Discussion

Larval development of the fox-tapeworm Echinococcus multilocularis is unusual in so far as its invading oncosphere does not directly develop into a head-like structure (scolex), as in most tapeworms, but into a continuously growing, cancer-like mass of vesicles (the metacestode) which infiltrates host tissue. We are studying Echinococcus development by using sophisticated in vitro cultivation systems for parasite larvae and cells. We showed that parasite development is essentially driven by a population of totipotent somatic stem cells, the germinative cells, which are the only mitotically active cells of the parasite and which give rise to all differentiated cells. Interestingly, the germinative cells are resistant to the currently used drugs against echinococcosis which can explain why echinococcosis chemotherapy is so inefficient. Contrasting to the oncosphere and the scolex, the cyst-like metacestode does not display clear body axes, so we hypothesized that modifications of the anterior-posterior (AP) axis might be an underlying principle for metacestode evolution. In free-living planarians, the AP axis is specified by the canonical Wnt pathway, where Wnt signaling defines the posterior and expression of Wnt antagonists (e.g. sFRP) the anterior pole. Using the Hymenolepis model, we show that this also applies to tapeworm oncospheres where Wnt orthologs are expressed posteriorly (close to the hooks) and sFRP orthologs anteriorly. In the E. multilocularis metacestode, we found ubiquitous expression of posterior Wnt factors and only in later stages of the infection, Wnt antagonists were locally expressed in metacestode tissue, which preceded the formation of protoscoleces. This indicates that E. multilocularis larvae temporarily give up their anterior pole to exclusively proliferate as posterior tissue, followed by local expression of sFRP to achieve protoscolex production (asexual multiplication). According to our data, canonical Wnt signaling plays a crucial role in metacestode development and, accordingly, RNA-interference against the central Wnt component beta-catenin resulted in metacestode tissue disorganization and prevented the formation of vesicles from parasite stem cells. Interestingly, aberrant regulation of Wnt signaling is also observed in many human cancers, pointing to similarities of malignant transformation of human tissue and metacestode formation.