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

Campbell V, Copland M - Stem Cells Cloning (2015)

Bottom Line: The stem cell paradigm was first demonstrated in hematopoietic stem cells.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.

View Article: PubMed Central - PubMed

Affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterninary and Life Sciences, University of Glasgow, Glasgow, UK.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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f1-sccaa-8-027: 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.

Mentions: Classically, the Hh signaling pathway is believed to be ligand-dependent. Three Hh ligands (Sonic [SHH], Indian [IHH], and Desert [DHH]) have been identified in vertebrates, affecting stem cell behavior in a time- and concentration-dependent manner.19 SHH is widely expressed, particularly during embryogenesis, with SHH deficiency being embryonically lethal.17 IHH is produced in hematopoietic cells, bone, and cartilage,20 whilst DHH is found in the peripheral nervous system and testes.21 Hh ligands are initially synthesized as an inactive 45 kDa precursor, undergoing post-translational modifications to form a 19 kDa amino-terminal active signaling molecule.22 This cholesterol and palmitoyl modification, catalyzed by Hh acyltransferase,23 not only enhances ligand activity but also modifies its diffusion capacity.24 The Hh ligands bind to the 12 trans-membrane receptor protein Patched 1 (PTCH1), causing its internalization and removing its repression of the 7-span trans-membrane protein Smoothened (SMO), allowing pathway activity.25 In vertebrates, activity of the Hh pathway appears intrinsically related to primary immotile cilia; in the absence of ligand, PTCH1 is located within the primary cilia. Following ligand binding, and the internalization of PTCH1, SMO is able to concentrate in the primary cilia where it interacts with the GLI transcription factors shifting the balance toward pathway activation.25 Whilst the intricacies of this interaction remain poorly understood, studies suggest these receptors do not physically interact, rather PTCH1 is thought to regulate SMO through an intermediary, with studies suggesting that oxysterols, including vitamin D3, are involved.26 SMO subsequently causes accumulation of the full length active form of the zinc transcription factors GLI-2 and GLI-3 in the nucleus, and potentiates the activity of other positive regulators of the pathway including serine threonine kinase 36 (STK36) and kinesin family member 7 (KIF7), resulting in transcription of key downstream targets such as GLI-1 and PTCH1, regulators of chromatin formation, cell cycle activity, cell mobility, and apoptosis, eg, bone morphogenetic protein 4, forkhead box protein M1, and WNT2a,27Figure 1A. Of the transcription factors, GLI-1 functions as a positive regulator, GLI-3 a transcriptional repressor, and GLI-2 both a positive and negative transcriptional regulator determined by post-transcriptional and post-translational modifications.28 It is the balance between these transcription factors which determines pathway activity.29


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

Campbell V, Copland M - Stem Cells Cloning (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325629&req=5

f1-sccaa-8-027: 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.
Mentions: Classically, the Hh signaling pathway is believed to be ligand-dependent. Three Hh ligands (Sonic [SHH], Indian [IHH], and Desert [DHH]) have been identified in vertebrates, affecting stem cell behavior in a time- and concentration-dependent manner.19 SHH is widely expressed, particularly during embryogenesis, with SHH deficiency being embryonically lethal.17 IHH is produced in hematopoietic cells, bone, and cartilage,20 whilst DHH is found in the peripheral nervous system and testes.21 Hh ligands are initially synthesized as an inactive 45 kDa precursor, undergoing post-translational modifications to form a 19 kDa amino-terminal active signaling molecule.22 This cholesterol and palmitoyl modification, catalyzed by Hh acyltransferase,23 not only enhances ligand activity but also modifies its diffusion capacity.24 The Hh ligands bind to the 12 trans-membrane receptor protein Patched 1 (PTCH1), causing its internalization and removing its repression of the 7-span trans-membrane protein Smoothened (SMO), allowing pathway activity.25 In vertebrates, activity of the Hh pathway appears intrinsically related to primary immotile cilia; in the absence of ligand, PTCH1 is located within the primary cilia. Following ligand binding, and the internalization of PTCH1, SMO is able to concentrate in the primary cilia where it interacts with the GLI transcription factors shifting the balance toward pathway activation.25 Whilst the intricacies of this interaction remain poorly understood, studies suggest these receptors do not physically interact, rather PTCH1 is thought to regulate SMO through an intermediary, with studies suggesting that oxysterols, including vitamin D3, are involved.26 SMO subsequently causes accumulation of the full length active form of the zinc transcription factors GLI-2 and GLI-3 in the nucleus, and potentiates the activity of other positive regulators of the pathway including serine threonine kinase 36 (STK36) and kinesin family member 7 (KIF7), resulting in transcription of key downstream targets such as GLI-1 and PTCH1, regulators of chromatin formation, cell cycle activity, cell mobility, and apoptosis, eg, bone morphogenetic protein 4, forkhead box protein M1, and WNT2a,27Figure 1A. Of the transcription factors, GLI-1 functions as a positive regulator, GLI-3 a transcriptional repressor, and GLI-2 both a positive and negative transcriptional regulator determined by post-transcriptional and post-translational modifications.28 It is the balance between these transcription factors which determines pathway activity.29

Bottom Line: The stem cell paradigm was first demonstrated in hematopoietic stem cells.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.

View Article: PubMed Central - PubMed

Affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterninary and Life Sciences, University of Glasgow, Glasgow, UK.

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.

No MeSH data available.


Related in: MedlinePlus