Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in the Patched Mouse Model of Embryonal Rhabdomyosarcoma
Anja Uhmann,
Hannah Niemann,
Bérénice Lammering,
Cornelia Henkel,
Ina Heß,
Albert Rosenberger,
Christian Dullin,
Anke Schraepler,
Walter Schulz-Schaeffer,
Heidi Hahn
Affiliations
Anja Uhmann
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Hannah Niemann
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Bérénice Lammering
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Cornelia Henkel
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Ina Heß
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Albert Rosenberger
Department of Genetic Epidemiology, University of Goettingen, 37073 Göttingen, Germany
Christian Dullin
Department of Diagnostic Radiology, University of Goettingen, 37073 Göttingen, Germany
Anke Schraepler
Central Animal Facility, University of Goettingen, 37073 Göttingen, Germany
Walter Schulz-Schaeffer
Department of Neuropathology, University of Goettingen, 37073 Göttingen, Germany
Heidi Hahn
Institute of Human Genetics, University of Goettingen, 37073 Göttingen, Germany
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D3, calcitriol, inhibits Hh signaling and proliferation of murine ERMS in vivo and in vitro. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth in Ptch-mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.
