Abstract
Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy.
Highlights
Thyroid cancer is the fifth most common cancer in women in the USA
We have reported that the sonic hedgehog (Shh) pathway is highly activated in approximately two-thirds of thyroid neoplasms and in thyroid cancer cell lines [95, 96]
The components of the Shh pathway are highly expressed in 7 medullary thyroid carcinomas (MTCs) specimens; GDC-0449, a Smooth ened (Smo) inhibitor, inhibits the proliferation of TT cells, an MTC cell line [98, 99]. These results collectively suggest that the Shh pathway is highly active in more than 50% of thyroid cancers to stimulate their cell proliferation
Summary
Reviewed by: Marialuisa Appetecchia, Istituti Fisioterapici Ospitalieri (IRCCS), Italy Michaela Luconi, University of Florence, Italy. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway plays an important role in cancer stem cell (CSC) self-renewal. We review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal.
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