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British Journal of Cancer Dec 2008Evidence from human studies suggests that angiogenesis commences during the pre-malignant stages of cancer. Inhibiting angiogenesis may, therefore, be of potential value... (Review)
Review
Evidence from human studies suggests that angiogenesis commences during the pre-malignant stages of cancer. Inhibiting angiogenesis may, therefore, be of potential value in preventing progression to invasive cancer. Understanding the mechanisms inducing angiogenesis in these lesions and identification of those important in human tumourigenesis are necessary to develop translational strategies that will help realise the goal of angioprevention.
Topics: Animals; Humans; Hypoxia; Neovascularization, Pathologic; Precancerous Conditions; Risk Factors
PubMed: 18941463
DOI: 10.1038/sj.bjc.6604733 -
Biochimica Et Biophysica Acta Apr 2006Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has... (Review)
Review
Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGF-beta) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Thrombospondin 1
PubMed: 16406676
DOI: 10.1016/j.bbcan.2005.11.002 -
Canadian Journal of Physiology and... Jun 2012Platelets, in addition to maintaining hemostasis, also stimulate angiogenesis by generating and releasing, upon activation, factors that promote the growth of new blood... (Review)
Review
Platelets, in addition to maintaining hemostasis, also stimulate angiogenesis by generating and releasing, upon activation, factors that promote the growth of new blood vessels. To date, at least 20 angiogenesis-regulating factors have been identified in platelets, including both promoters and inhibitors. Platelet-derived angiogenesis regulators promote angiogenesis during wound healing, tumor growth, and in response to ischemia. Within platelets, angiogenesis regulators are primarily stored in α-granules, but are also found in the cytosol or derived from membrane lipids. Their release can be inhibited pharmacologically by anti-platelet agents, which consequently suppress platelet-stimulated angiogenesis. Several years ago, our research group discovered that platelets generate the angiogenesis inhibitor angiostatin independent of the activation state of platelets, and that platelet-derived angiostatin serves to limit the angiogenesis-stimulating effects of platelets. In this review, we summarize the current knowledge of platelet-associated angiogenesis regulators, how they impact angiogenesis, and how they are controlled pharmacologically.
Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Blood Platelets; Humans; Neovascularization, Physiologic
PubMed: 22512504
DOI: 10.1139/y2012-036 -
PloS One 2013The formation of new blood vessels is an essential therapeutic target in many diseases such as cancer, ischemic diseases, and chronic inflammation. In this regard,...
The formation of new blood vessels is an essential therapeutic target in many diseases such as cancer, ischemic diseases, and chronic inflammation. In this regard, extremely low-frequency (ELF) electromagnetic fields (EMFs) seem able to inhibit vessel growth when used in a specific window of amplitude. To investigate the mechanism of anti-angiogenic action of ELF-EMFs we tested the effect of a sinusoidal magnetic field (MF) of 2 mT intensity and frequency of 50 Hz on endothelial cell models HUVEC and MS-1 measuring cell status and proliferation, motility and tubule formation ability. MS-1 cells when injected in mice determined a rapid tumor-like growth that was significantly reduced in mice inoculated with MF-exposed cells. In particular, histological analysis of tumors derived from mice inoculated with MF-exposed MS-1 cells indicated a reduction of hemangioma size, of blood-filled spaces, and in hemorrhage. In parallel, in vitro proliferation of MS-1 treated with MF was significantly inhibited. We also found that the MF-exposure down-regulated the process of proliferation, migration and formation of tubule-like structures in HUVECs. Using western blotting and immunofluorescence analysis, we collected data about the possible influence of MF on the signalling pathway activated by the vascular endothelial growth factor (VEGF). In particular, MF exposure significantly reduced the expression and activation levels of VEGFR2, suggesting a direct or indirect influence of MF on VEGF receptors placed on cellular membrane. In conclusion MF reduced, in vitro and in vivo, the ability of endothelial cells to form new vessels, most probably affecting VEGF signal transduction pathway that was less responsive to activation. These findings could not only explain the mechanism of anti-angiogenic action exerted by MFs, but also promote the possible development of new therapeutic applications for treatment of those diseases where excessive angiogenesis is involved.
Topics: Animals; Cell Cycle; Cell Line; Cell Movement; Cell Proliferation; Electromagnetic Fields; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Magnetic Fields; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2
PubMed: 24244477
DOI: 10.1371/journal.pone.0079309 -
Recent Results in Cancer Research.... 2007Angiogenesis is necessary for solid tumor growth and dissemination. In addition to angiogenesis, it has become increasingly clear that inflammation is a key component in... (Review)
Review
Angiogenesis is necessary for solid tumor growth and dissemination. In addition to angiogenesis, it has become increasingly clear that inflammation is a key component in cancer insurgence that can promote tumor angiogenesis. We noted that angiogenesis is a common and key target of most chemopreventive molecules, where they most likely suppress the angiogenic switch in premalignant tumors, a concept we termed angioprevention. We have shown that various molecules, such as flavonoids, antioxidants, and retinoids, act in the tumor microenvironment, inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. N-acetyl-cysteine, and the green tea flavonoid epigallocatechin-3-gallate (EGCG) and the beer/ hops-derived chalcone Xanthohumol all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi's sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows anti-angiogenic effects. We analyzed the regulation of gene expression they exert in primary human umbilical endothelial cells (HUVEC) in culture with functional genomics. Expression profiles obtained through Affymetrix GeneChip arrays identified overlapping sets of genes regulated by anti-oxidants. In contrast, the ROS-producing 4HPR induced members of the TGFbeta-ligand superfamily, which, at least in part, explains its anti-angiogenic activity. NAC and the flavonoids all suppressed the IkB/NF-kappaB signaling pathway even in the presence of NF-kappaB stimulation by TNFalpha, and showed reduced expression of many NF-kappaB target genes. A selective apoptotic effect on transformed cells, but not on endothelial cells, of the anti-oxidants may be related to the reduced expression of the NF-kappaB-dependent survival factors Bcl2 and Birc5/surviving, which are selectively overexpressed in transformed cells by these factors. The repression of the NF-kappaB pathway suggests anti-inflammatory effects for the antioxidant compounds that may also represent an indirect role in angiogenesis inhibition. The green tea flavonoid EGCG does target inflammatory cells, mostly neutrophils, and inhibits inflammation-associated angiogenesis. The other angiopreventive molecules are turning out to be effective modulators of phagocyte recruitment and activation, further linking inflammation and vascularization to tumor onset and progression and providing a key target for cancer prevention.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic
PubMed: 17302199
DOI: 10.1007/978-3-540-37696-5_19 -
Australian Veterinary Journal Oct 2018In order for a tumour to continue to grow and disseminate, it must acquire a new blood supply. Neovascularisation can be enacted by a number of different mechanisms.... (Review)
Review
In order for a tumour to continue to grow and disseminate, it must acquire a new blood supply. Neovascularisation can be enacted by a number of different mechanisms. This dependence of tumour progression on an augmented vascular supply has been exploited by the development of anti-angiogenic drugs, which are designed to inhibit new blood vessel formation or disrupt existing tumour-associated vasculature, both leading to ischaemic-hypoxic tumour cell death. However, the clinical benefits of these therapeutic approaches are frequently variable and often transient, the neoplasm sometimes being able to use other neovascularisation mechanisms to maintain its blood supply and thus evade the current anti-angiogenic therapy. Tumours may also develop a more malignant phenotype following this treatment. Clinical outcomes may be improved by simultaneously inhibiting different angiogenic pathways, abetted by more effective drug delivery regimens such as metronomic chemotherapy and the concurrent use of other antitumour modalities.
Topics: Angiogenesis Inhibitors; Animals; Drug Resistance, Neoplasm; Neoplasms; Neovascularization, Pathologic; Tumor Hypoxia
PubMed: 30255577
DOI: 10.1111/avj.12747 -
Cancer Journal (Sudbury, Mass.) 2001Integrins area widely distributed family of cell surface alpha/beta heterodimers that bind cells to components of the extracellular matrix and mediate cell-cell... (Review)
Review
Integrins area widely distributed family of cell surface alpha/beta heterodimers that bind cells to components of the extracellular matrix and mediate cell-cell interactions. Integrin alpha(v)beta3 interacts with RGD (Arg-Gly-Asp) sequence-containing proteins in the extracellular matrix. The distribution of alpha(v)beta3 is highly restricted, with expression on activated endothelium, activated vascular smooth muscle, tumors, and osteoclasts. Expression of alpha(v)beta3 may contribute to a malignant phenotype by supporting the growth and persistence of small blood vessels that nourish the primary and metastatic tumors and increasing invasive potential. Inhibition of alpha(v)beta3 can modulate tumor-induced angiogenesis and can increase apoptosis of tumor-associated small blood vessels. It might also help control humoral hypercalcemia of malignancy through direct or indirect activity on the osteoclast. Preclinical studies found that several RGD peptidomimetics and a monoclonal antibody to alpha(v)beta3 can inhibit tumor growth by blocking tumor-induced angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Drug Design; Humans; Neovascularization, Pathologic; Oligopeptides; Receptors, Vitronectin
PubMed: 11779085
DOI: No ID Found -
Blood May 1996Interleukin 12 (IL-12), a multifunctional cytokine produced by macrophages and B-cell lines, induces interferon-gamma (IFN-gamma) production, stimulates growth of both T...
Interleukin 12 (IL-12), a multifunctional cytokine produced by macrophages and B-cell lines, induces interferon-gamma (IFN-gamma) production, stimulates growth of both T and natural killer cells, promotes Th1-type helper T-cell responses, and inhibits neovascularization. Because the human interferon-inducible protein 10 (IP-10) can also inhibit neovascularization, we tested whether IP-10, induced by IL-12 through the intermediate IFN-gamma, might be a mediator of IL-12 angiogenesis inhibition. We report here that murine IL-12 profoundly inhibited basic fibroblast growth factor (bFGF)-induced Matrigel neovascularization in vivo, and that this effect of IL-12 was neutralized by systemic administration of antibodies to either murine IFN-gamma or IP-10. Murine IL-12 induced murine IP-10 expression in mouse splenocytes, and human IFN-gamma induced human IP-10 expression in purified human endothelial cells, suggesting that IL-12 can induce IP-10 expression in certain cells. These results document the important role of IP-10 as a mediator of angiogenesis inhibition by IL-12, and raise the possibility that IP-10 may also contribute to the antitumor effect of IL-12.
Topics: Animals; Base Sequence; Cells, Cultured; Chemokine CXCL10; Chemokines, CXC; Cytokines; Endothelium, Vascular; Female; Fibroblast Growth Factor 2; Humans; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Neovascularization, Physiologic
PubMed: 8611715
DOI: No ID Found -
Gene Therapy Nov 2015The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example,...
The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example, age-related macular degeneration. We hypothesized that adeno-associated viral vector (AAV)-mediated sFLT1 expression could be used to inhibit abnormal brain angiogenesis. We tested the anti-angiogenic effect of sFLT1 and the feasibility of using AAV serotype 9 to deliver sFLT1 through intravenous injection (IV) to the brain angiogenic region. AAVs were packaged in AAV serotypes 1 and 2 (stereotactic injection) and 9 (IV injection). Brain angiogenesis was induced in adult mice through stereotactic injection of AAV1-VEGF. AAV2-sFLT02 containing sFLT1 VEGF-binding domain (domain 2) was injected into the brain angiogenic region, and AAV9-sFLT1 was injected into the jugular vein at the time of or 4 weeks after AAV1-VEGF injection. We showed that AAV2-sFLT02 inhibited brain angiogenesis at both time points. IV injection of AAV9-sFLT1 inhibited angiogenesis only when the vector was injected 4 weeks after angiogenic induction. Neither lymphocyte infiltration nor neuron loss was observed in AAV9-sFLT1-treated mice. Our data show that systemically delivered AAV9-sFLT1 inhibits angiogenesis in the mouse brain, which could be utilized to treat brain angiogenic diseases such as brain arteriovenous malformation.
Topics: Angiogenesis Inhibitors; Animals; Brain; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Random Allocation; Vascular Endothelial Growth Factor Receptor-1
PubMed: 26090874
DOI: 10.1038/gt.2015.57 -
Pathology, Research and Practice Jan 2024Cancer remains the primary cause of mortality in developed nations. Although localized tumors can be effectively addressed through surgery, radiotherapy, and other... (Review)
Review
Cancer remains the primary cause of mortality in developed nations. Although localized tumors can be effectively addressed through surgery, radiotherapy, and other targeted methods, drug efficacy often wanes in the context of metastatic diseases. As a result, significant efforts are being made to develop drugs capable of not only inhibiting tumor growth but also impeding the metastasis of malignant tumors, with a focus on hindering their migration to adjacent organs. Cancer stem cells metastasize via blood and lymphatic vessels, exhibiting a high mutation rate, significant variability, and a predisposition to drug resistance. In contrast, endothelial cells, being less prone to mutation, are less likely to give rise to drug-resistant clones. Furthermore, the direct contact of circulating anti-angiogenic drugs with vascular endothelial cells expedites their therapeutic impact. Hence, anti-angiogenesis targeted therapy assumes a pivotal role in cancer treatment. This paper provides a succinct overview of the molecular mechanisms governing the interaction between cancer stem cells and angiogenesis.
Topics: Humans; Neovascularization, Pathologic; Endothelial Cells; Angiogenesis; Neoplasms; Neoplastic Stem Cells
PubMed: 38160481
DOI: 10.1016/j.prp.2023.155064