Hedgehog Signaling in the Maintenance of Cancer Stem Cells
Abstract
:1. Introduction
2. The Hedgehog Signaling Network
2.1. Hedgehog Biogenesis and Secretion
2.2. Hedgehog Signal Transduction
3. Roles for Hedgehog Signaling in Cancer
3.1. Modes of Signaling in Hh-Pathway-Dependent Cancers
3.2. Type I: Ligand-Independent, Tumour Cell-Intrinsic Signaling
3.3. Type II: Ligand-Dependent, Autocrine Signaling
3.4. Type III: Ligand-Dependent, Paracrine Signaling
3.5. Type IIIb: Ligand-Dependent, Reverse Paracrine Signaling
3.6. Type IV: Cancer Stem Cells
Tumour Type | CSC Marker | Stemness Genes Expressed | Mode of Hedgehog Inhibition | Experimental Evidence | Combination Therapy | Refs. |
---|---|---|---|---|---|---|
Chronic Myeloid Leukaemia (CML) | CD34+, Lin−, Sca+, cKit+ | - | Cyclopamine, Bcr-Abl infected Smo−/− embryonic liver cells, Smo KO in CML mouse model, PF-04449913 | 14-fold reduction in CML LSCs, 60% of mice survived after 7 weeks | Cyclopamine and nilotinib, PF-04449913 and dasatinib | [104,105,106,107,108] |
Acute Myeloid Leukaemia (AML) | - | - | IPI-926, PF-04449913, Cyclopamine, Endogenous Hhip, 5E1 | Inhibits self-renewal and promotes myelomonocytic differentiation | Sorafenib and IPI-926, cyclopamine or Hhip or 5E1 and cytarabine | [109,110,111,112] |
Acute Lymphoblastic Leukaemia(ALL) | - | - | Cyclopamine, IPI-926, KAAD-cyclopamine, SANT-1 | Reduces long-term self-renewal in B-ALL, promotes apoptosis in T-ALL | - | [113,114] |
Multiple Myeloma | CD138neg, CD19+ | - | Cyclopamine, 5E1 | Reduces CD138neg self-renewal by inducing plasma cell differentiation | - | [98] |
Glioma | CD133+, ALDH1+, ABCG2+ | NANOG, OCT4, SOX2, NESTIN, BMI1 | Cyclopamine | Abolishes tumour engraftment | Cyclopamine, temozolomide and/or 10 Gys of radiation | [101,115,116,117] |
Breast Cancer | CD44+, CD24−/low, Lin−, ALDH1+ | p63, OCT4, NESTIN, NANOG, BMI1 | Cyclopamine | Reduces mammosphere self-renewal and secondary formation | - | [118,119,120] |
Small Cell Lung Cancer | - | BMP4, NESTIN, ASH-1 | Cyclopamine, LDE-225, shSMO, 5E1 | Prevents tumour relapse in LX22 xenografts | LDE-225, carboplatin and etoposide or, GDC-0449 and cisplatin | [82,121,122] |
Non-Small Cell Lung Cancer | - | SOX2, OCT4, NANOG, ALDHA1 | siSHH GDC-0449 | Decreases colony formation and growth in soft agar | GDC-0440, erlotinib and cisplatin | [103,122,123] |
Gastric Cancer | CD44+, CD24+ | SOX2, NANOG | Cyclopamine, Vismodegib, 5E1, shSMO | Reduces CD44+ tumourspheres and number and diameter of colonies | Vismodegib, 5-flurouracil and/or cisplatin or cyclopamine, oxaliplatin and mitomycin | [124,125] |
Colon Cancer | CD133+ | NANOG, OCT4 | shSMO Cyclopamine | Reduction of the CD133+ CSC population | - | [83,102] |
Pancreatic Cancer | CD44+, CD24+, ESA+ | NANOG, OCT4 | GDC-0449, Cyclopamine derivative - CyT | Reduces tumoursphere viability and chemoresistance | CyT and 2 Gys of radiation | [86,126,127,128,129,130,131,132] |
Prostate Cancer | - | NANOG, OCT4 | Cyclopamine, shGLI1,2, GANT61 | Suppresses tumoursphere and colony formation | Cyclopamine and paclitaxel | [133,134,135,136] |
Metastatic Melanoma | ALDH+ | SOX2, NANOG, OCT4, KLF4 | shSMO, shGLI1 | Reduces ALDH+ melanospheres fraction, clonogenicity and xenograft growth | - | [137,138,139] |
4. Evidence for the Role of Hedgehog Signaling in Cancer Stem Cell Maintenance
4.1. Leukemic Stem Cells
4.2. Chronic Myeloid Leukaemia
4.3. Acute Myeloid Leukaemia
4.4. Acute Lymphoblastic Leukaemia
4.5. Multiple Myeloma
4.6. Glioma
4.7. Breast Cancer
4.8. Gastrointestinal Cancers
4.9. Pancreatic Cancer
4.10. Prostate Cancer
4.11. Lung Cancer
4.12. Melanoma
5. Targeting Hedgehog Signaling in Cancer Stem Cells
6. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Cochrane, C.R.; Szczepny, A.; Watkins, D.N.; Cain, J.E. Hedgehog Signaling in the Maintenance of Cancer Stem Cells. Cancers 2015, 7, 1554-1585. https://doi.org/10.3390/cancers7030851
Cochrane CR, Szczepny A, Watkins DN, Cain JE. Hedgehog Signaling in the Maintenance of Cancer Stem Cells. Cancers. 2015; 7(3):1554-1585. https://doi.org/10.3390/cancers7030851
Chicago/Turabian StyleCochrane, Catherine R., Anette Szczepny, D. Neil Watkins, and Jason E. Cain. 2015. "Hedgehog Signaling in the Maintenance of Cancer Stem Cells" Cancers 7, no. 3: 1554-1585. https://doi.org/10.3390/cancers7030851