Spontaneous metastasis in mouse models of testicular germ‐cell tumours

Abstract

Summary Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which metastatic potential is acquired and on their modes of dissemination. We report a new model of spontaneous TGCT metastasis in the 129 family of mice and provide evidence that these are true metastases derived directly from primary testicular cancers rather than independently from ectopic stem cells. These putative metastases (pMETs) occur at similar frequencies among TGCT-affected males in six genetically distinct TGCT-susceptible strains and were largely found in anatomical sites that are consistent with patterns of TGCT metastasis in humans. Various lines of evidence support their pluripotency and germ-cell origin, including presence of multiple endodermal, mesodermal and ectodermal derivatives as well as cells showing OCT4 and SSEA-1 pluripotency markers. In addition, pMETs were never found in males that did not have a TGCT, suggesting that metastases are derived from primary tumours. Finally, pMETS and primary TGCTs shared several DNA copy number variants suggesting a common cellular and developmental origin. Together, these results provide the first evidence for spontaneous TGCT metastasis in mice and show that these metastases originate from primary TGCTs rather than independently from ectopic stem cells.

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

“…ǂ Offspring from Dnd1 +/KO × Dnd1 +/Ter crosses; * offspring from Dnd1 +/Ter × Dnd1 +/Ter . ǂData are from Zechel et al [51]. …”

‘Snail factors in testicular germ cell tumours and their regulation by the BMP4 signalling pathway’

“…Despite the widespread use of mice for studies examining molecular mechanisms involved in testis development, spermatogenesis and the processes relating to human foetal testis growth, they have significant limitations as model for human TGCT research. The absence of a mouse model developing GCNIS and a seminoma‐type tumours 62 restricts investigations of TGCT formation and acquisition of metastatic potential to primary tissue materials and human cell lines. The identification of SNAI1 and SNAI2 in TGCTs through histological analyses of human samples has prompted us to examine whether they may contribute to tumour cell behaviours.…”

The ter Mutation in the Rat Dnd1 Gene Initiates Gonadal Teratomas and Infertility in Both Genders

“…Spontaneous formation of testicular teratomas was described in the 129/Sv mouse strain in the early 1950ies [19] and these tumors can be accompanied by metastases [20] . TGCT development was detected in 1% of male 129/Sv mice, while an additional mutation in a modifier gene referred to as Ter increased the incidence of TGCT to 17% in Ter /+ and to 94% in Ter/Ter males.…”