Title:Current Status of Therapeutic Targeting of Developmental Signalling Pathways in Oncology
Volume: 13
Issue: 11
Author(s): Tobias Kiesslich, Frieder Berr, Beate Alinger, Ralf Kemmerling, Martin Pichler, Matthias Ocker and Daniel Neureiter
Affiliation:
Keywords:
Apoptosis, BMP, cancer, developmental signalling pathway, hedgehog, notch, TGF-β, Wnt, cancer initiation, tumourigenesis, signal transduction mechanisms, apoptosis inhibition
Abstract: Signalling pathways such as Hedgehog (Hh), Wnt, Notch, bone morphogenetic protein (BMP) and transforming
growth factor-β (TGF-β) hold a central position in regulation of vertebrate development by controlling vital processes
such as migration, differentiation and proliferation. Insights into the mechanistic aspects of cancer initiation and progression
have pointed to striking similarities between tumourigenesis and embryonic development. These observations can
partly be explained by the fact that similar cellular signalling mechanisms are employed in both situations. This review
focuses on the role and therapeutic potential of Hh, Wnt, Notch and BMP/TGF-β signalling and discusses i) their signal
transduction mechanisms during development and tumourigenesis, ii) evidence of pathway activation in different types of
cancers, and, iii) strategies for pharmacological targeting. Numerous studies have demonstrated a crucial role of developmental
signalling in a variety of tumours, where their signalling mechanisms contribute to oncogenic properties such as
tumour cell proliferation, apoptosis inhibition and / or metastatic migration. From the literature available, it is obvious that
the relative importance and the oncogenic mechanisms of developmental pathways vary with the tumour type, the stage of
the disease as well as the interaction with the tumour microenvironment, thus highlighting the complexity of cellular signalling
strategies employed during tumourigenesis. Intensive research activities are devoted to identification of drugs that
interfere with oncogenic signalling by developmental pathways. First clinical data for such compounds – e.g. GDC-0449
for the Hh pathway – are promising and indicate that targeted therapy of developmental signalling pathways has potential
for future anti-cancer therapies.
