Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Cancer Res. 2016 Nov 1;76(21):6382-6395. doi: 10.1158/0008-5472.CAN-16-0179. Epub 2016 Aug 19.


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.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Division
  • Extracellular Matrix Proteins / analysis
  • Extracellular Matrix Proteins / physiology*
  • Fertility*
  • HeLa Cells
  • Humans
  • Hyaluronan Receptors / analysis
  • Hyaluronan Receptors / physiology*
  • Male
  • Mice
  • Neoplasms, Germ Cell and Embryonal / etiology*
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Seminoma / etiology*
  • Seminoma / pathology
  • Spindle Apparatus / chemistry*
  • Testicular Neoplasms / etiology*
  • Testicular Neoplasms / pathology
  • Testis / cytology*
  • Tumor Suppressor Protein p53 / physiology


  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • Tumor Suppressor Protein p53
  • hyaluronan-mediated motility receptor

Supplementary concepts

  • Testicular Germ Cell Tumor