Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma
| Autor: | Anne Winkler, Marco Groth, Moritz Schütte, Stefan Taudien, Aspasia Ploubidou, Jürgen Moll, Iris Kufferath, Kurt Zatloukal, Peter Herrlich, Huaibiao Li, Heike Heuer, Lucien Frappart, Torsten Kroll, Marie-Laure Yaspo, Matthias Platzer, Bodo Lange, Jana Hamann |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine endocrine system Cancer Research Cell division Polyadenylation Apoptosis Spindle Apparatus Biology Extracellular matrix Mice 03 medical and health sciences Testicular Neoplasms Testis medicine Animals Humans Extracellular Matrix Proteins Seminoma Neoplasms Germ Cell and Embryonal medicine.disease Cell biology Spindle apparatus Fertility Hyaluronan Receptors 030104 developmental biology Seminiferous tubule medicine.anatomical_structure Oncology Immunology Tumor Suppressor Protein p53 Cell Division Germ cell HeLa Cells |
| Zdroj: | Cancer research : an official organ of the American Association for Cancer Research |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-16-0179 |
| Popis: | Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM—a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self-renewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382–95. ©2016 AACR. |
| Databáze: | OpenAIRE |
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