Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

One of the hallmarks of cancer is angiogenesis, a series of events leading to the formation of the abnormal vascular network required for tumor growth, development, progression, and metastasis. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs whose functions include modulation of the expression of pro- and anti-angiogenic factors and regulation of the function of vascular endothelial cells. Vascular-associated microRNAs can be either pro- or anti-angiogenic. In cancer, miRNA expression levels are deregulated and typically vary during tumor progression. Experimental data indicate that the tumor phenotype can be modified by targeting miRNA expression. Based on these observations, miRNAs may be promising targets for the development of novel anti-angiogenic therapies. This review discusses the role of various miRNAs and their targets in tumor angiogenesis, describes the strategies and challenges of miRNA-based anti-angiogenic therapies and explores the potential use of miRNAs as biomarkers for anti-angiogenic therapy response.

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M-CSF Inhibition Selectively Targets Tumor Angiogenesis and Lymphangiogenesis

Blood ◽

10.1182/blood.v112.11.1256.1256 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1256-1256

Author(s):

Yoshiaki Kubota ◽

Toshio Suda

Keyword(s):

Tumor Angiogenesis ◽

Therapeutic Potential ◽

Physiological Role ◽

Osteosarcoma Cell ◽

Angiogenic Therapy ◽

High Dependency ◽

Lymphatic Development ◽

Vegf Pathway ◽

Vessel Network ◽

Macrophage Colony

Abstract Anti-angiogenic therapy in cancer is desired to be selective for tumor angiogenesis. The best validated approaches for limiting tumor angiogenesis involve blockade of the VEGF pathway. However, recent studies show that VEGF blockade damages healthy vessels resulting in toxic side effects (Maharaj et al. J. Exp. Med. 2008) and that interrupting the VEGF blockade induces rapid vascular regrowth in tumors (Mancuso et al. J. Clin. Invest. 2006). Therefore, other targets are currently being explored. Macrophage-colony stimulating factor (M-CSF), a cytokine required for differentiation of monocyte-lineage cells including macrophages promotes formation of a high-density vessel network in tumors suggesting therapeutic potential of M-CSF inhibition (Lin et al. J. Exp. Med. 2001). Moreover, M-CSF is abundantly expressed in highly-metastatic cancers such as breast cancer and osteosarcoma, suggesting high dependency on macrophages. However, the physiological role of M-CSF in vascular and lymphatic development as well as the precise mechanisms underlying anti-angiogenic effects of M-CSF inhibition is not clarified. Here, utilizing osteopetrotic (op/op) mice, we show that M-CSF deficiency leads to lack of both LYVE-1+ and LYVE1− macrophages, resulting in defects not only in vascular but also lymphatic development. To clarify the anti-cancer effects of M-CSF inhibition, we utilized a novel mouse model of osteosarcoma, in which mice were transplanted with a newly established osteosarcoma cell line, AX, which were developed from c-Myc-overexpressing Ink4a/ARF−/− bone marrow-derived stromal cells. In this model, systemic treatment with small molecule c-fms inhibitors (Ki20227) effectively suppressed tumor angiogenesis and lymphangiogenesis disorganizing extracellular matrices. Consequently, c-fms inhibitors almost completely suppressed tumor metastasis, and protected mice from cancer death. Different from VEGF blockade, interruption of M-CSF inhibition did not promote rapid tumor regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside the tumor. These results suggest M-CSF-targeted therapy is an ideal therapeutic strategy against cancer alternative to VEGF blockade.

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Biological Pathways Involved in Tumor Angiogenesis and Bevacizumab Based Anti-Angiogenic Therapy with Special References to Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms18091967 ◽

2017 ◽

Vol 18 (9) ◽

pp. 1967 ◽

Cited By ~ 30

Author(s):

Vera Loizzi ◽

Vittoria Del Vecchio ◽

Giulio Gargano ◽

Maria De Liso ◽

Anila Kardashi ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Angiogenesis ◽

Biological Pathways ◽

Angiogenic Therapy

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Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

Advances in Cell Biology ◽

10.1515/acb-2017-0005 ◽

2017 ◽

Vol 5 (1) ◽

pp. 50-71 ◽

Cited By ~ 4

Author(s):

Agnieszka Knopik-Skrocka ◽

Patrycja Kręplewska ◽

Donata Jarmołowska-Jurczyszyn

Keyword(s):

Endothelial Cells ◽

Blood Vessels ◽

Tumor Angiogenesis ◽

Current Knowledge ◽

Vasculogenic Mimicry ◽

High Plasticity ◽

Drug Induced ◽

Cellular Targets ◽

Angiogenic Therapy ◽

And Migration

SummaryBlood vessel formation in tumor is defined as tumor angiogenesis. So far, the most known its mechanism is sprouting, which means formation of blood vessels from existing ones, as a result of the proliferation and migration of endothelial cells. The main mitogenic factor of these cells is vascular endothelial growth factor VEGF, acting by VEGFR-2 receptors. Recent studies have provided knowledge about the ability of tumors to form vessel-like structures. The phenomenon was called vascular mimicry. Tumor cells show a high plasticity and they can undergo differentiation to the ones with phenotype similar to endothelial cells. Each of the known tumor angiogenesis mechanisms is a result of many different factors and cell cooperation in tumor microenvironment. Tumor ability to the heterogeneous vascularization forces developing of complex, anti-angiogenic therapy directed to different molecular and cellular targets. Therapies, used so far, often lead to drug-induced hypoxia, which increases tumor cell aggressiveness and metastasis.

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Implication of Heat Shock Protein 90 (HSP90) in Tumor Angiogenesis: A Molecular Target for Anti-Angiogenic Therapy?

Current Cancer Drug Targets ◽

10.2174/156800910793357934 ◽

2010 ◽

Vol 10 (8) ◽

pp. 890-897 ◽

Cited By ~ 21

Author(s):

K. Staufer ◽

O. Stoeltzing

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Tumor Angiogenesis ◽

Heat Shock Protein 90 ◽

Molecular Target ◽

Angiogenic Therapy

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Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Journal of Clinical Medicine ◽

10.3390/jcm9103308 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3308

Author(s):

Céline A. Schoonjans ◽

Barbara Mathieu ◽

Nicolas Joudiou ◽

Luca X. Zampieri ◽

Davide Brusa ◽

...

Keyword(s):

Endothelial Cell ◽

Tumor Angiogenesis ◽

Pyruvate Dehydrogenase ◽

Umbilical Vein ◽

Cell Metabolism ◽

Tube Formation ◽

Pyruvate Dehydrogenase Kinase ◽

Angiogenic Therapy ◽

Umbilical Vein Endothelial Cells ◽

Glutaminase 1

Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.

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Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21155418 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5418 ◽

Cited By ~ 2

Author(s):

Song Yi Ko ◽

Honami Naora

Keyword(s):

Tumor Angiogenesis ◽

Therapy Resistance ◽

Extracellular Vesicle ◽

Biological Functions ◽

Vesicle Membrane ◽

Angiogenic Therapy ◽

Anti Cancer ◽

Associated Proteins ◽

Tumor Growth And Metastasis ◽

Prime Target

The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy.

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Tumor Angiogenesis and Anti-angiogenic Therapy

The Keio Journal of Medicine ◽

10.2302/kjm.61.47 ◽

2012 ◽

Vol 61 (2) ◽

pp. 47-56 ◽

Cited By ~ 85

Author(s):

Yoshiaki Kubota

Keyword(s):

Tumor Angiogenesis ◽

Angiogenic Therapy

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Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-020-03111-7 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Haoran Feng ◽

Kun Liu ◽

Xiaonan Shen ◽

Juyong Liang ◽

Changgang Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Candidate Gene ◽

Tumor Angiogenesis ◽

Mapk Signaling ◽

Gene Set Enrichment Analysis ◽

High Expression ◽

Angiogenic Therapy ◽

Therapy Strategy

AbstractIn our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC.

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