal carcinoma testicular germ cell tumor
MeSH Terms
Animals Antineoplastic Agents/pharmacology Apoptosis Carcinoma/metabolism,pathology Cell Transformation, Neoplastic Cisplatin/pharmacology Male Mice Mice, Inbred C57BL Neoplastic Stem Cells/drug effects,metabolism,pathology Octamer Transcription Factor-3/genetics,metabolism Teratoma/metabolism,pathology Testicular Neoplasms/metabolism,pathology
Chemicals
Antineoplastic Agents Octamer Transcription Factor-3 Pou5f1 protein, mouse Cisplatin
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Pierpont Timothy M
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Lyndaker Amy M
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: [email protected].
Anderson Claire M
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Jin Qiming
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Moore Elizabeth S
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Roden Jamie L
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Braxton Alicia
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Bagepalli Lina
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Kataria Nandita
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Hu Hilary Zhaoxu
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Garness Jason
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Cook Matthew S
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Capel Blanche
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Schlafer Donald H
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Southard Teresa
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Weiss Robert S
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: [email protected].
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Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.10.078
Email
[email protected]
[email protected]
Published
2017-11-14
Pages
1896-1909
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC5695237
Subset
IM
Grants
NICHD NIH HHS · T32 HD040372 · United States
NCI NIH HHS · R21 CA185256 · United States
NIGMS NIH HHS · R01 GM087500 · United States
NICHD NIH HHS · T32 HD052471 · United States
NIAID NIH HHS · T35 AI007227 · United States
NIH HHS · T32 OD011000 · United States
NIGMS NIH HHS · T32 GM007273 · United States
NIH HHS · T32 OD011089 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2017.10.078 PMC Full Text View journal details
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