A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma
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Alessia Parascandolo1,*, Mikko O. Laukkanen1,*, Nancy De Rosa2, Clara Ugolini3, Maria Carmela Cantisani2, Anna Maria Cirafici4, Fulvio Basolo5, Massimo Santoro2,# and Maria Domenica Castellone4,#
1IRCCS SDN, Naples, Italy
2Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Naples, Italy
3Department of Laboratory Medicine Section of Pathology Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
4Istitute of Experimental Endocrinology and Oncology “G. Salvatore” (IEOS), C.N.R., Naples, Italy
5Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
*These authors share co-first authorship
#These authors share co-senior authorship
Maria Domenica Castellone, email: [email protected]
Keywords: hedgehog signaling; thyroid cancer; tumor stroma; MSC; co-culture
Received: September 13, 2017 Accepted: December 04, 2017 Published: December 17, 2017
Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers.
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