Normal and Malignant Germ Cell Development

All articles of this thesis are reproduced with kind permission. Permission is granted by Oxford Journals (chapter 2), John Wiley & Sons Ltd. on behalf of PathSoc. (chapters 3, 5 and 6), Elsevier (chapter 4, and Nature Publishing Group (chapter 7).Defining normal and malignant germ cell development is crucial for understanding the biology and behaviour of germ cell tumours. Germ cell tumours show significant similarities with immature germ cells. Furthermore, treatment sensitivity of germ cell tumours reflects the intrinsic characteristics of the cell of origin. The aim of this thesis was to identify factors involved in the development of normal and malignant human germ cells. The marker profile of male and female germ cells during normal foetal development was established and compared to the profile found in dysgenetic gonads. Furthermore, the role of extracellular factors like the microenvironment was addressed, and links between pluripotency, cellular differentiation, and treatment response were investigated. A number of markers for early germ cells could be confirmed and further characterized. From our results, we conclude that external factors like cell-cell signalling create a niche that is essential to ensure normal germ cell development. The analyses were then extended to tissue samples showing delayed or disturbed maturation. An amazing finding was the detection of germ cell-lineage differentiation in nonseminomatous germ cell tumours. Human germ cell tumours must therefore be regarded as truly totipotent tumours with unrestricted developmental potential. Finally, our investigations present findings of different factors supposedly involved in chemotherapy resistance. Rather than being involved in treatment resistance, several factors investigated were found to be differentially regulated during germ cell development. This illustrates that in germ cell tumours it is particularly important to be able to interpret results in view of aspects of developmental biology

POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors

Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblasto