Abstract
The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC-targeted therapy.
Highlights
The Hedgehog (Hh) signaling pathway was first discovered in 1980 by Nusslein-Volhard and Wieschaus in a large-scale genetic screening to find mutations that affect larval body segment development in the fruit fly, Drosophila melanogaster (D. melanogaster) [1]
As the Hh pathway plays an essential role in the maintenance of somatic stem cells and pluripotent cells, it is involved in the regenerative proliferation of epithelial stem cells in the lung [19], tooth [20], liver [21], prostate [22], and bladder [23], and this signaling pathway may be correlated with the maintenance of cancer stem cells (CSCs)
Cyclopamine and nilotinib, as well as an SMO antagonist (PF-04449913) and dasatinib, showed effective elimination of Chronic myelogenous leukemia (CML) leukemic stem cells (LSCs) [176,179]. These findings show that the combination of Hh inhibitors and tyrosine kinase inhibitor (TKI) reduces LSC self-renewal and clinically improves survival [177]
Summary
The Hedgehog (Hh) signaling pathway was first discovered in 1980 by Nusslein-Volhard and Wieschaus in a large-scale genetic screening to find mutations that affect larval body segment development in the fruit fly, Drosophila melanogaster (D. melanogaster) [1]. The Hh signal transduction pathway is an evolutionarily conserved pathway [2] that plays an important role in the regulation of a variety of developmental and physiological processes involving normal stem cell differentiation and proliferation, as well as proper segregation in invertebrates and vertebrates [3,4,5]. As the Hh pathway plays an essential role in the maintenance of somatic stem cells and pluripotent cells, it is involved in the regenerative proliferation of epithelial stem cells in the lung [19], tooth [20], liver [21], prostate [22], and bladder [23], and this signaling pathway may be correlated with the maintenance of cancer stem cells (CSCs). This review describes the signaling pathway of Hh and its aberrant activation in several cancers and highlights the current clinical trials involving Hh inhibitors for cancer therapy
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