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Review
. 2015 Jan 16:8:27-38.
doi: 10.2147/SCCAA.S58613. eCollection 2015.

Hedgehog signaling in cancer stem cells: a focus on hematological cancers

Victoria Campbell  1 , Mhairi Copland  1
Affiliations
Review

Hedgehog signaling in cancer stem cells: a focus on hematological cancers

Victoria Campbell et al. Stem Cells Cloning. .

Abstract

The stem cell paradigm was first demonstrated in hematopoietic stem cells. Whilst classically it was cytokines and chemokines which were believed to control stem cell fate, more recently it has become apparent that the stem cell niche and highly conserved embryonic pathways play a key role in governing stem cell behavior. One of these pathways, the hedgehog signaling pathway, found in all organisms, is vitally important in embryogenesis, performing the function of patterning through early stages of development, and in adulthood, through the control of somatic stem cell numbers. In addition to these roles in health however, it has been found to be deregulated in a number of solid and hematological malignancies, components of the hedgehog pathway being associated with a poor prognosis. Further, these components represent viable therapeutic targets, with inhibition from a drug development perspective being readily achieved, making the hedgehog pathway an attractive potential therapeutic target. However, although the concept of cancer stem cells is well established, how these cells arise and the factors which influence their behavior are not yet fully understood. The role of the hedgehog signaling pathway and its potential as a therapeutic target in hematological malignancies is the focus of this review.

Keywords: cancer stem cell; hedgehog signaling pathway; hematopoiesis; lymphoid; myeloid; stem cell.

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Figures

Figure 1
Figure 1
Canonical Hedgehog (Hh) signaling. Notes: (A) In the inactive state the transcription factors GLI-2 and GLI-3 are non-specifically phosphorylated by casein kinase (CKI), glycogen synthase 3β (GSK3β) and protein kinase A (PKA) and retained in the cytoplasm in a protein complex associated with the inhibitory molecule suppressor of fused (SUFU). This complex undergoes E3 ubiquitin mediated proteolysis to the truncated repressor form which, on translocating to the nucleus, strongly inhibits the Hh pathway. (B) The Hh pathway is activated by the binding of Hh ligands (sonic [SHH], Indian [IHH] or desert [DHH]) to the receptor Patched1 (PTCH1), causing its internalisation and removing repression of Smoothened (SMO). SMO causes accumulation of the active from of GLI-2 and GLI-3 in the nucleus, and potentiates the activity of other positive regulators of the pathway resulting in transcription of key downstream targets and regulators of chromatin formation, cell cycle activity, cell mobility and apoptosis. Abbreviations: DISP, Dispatched; KIF 7, Kinesin family member 7; EMT, epithelial mesenchymaltransition; SCF(β-TRCP), Skp1-Cullin1-F-Box.
Figure 2
Figure 2
Non-canonical Hh signaling. Note: The Hh pathway can be activated directly through PTCH1 or SMO, or via alternative pathways including the PI3K/AKT and RAS/RAF/MEK/ERK signaling cascades. Abbreviations: Hh, hedgehog; EMT, epithelial-mesenchymal transition; PTCH1, Patched 1; SMO, Smoothened.
Figure 3
Figure 3
Targets of the Hh signaling pathway. Abbreviations: Hh, hedgehog; EMT, epithelial-mesenchymal transition.
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