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Methods in Molecular Biology (Clifton,... 2023The angiogenesis process was described in its basic concepts in the works of the Scottish surgeon John Hunter and terminologically assessed in the early twentieth...
The angiogenesis process was described in its basic concepts in the works of the Scottish surgeon John Hunter and terminologically assessed in the early twentieth century. An aberrant angiogenesis is a prerequisite for cancer cells in solid tumors to grow and metastasize. The sprouting of new blood vessels is one of the major characteristics of cancer and represents a gateway for tumor cells to enter both the blood and lymphatic circulation systems. In vivo, ex vivo, and in vitro models of angiogenesis have provided essential tools for cancer research and antiangiogenic drug screening. Several in vivo studies have been performed to investigate the various steps of tumor angiogenesis and in vitro experiments contributed to dissecting the molecular bases of this phenomenon. Moreover, coculture of cancer and endothelial cells in 2D and 3D matrices have contributed to improve the recapitulation of the complex process of tumor angiogenesis, including the peculiar conditions of tumor microenvironment.
Topics: Angiogenesis Inhibitors; Coculture Techniques; Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 36161404
DOI: 10.1007/978-1-0716-2703-7_1 -
International Journal of Molecular... Apr 2022A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis...
A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of -methyl--bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation.
Topics: Angiogenesis Inhibitors; Cell Movement; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 35457095
DOI: 10.3390/ijms23084277 -
Asia-Pacific Journal of Clinical... Aug 2019Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various... (Review)
Review
Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti-angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR)-2 monoclonal antibodies, VEGF-Trap and VEGFR tyrosine kinase inhibitors, the anti-VEGFR-2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second-line chemotherapy. Additionally, apatinib, a selective VEGFR-2 tyrosine kinase inhibitor, prolonged survival as a third-line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti-angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Humans; Stomach Neoplasms
PubMed: 31111678
DOI: 10.1111/ajco.13174 -
Critical Reviews in Oncology/hematology Nov 2017Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment... (Review)
Review
Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 28916378
DOI: 10.1016/j.critrevonc.2017.08.010 -
Drug Discovery Today Oct 2017The tumor vasculature transports oxygen, nutrients and drugs for crucial roles in tumor therapy. Antivascular therapy directly targets existing tumor vessels to reduce... (Review)
Review
The tumor vasculature transports oxygen, nutrients and drugs for crucial roles in tumor therapy. Antivascular therapy directly targets existing tumor vessels to reduce blood perfusion and then inhibit tumor growth. Vascular disrupting agents and ultrasound-stimulated microbubble destruction use chemical toxicity and physical effect, respectively, to damage vascular endothelial cells for antivascular therapy. Moreover, antivascular therapy can break vessel wall barriers and change the tumor microenvironment to compensate for the limitations of conventional chemotherapy or radiotherapy. This review presents current progress and an overview of antivascular therapy, which can inform the development and application in cancer research.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 28625610
DOI: 10.1016/j.drudis.2017.06.001 -
Biochemical and Biophysical Research... Nov 2021Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment...
Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Male; Mefloquine; Mice, SCID; Neovascularization, Pathologic; Mice
PubMed: 34607260
DOI: 10.1016/j.bbrc.2021.09.069 -
Journal of Thrombosis and Haemostasis :... Aug 2021Over the past two decades, therapies targeting angiogenesis have developed into a major class of cancer therapeutics. The vascular endothelial growth factor (VEGF)... (Review)
Review
Over the past two decades, therapies targeting angiogenesis have developed into a major class of cancer therapeutics. The vascular endothelial growth factor (VEGF) family of signaling proteins, a group of potent angiogenic growth factors, and their receptors represent the main targets of this therapeutic class. To date, 16 antiangiogenic agents have been approved in the United States for the treatment of cancer and several more are in development. An important consideration with antiangiogenic therapy is toxicity, in particular thrombotic and bleeding risks. These complications have emerged as a major clinical concern that may affect the use of these agents in patients both with and without cancer who may already have an elevated risk of thrombosis and bleeding. Although these agents are frequently considered together as a class when contemplating their bleeding and thrombotic risks, in fact the risks for venous thromboembolism, arterial thrombosis, and bleeding vary significantly between different classes of antiangiogenic agents and even among different agents within a class. In this narrative review, we describe the literature investigating the venous and arterial thrombotic and bleeding risks associated with the currently available antiangiogenic drugs. In addition, we discuss these specific complications in the context of both cancer therapy as well as the management of nonmalignant disorders now managed with antiangiogenic agents, including hereditary hemorrhagic telangiectasia and neovascular age-related macular degeneration.
Topics: Angiogenesis Inhibitors; Hemorrhage; Humans; Neoplasms; Neovascularization, Pathologic; Thrombosis; Vascular Endothelial Growth Factor A
PubMed: 33928747
DOI: 10.1111/jth.15354 -
Current Pharmaceutical Design 2020The role of angiogeneses during the growth and progression of tumors is well documented. Likewise, a balance is generally maintained between the cellular proliferation... (Review)
Review
The role of angiogeneses during the growth and progression of tumors is well documented. Likewise, a balance is generally maintained between the cellular proliferation and the apoptosis, therefore, the tumors can persist for years in a dormant phase. During the past few years, many hypotheses have been proposed relating to the importance of tumor angiogenesis for the development and spread of tumors and preventive or therapeutic capacity of angiogenesis inhibitors as a potential target for controlling the growth of cancerous tissue. The antiangiogenic based therapeutic approaches are considered as the most promising method for the control of tumors, as this therapeutic approach is less likely to attain the drug resistance. Further, the tumor vasculature is an important prognostic marker that can independently predict the pathological stages as well as the metastatic potential of tumors. Various biologically active phytochemicals have been extracted from the dietary sources and the plants that have engaged the scientist and pharmaceutical industries around the globe. The antioxidant, antiinflammatory, anti-proliferative and anti-angiogenic potential of these bioactive phytochemicals is evident from the in vitro studies using cell lines and investigations involving the animal models. The present review is focused on the promising role of anti-angiogenesis-based therapies for the management of tumors and the recent developments relating to the interplay of phytochemicals and angiogenesis for the suppression of tumor cells.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Phytochemicals
PubMed: 31886747
DOI: 10.2174/1381612826666191230142638 -
Expert Opinion on Pharmacotherapy Oct 2017Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents.... (Review)
Review
Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies. Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib. Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Disease-Free Survival; Drug Evaluation, Preclinical; Female; Humans; Ovarian Neoplasms; Quinazolines
PubMed: 28933580
DOI: 10.1080/14656566.2017.1383384 -
Drug Metabolism Reviews Nov 2022Anti-angiogenic therapy is a practical approach to managing diseases with increased angiogenesis, such as cancer, maculopathies, and retinopathies. Considering the... (Review)
Review
Anti-angiogenic therapy is a practical approach to managing diseases with increased angiogenesis, such as cancer, maculopathies, and retinopathies. Considering the fundamental gaps in the knowledge of the vital pathways involved in angiogenesis and its inhibition and the insufficient efficiency of existing angiogenesis inhibitors, there is an increasing focus on the emergence of new therapeutic strategies aimed at inhibiting pathological angiogenesis. Angiogenesis is forming a new vascular network from existing vessels; endothelial cells (ECs), vascular lining cells, are the main actors of angiogenesis in physiological or pathological conditions. Switching from a quiescent state to a highly migratory and proliferative state during new vessel formation called "angiogenic switch" is driven by a "metabolic switch" in ECs, angiogenic growth factors, and other signals. As the characteristics of ECs change by altering the surrounding environment, they appear to have a different metabolism in a tumor microenvironment (TME). Therefore, pathological angiogenesis can be inhibited by targeting metabolic pathways. In the current review, we aim to discuss the EC metabolic pathways under normal and TME conditions to verify the suitability of targeting them with novel therapies.
Topics: Humans; Endothelial Cells; Neovascularization, Pathologic; Neoplasms; Angiogenesis Inhibitors; Intercellular Signaling Peptides and Proteins; Tumor Microenvironment
PubMed: 36031813
DOI: 10.1080/03602532.2022.2116033