The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?
Abstract
:1. Introduction
2. Chronic Myeloproliferative Neoplasms
MPNs | ||||
---|---|---|---|---|
CML | ET | PV | PMF | |
Main phenotype | Granulocytosis Basophilia | Thrombocytosis | Polycythaemia | Abnormal megakaryocytopoiesis Variable blood counts |
Main genetic alteration(s) | Bcr-Abl rearrangement | JAK2V617F (heterozygous) CALR mutants MPLW515L/K mutants | JAK2V617F (homozygous) | JAK2V617F (heterozygous or homozygous) CALR mutants MPLW515L/K mutants |
Main activated pathway | Abl | Jak2/Stat5 Jak2/Stat1 Protein trafficking (CALR mutants) | Jak2/Stat5 | Jak2/Stat5 Protein trafficking (CALR mutants) |
Inflammation | Mild | Variable | Severe | |
Myelofibrosis | Variable | Limited | Variable | Severe |
Hepato-splenomegaly | Variable /Severe | Rare | Variable | Severe |
HGF levels | High | Moderately elevated | High | High |
Met levels | Absent in chronic phase; present in acute phase | Not studied | High in erythroblasts | Not studied |
Main treatment | Bcr-Abl inhibitors (imatinib…) | Salicylic acid Hydroxyurea | Phlebotomy Hydroxyurea Interferon-α | Hydroxyurea Interferon-α Jak inhibitors |
Clinical and molecular response * (main disease marker) | Yes | No | Only with Interferon-α2a | No |
Cure* | No | No | No | No |
3. HGF and Metexpression in CML and in MPNs
3.1. Paracrine and Autocrine HGF Production and Autocrine HGF/Met Loop
3.2. Met as a Pro-Survival Receptor
3.3. Cross-Talk between the HGF/Met Axis and Cytokines Linked to Inflammation
Regulators of HGF and Met expression | ||
---|---|---|
HGF | Met | |
Stimulants | b-FGF, IL-3, OSM IFN-γ (only weakly) HIF-1α NF-κB | SCF IL-3 IL-11 |
Inhibitors | TGF-β | ? |
Cytokines regulated by activation of the HGF/Met axis | ||
Stimulated | IL-11, IL-6, IL-8 VEGF, SCF, SDF-1α | |
Inhibited | IFN-γ TNF-α, TGF-β |
4. Activation of the HGF/Met Axis as an Early Event in MPNs
5. Molecular Mechanisms of Activation of the HGF/Met Axis
5.1. Genetic Alteration of the HGF and MET Genes
5.2. MET Over-Expression
5.3. HGF Over-Expression
5.3.1. Role of Bcr-Abl and the Jak2V617F, MplW515 or CalR Mutants
5.3.2. Role of Hypoxia
5.3.3. Role of NF-kB
6. HGF Overproduction as Prognosis Marker of Disease Severity
7. The HGF/Met Axis as a New Target in the Treatment of CML and MPNs
7.1. Abl-Bcr Inhibitors
7.2. Neutralising Antibodies
7.3. MET Small Molecule Inhibitors
7.4. Interferon (IFN)-α
7.5. Other Molecules
8. Combination of Inhibitors of the HGF/Met Axis and Drugs Commonly Used in the Treatment of MPNs or CML
9. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Boissinot, M.; Vilaine, M.; Hermouet, S. The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms? Cancers 2014, 6, 1631-1669. https://doi.org/10.3390/cancers6031631
Boissinot M, Vilaine M, Hermouet S. The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms? Cancers. 2014; 6(3):1631-1669. https://doi.org/10.3390/cancers6031631
Chicago/Turabian StyleBoissinot, Marjorie, Mathias Vilaine, and Sylvie Hermouet. 2014. "The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?" Cancers 6, no. 3: 1631-1669. https://doi.org/10.3390/cancers6031631