Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment
Abstract
:Simple Summary
Abstract
1. Introduction
2. Metronomic Chemotherapy: A Multimodal Therapy
3. Cellular Components of the Tumor Microenvironment and Their Modulation by Metronomic Therapy
3.1. Tumor Vasculature as a Support for Cancer Cells and Tumor-Initiating Cells or Cancer Stem Cells (CSCs)
Metronomic Chemotherapy to Target Endothelial, Cancer, and Cancer Stem Cells
3.2. Tumour Microenvironment May Reprogram Non-Immunological Bone Marrow-Derived Cells to Support Tumor Growth and Metastases
Metronomic Chemotherapy Has a Systemic Antiangiogenic Effect by Reducing Mobilization and Viability of Bone-Marrow-Derived CEPs
3.3. Tumour Microenvironment May Reprogram Immunological Bone-Marrow-Derived Cells to Support Tumor Growth and Metastases
Metronomic Chemotherapy as Immune Modulator by Targeting Bone-Marrow-Derived Myeloid Cells
3.4. Heterogeneity and Plasticity in Cancer-Associated Fibroblasts (CAF), a Subset of the Tumor Microenvironment
Metronomic Chemotherapy Prevents the Pro-Stemness Function of CAFs
4. Simulated Metronomic Therapies: Nanocarriers for Cancer Therapy
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cancer Type | Therapeutic Agents | In Vivo Studies | Mechanisms | Cites |
---|---|---|---|---|
Section: Metronomic Chemotherapy to Target Endothelial, Cancer, and Cancer Stem Cells. | ||||
Pancreatic | MC gemcitabine | PC patient-derived xenograft | ↓hypoxia ↓necrosis | [91] |
Glioma | MC CTX 1 | PC xenograft | ↓CSCs | [74] |
Pancreatic | MC gemcitabine | PC xenograft | ↓CSCs | [92] |
Section: Metronomic Chemotherapy Has a Systemic Antiangiogenic Effect by Reducing Mobi-lization and Viability of Bone-Marrow-Derived CEPs. | ||||
Acute lymphoid leukemia (ALL) | ALL maintenance therapy (MC Mercaptopurin + MC MTX 2) | clinical | ↓blood CEPs ↑blood TSP-1 | [113] |
Advanced breast carcinoma | MCCTX/MCMTX +/− thalidomide | clinical | ↑apoptotic blood CECs | [114] |
Chronic myeloid leukemia | lenalidomide + MCmelphalan | clinical | ↑apoptotic blood CECs | [115] |
Advanced NSCLC | MCvinorelbine + sorafenib | clinical | dynamic changes of CECs | [116] |
Lymphoma | MCCTX | PC xenograft | ↓blood CEPs | [117] |
Lewis lung carcinoma (LLC) | endostar + MCvinorelbine | PC syngeneic mouse model | ↓blood CEPs ↓microvessel density, ↓VEGF, HIF-1α | [124] |
Neuroblastoma, osteosarcoma, rhabdomyo-sarcoma | MCtopotecan + pazopanib | PC xenograft | ↓viable blood CEPs and CECs ↓microvessel density | [127] |
Colon adenocarcinoma and liver metastasis | MC capecitabine MC capecitabine + MC CTX | PC xenograft | ↓HIF-1α ↓intrametastatic hypoxia | [128] |
Section: Metronomic Chemotherapy as Immune Modulator by Targeting Bone-Marrow-Derived Myeloid Cells. | ||||
Pancreatic adenocarcinoma | MTD gemcitabine + MC gemcitabine | PC syngeneic mouse model PC xenograft | ↓tumor MDSCs | [156] |
Brain | MC CTX (Q6day cycle) | PC xenograft | ↓CD11b+GR1+ bone marrow & spleen | [158,159] |
Glioblastoma | MC 5-FU 3 | PC xenograft | ↓blood MDSCs ↑CD8+-T cells ↓Treg | [135] |
Breast carcinoma | MC capecitabine | PC patient-derived xenograft | ↓blood MDSCs ↑cytotoxic T cells ↓Treg | [160] |
Recurrent glioblastoma | MC capecitabine | clinical | ↓blood MDSCs ↑CD8+-T cells ↑NK cells | [161,162] |
Lewis lung carcinoma (LLC) | MC gemcitabine + anti-Ang-2 + anti VEGF | PC syngeneic mouse model | ⊗MDSC recruitment in metastasis. ⊗infiltration of MΦ at metastasis site | [163] |
Glioma | MC temozolomide | PC syngeneic rat model | ↓Treg/CD4+-T cells in spleen | [169] |
ER 4-positive breast | letrozol letrozol +MC CTX | clinical | ↓Treg | [170] |
ER-positive breast | letrozol letrozol + MC vinorelbine | clinical | ↑tumor infiltrating lymphocytes | [171] |
Metastatic solid tumors | MC CTX | clinical | ↓blood Treg enhancing T and NK cell functions | [172] |
Metastatic colorectal cancer | MC CTX | clinical | ↓blood Treg ↑CD8+-T cells | [173] |
Section: Metronomic Chemotherapy Prevents the Pro-Stemness Function of CAFs | ||||
Breast and pancreatic ductal adenocarcinoma | MC doxorubicin MC paclitaxel MC CTX | PC xenograft and human breast cancer tissues | ↓ ELR+-chemokines CAF expression ↓expansion of CSCs | [210] |
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Muñoz, R.; Girotti, A.; Hileeto, D.; Arias, F.J. Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment. Cancers 2021, 13, 5414. https://doi.org/10.3390/cancers13215414
Muñoz R, Girotti A, Hileeto D, Arias FJ. Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment. Cancers. 2021; 13(21):5414. https://doi.org/10.3390/cancers13215414
Chicago/Turabian StyleMuñoz, Raquel, Alessandra Girotti, Denise Hileeto, and Francisco Javier Arias. 2021. "Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment" Cancers 13, no. 21: 5414. https://doi.org/10.3390/cancers13215414