Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Cripto in testicular germ cell tumours: from development to disease (#32)

Cassy Spiller 1 , Ee Ting Ng 1 , Guillaume Burnet 1 , Leendert Looijenga 2 , Peter Koopman 1 , Josephine Bowles 1
  1. University of Queensland, Brisbane, QLD, Australia
  2. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

Testicular germ cell cancer (GCC) accounts for 60% of all malignancies diagnosed in young men and is rapidly on the increase in industrialised countries. While GCCs are sometimes fatal, treatment commonly results in infertility. Type II GCCs arise from germ cell neoplasia in situ (GCNIS) precursor cells that emerge during fetal development. It is believed that incorrect regulation of pluripotency in the developing germline leads to GCNIS formation, which then lies dormant until puberty. The cause of this common and deadly disease remains unknown. 

Our studies in mice identified the Nodal co-receptor Cripto as controlling pluripotency of male germ cells during the time in which they are particularly susceptible to malignant transformation. Nodal/Cripto is a classical developmental signaling pathway that also controls pluripotency in ES cells and is overexpressed in many cancers. We hypothesised that incorrect regulation of Nodal/Cripto signaling in fetal germ cells would lead to GCNIS transformation. Investigating Cripto expression in human GCC we find strong expression in GCNIS cells and pluripotent/malignant subtypes of type II GCC. In our mouse model of Cripto-overexpressing germ cells we find that germ cells fail to differentiate into sperm, and over time, we find clusters of cells that maintain stem cell and pluripotency markers, similar to human GCNIS. We are now investigating the molecular identity of these cell clusters and are determining their cancer stem cell potential.