Normal and malignant germ cell development.

Defining normal and malignant germ cell development is crucial for understanding the biology and behavior of germ cell tumors. Germ cell tumors show significant similarities with immature germ cells. Furthermore, treatment sensitivity of germ cell tumors reflects the intrinsic characteristics of the cell of origin, and their derivatives. 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 such as 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.1,2 In particular, the timing of the regulation of the most relevant markers during normal germ cell maturation was established, distinguishing an immature and a more mature phenotype of human germ cells. The investigated markers were, among others, E-cadherin, β-catenin, TSPY (testis-specific protein, Y-encoded), VASA, and OCT3/4. From our results, we conclude that external factors such as cell-cell signaling 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. This confirmed makers for the diagnosis of preinvasive malignant germ cells in postpubertal gonads, and resulted in the model that immature germ cells in preinvasive lesions express OCT3/4 and TSPY before progressing to invasive growth.3 An amazing finding was the detection of germ cell-lineage differentiation in nonseminomatous germ cell tumors.4 Human germ cell tumors must therefore be regarded as truly totipotent tumors with unrestricted developmental potential. From a technical point of view, this finding should encourage efforts to cultivate cells with germ cell properties from pluripotent embryonal carcinoma cell lines. If successful, this could result in a readily accessible cell system without the ethical issues and legal restrictions associated with the use of normal primordial germ cells derived from healthy human sources.