NOTCH Signaling in Osteosarcoma
Abstract
:1. Introduction
2. Composition of the NOTCH Signaling Pathway
3. Biological Functions of the NOTCH Signaling Pathway
4. Clinical Significance of Dysfunction of the NOTCH Signaling Pathway in Osteosarcoma Signaling
5. Effect of the NOTCH Signaling Pathway on Osteosarcoma
5.1. The NOTCH Signaling Pathway Regulates Osteogenic Differentiation in Osteosarcoma
5.2. The NOTCH Signaling Pathway Maintains the Self-Renewal Ability of Cancer Stem Cells in Osteosarcoma
5.3. The NOTCH Signaling Pathway Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma
Component | Gene | Study/Reference | Functional Status or Expression Level | Clinical Outcome | Cases | Detection Methods |
---|---|---|---|---|---|---|
Ligands | Jag1 | [30] | Upregulated | No report | 10 | RT-PCR |
[16] | Upregulated | Increased metastasis rate and recurrence rate | 68 | IHC | ||
[54] | Upregulated | No report | 10 | RT-PCR | ||
Dll1 | [54] | Downregulated | No report | 10 | RT-PCR | |
Receptors | NOTCH1 | [33] | Upregulated | Reduced cisplatin sensitivity; lower overall survival | 12 | IHC |
[30] | Upregulated | No report | 10 | RT-PCR | ||
[54] | Downregulated | No report | 10 | RT-PCR | ||
[31] | High heterogeneity | Positively correlated with cisplatin sensitivity | 8 | IHC | ||
NOTCH2 | [54] | Upregulated | No report | 10 | RT-PCR | |
NOTCH3 | [32] | Upregulated | Lower survival rates; increased metastasis rates | 70 | IHC | |
Downstream targets | Hes1 | [33] | Upregulated | Reduced cisplatin sensitivity; lower overall survival | 12 | IHC |
[17] | Upregulated | Decreased survival rates | 16 | RT-PCR | ||
[30] | Upregulated | No report | 10 | RT-PCR | ||
Hey1 | [54] | Upregulated | No report | 10 | RT-PCR | |
Hey2 | [30] | Upregulated | No report | 10 | RT-PCR | |
[54] | Upregulated | No report | 10 | RT-PCR |
5.4. The NOTCH Signaling Pathway Promotes Tumor Metastasis and Invasion
5.5. The NOTCH Signaling Pathway Promotes Tumor Angiogenesis
5.6. The NOTCH Signaling Pathway Induces Chemoresistance
5.7. The NOTCH Signaling Pathway Regulates Immune Infiltration in Osteosarcoma Environment
6. NOTCH Signaling in Animal Models of Osteosarcoma
6.1. Animal Model of Spontaneous Osteosarcoma
6.2. Animal Transplantation Model of Human Osteosarcoma
6.3. Animal Transplantation Model of Allogeneic Osteosarcoma
6.4. Genetically Engineered Animal Osteosarcoma Model
7. Osteosarcoma Treatment Strategy Based on NOTCH Signaling
7.1. The Biological Agents Targeting the NOTCH Signaling Pathway
7.1.1. Monoclonal Antibodies
7.1.2. Blocking Peptides
7.2. γ-Secretase Inhibitors
7.3. Natural Products
Drug | Target | Study Types | Study/Reference |
---|---|---|---|
Demcizumab | Dll4 | Clinical trial phase I | [101] |
OMP-5948 | NOTCH2 and NOTCH3 | Clinical trial phase I | [98] |
DAPT | γ-secretase | Studies performed in in vitro cells and pre-clinical animal models | [106,107,108] |
RO4929097 | γ-secretase | Trial performed in pre-clinical animal models | [110] |
Clinical trial phase I | [111] | ||
Diallyl trisulfide | A natural product (non-selective inhibitors) | Studies performed in invitro cells | [77] |
Oleanolic acid | A natural product (non-selective inhibitors) | Studies performed in invitro cells | [57] |
Curcumin | A natural product (non-selective inhibitors) | Studies performed in invitro cells | [122] |
Cinobufacin | A natural product (non-selective inhibitors) | Studies performed in invitro cells and pre-clinical animal models | [56] |
8. Discussion and Future Directions
Component | Gene | Study/Reference | Major Effect | Cell Line | Animal Mode |
---|---|---|---|---|---|
Ligands | Jag1 | [16] | Inducing proliferation, migration, and invasion; | F5M2 | No |
[55] | Inducing angiogenesis; promoting tumor growth and metastasis; | K7M2 | Orthotopic allograft mouse model and lung metastatic allograft mouse model | ||
[91] | Inducing proliferation, migration, and invasion | 143B, SJSA1, SAOS2, U2OS, MG63 | Orthotopic xenograft mouse model | ||
Dll1 | [17] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | OS 187, COL, LM7, SAOS2 | Orthotopic xenograft mouse model | |
Receptors | NOTCH1 | [39] | Inducing osteoblast differentiation | MG63 | No |
[40] | Inducing osteoblast carcinogenesis; inducing proliferation, migration, and invasion; inducing genomic instability | Primary osteosarcoma cells isolated form mice | Genetically engineered mouse model | ||
[46] | Inducing the activity of cancer stem cell | 143B, MG63 | Subcutaneous xenograft mouse model | ||
[47] | Promoting tumor recurrence and metastasis | hFOB, SAOS2, MG63, MNNG/HOS, LM5, HuO9, LM132 | Subcutaneous xenograft mouse model | ||
[48] | Inducing the activity of cancer stem cell | U2OS, 143B | No | ||
[49] | Inducing the activity of cancer stem cells; promoting tumor proliferation and recurrence | 143B, U2OS, MG63 | Subcutaneous xenograft mouse model | ||
[55] | Inducing angiogenesis; promoting tumor proliferation and metastasis | K7M2 | Orthotopic allograft mouse model and lung metastatic allograft mouse model | ||
[33] | Enhancing chemoresistance; inducing the activity of cancer stem cells; inducing proliferation, migration, and invasion; promoting tumor growth, recurrence, and metastasis | U2OS, MG63, 143B | Subcutaneous xenograft mouse model | ||
[56] | Inhibiting apoptosis | U2OS, MG-63, 143B | Subcutaneous xenograft mouse model | ||
[57] | Inhibiting apoptosis | SAOS2, MG63 | No | ||
[58] | Inhibiting apoptosis | MG63 | No | ||
[77] | Inducing angiogenesis | U2OS, SAOS2, MG63 | No | ||
[31] | Enhancing chemosensitivity; inhibiting apoptosis | SAOS2, MG63 | No | ||
[79] | Enhancing chemoresistance | 143B | No | ||
[84] | Inhibiting the polarization of TAMs to the M2 phenotype | S180, mouse macrophages differentiated by primary bone marrow cells | Subcutaneous xenograft mouse model | ||
[91] | Inducing proliferation, migration, and invasion | 143B, SJSA1, SAOS2, U2OS, MG63 | Orthotopic xenograft mouse model | ||
[17] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | OS 187, COL, LM7, SAOS2 | Orthotopic xenograft mouse model | ||
[30] | Inducing the activity of cancer stem cells; inducing proliferation, migration, and invasion; promoting tumor growth | SJSA1, SaOs2, CRL1423 | Subcutaneous xenograft mouse model | ||
NOTCH2 | [39] | Inducing osteoblast differentiation | MG63 | No | |
[59] | Inducing proliferation | 143B, U2OS, MG63, HOS, hFOB | No | ||
[65] | Attenuating EMT; inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | 143B | Subcutaneous xenograft mouse model | ||
[17] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | OS 187, COL, LM7, SAOS2 | Orthotopic xenograft mouse model | ||
NOTCH3 | [39] | Inducing osteoblast differentiation | MG63 | No | |
[32] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | U2OS, hFOB1.19, MTH | Lung metastatic allograft mouse model | ||
NOTCH4 | [39] | Inducing osteoblast differentiation | MG63 | No | |
Downstream targets | Hey1 | [39] | Inducing osteoblast differentiation; | MG63 | No |
[48] | Increasing the activity of cancer stem cell | U2OS, 143B | No | ||
[49] | Increasing the activity of cancer stem cells; inducing proliferation; promoting tumor growth and recurrence | 143B, U2OS, MG63 | Subcutaneous xenograft mouse model | ||
[65] | Attenuating EMT; inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | 143B | Subcutaneous xenograft mouse model | ||
[79] | Enhancing chemoresistance | 143B | No | ||
Hey2 | [91] | Inducing proliferation, migration, and invasion | 143B, SJSA1, SAOS2, U2OS, MG63 | Orthotopic xenograft mouse model | |
Hes1 | [46] | Inducing the activity of cancer stem cell | 143B, MG63 | Subcutaneous xenograft mouse model | |
[47] | Promoting tumor growth, recurrence, and metastasis | hFOB, SAOS2, MG63, MNNG/HOS, LM5, HuO9, LM132 | Subcutaneous xenograft mouse model | ||
[48] | Inducing the activity of cancer stem cell | U2OS, 143B | No | ||
[49] | Inducing the activity of cancer stem cells; promoting tumor growth and recurrence | 143B, U2OS, MG63 | Subcutaneous xenograft mouse model | ||
[54] | Inducing proliferation; promoting tumor growth | HOS, 143B, SAOS2, U2OS | Subcutaneous xenograft mouse model | ||
[33] | Enhancing chemoresistance; inducing the activity of cancer stem cells; inducing proliferation, migration, and invasion; promoting tumor growth, recurrence, and metastasis | U2OS, MG63, 143B | Subcutaneous xenograft mouse model | ||
[17] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | OS 187, COL, LM7, SAOS2 | Orthotopic xenograft mouse model | ||
[32] | Inducing proliferation, migration, and invasion; promoting tumor growth and metastasis | U2OS, hFOB1.19, MTH | Lung metastatic allograft mouse model | ||
[79] | Enhancing chemoresistance | 143B | No | ||
[30] | Inducing the activity of cancer stem cells; inducing proliferation, migration, and invasion; promoting tumor growth | SJSA1, SaOs2, CRL1423 | Subcutaneous xenograft mouse model |
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Zhang, Z.; Wu, W.; Shao, Z. NOTCH Signaling in Osteosarcoma. Curr. Issues Mol. Biol. 2023, 45, 2266-2283. https://doi.org/10.3390/cimb45030146
Zhang Z, Wu W, Shao Z. NOTCH Signaling in Osteosarcoma. Current Issues in Molecular Biology. 2023; 45(3):2266-2283. https://doi.org/10.3390/cimb45030146
Chicago/Turabian StyleZhang, Zhenhao, Wei Wu, and Zengwu Shao. 2023. "NOTCH Signaling in Osteosarcoma" Current Issues in Molecular Biology 45, no. 3: 2266-2283. https://doi.org/10.3390/cimb45030146