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

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Timothy M. Pierpont, Amy M. Lyndaker, Claire M. Anderson, Qiming Jin, Elizabeth S. Moore, Jamie L. Roden, Alicia Braxton, Lina Bagepalli, Nandita Kataria, Hilary Zhaoxu Hu, Jason Garness, Matthew S. Cook, Blanche Capel, Donald H. Schlafer, Teresa Southard, Robert S. Weiss
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.

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Teaser

Using a mouse testicular germ cell tumor model, Pierpont et al. establish that male germ cells are susceptible to malignant transformation during a restricted window of embryonic development. The cancer stem cells of the resulting testicular cancers demonstrate genotoxin hypersensitivity, rendering these malignancies highly responsive to conventional chemotherapy.


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