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The Role of Ets Factors in Tumor Angiogenesis  [PDF]
Peter Oettgen
Journal of Oncology , 2010, DOI: 10.1155/2010/767384
Abstract: Angiogenesis is a critical component of tumor growth. A number of growth factors, including VEGF, FGF, and HGF, have been implicated as angiogenic growth factors that promote tumor angiogenesis in different types of cancer. Ets-1 is the prototypic member of the Ets transcription factor family. Ets-1 is known to be a downstream mediator of angiogenic growth factors. Expression of Ets-1 in a variety of different tumors is associated with increased angiogenesis. A role for other selected members of the Ets transcription factor family has also been shown to be important for the development of tumor angiogenesis. Because Ets factors also express a number of other important genes involved in cell growth, they contribute not only to tumor growth, but to disease progression. Targeting Ets factors in mouse tumor models through the use of dominant-negative Ets proteins or membrane permeable peptides directed at competitively inhibiting the DNA binding domain has now demonstrated the therapeutic potential of inhibiting selected Ets transcription factors to limit tumor growth and disease progression. Ets-1 is the prototypic member of the Ets transcription factor family [1]. Several studies have demonstrated a role for Ets transcription factors in the regulation of endothelial-specific genes including VEGF-R1, VEGF-R2, Tie1, and Tie2. Whereas, the Ets factors Ets-1 and Ets-2 potently transactivate the Flt-1 gene promoter, they do not appear to regulate the Tie1 or Tie2 gene promoters [2, 3]. Ets-1 has been shown to cooperate with HIF-2α in the setting of hypoxia to regulate the expression of the VEGF-R2 [4, 5]. In contrast, the Ets factor ELF-1 is a potent transactivator of the Tie1 and Tie2 genes [2, 3]. ELF-1 has been shown to regulate other genes involved in angiogenesis including angiopoietin-2 and endothelial nitric oxide synthase [6, 7]. Ets-2 regulates the expression of CD13/aminopeptidase N (APN) in human endothelial cells [8]. Knockdown of Ets-2 in human endothelial cells using siRNA oligonucleotides significantly reduced the ability of the endothelial cells to form tubes and capillary networks. The selectivity of the different Ets factors to transactivate different target genes also correlates with their ability to bind to specific conserved Ets binding sites within these genes. However, when the DNA binding domain is highly homologous, as is the case for Ets-1 and Ets-2, there may be a significant overlap with respect to their downstream target genes. Ets factors can be subcategorized into subfamilies based on DNA and protein sequence homology. For
Oxidative stress in tumor microenvironment—Its role in angiogenesis
Chinese Journal of Lung Cancer , 2008,
Abstract: The tumor angiogenesis process is believed to be dependent on an "angiogenic switch" formed by a cascade of biologic events as a consequence of the "cross-talk" between tumor cells and several components of local microenvironment including endothelial cells, macrophages, mast cells and stromal components. Oxidative stress represents an important stimulus that widely contributes to this angiogenic switch, which is particularly relevant in lungs, where oxidative stress is originated from different sources including the incomplete reduction of oxygen during respiration, exposure to hypoxia/reoxygenation, stimulated resident or chemoattracted immune cells to lung tissues, as well as by a variety of chemicals compounds. In the present review we highlight the role of oxidative stress in tumor angiogenesis as a key signal linked to other relevant actors in this complex process.
PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis  [PDF]
Naoko Okumura,Hitomi Yoshida,Yasuko Kitagishi,Mutsumi Murakami,Yuri Nishimura,Satoru Matsuda
Advances in Hematology , 2012, DOI: 10.1155/2012/843085
Abstract: PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis. 1. Introduction Angiogenesis is the process by which new blood capillaries are generated from the preexisting blood vessels [1, 2]. Tumor angiogenesis is essential for tumor growth, invasion, and metastasis [3, 4]. This process can be triggered by a series of signal pathways including extracellular signals such as growth factors (Figure 1). It is a complex process that is also regulated by pro- and antiangiogenic factors. In other words, the angiogenesis and vasculature are regulated through the change of balance between the collective actions of proangiogenic factors such as vascular endothelial growth factor (VEGF) and angiogenic inhibitors such as thrombospondin-1(TSP-1). These factors can be derived from different sources such as stromal cells, extracellular matrix, and cancer cells. Their relative contribution is likely to be different according to the difference in tumor types. The interaction btween cancer cells and vascular endothelial cells in the tumor microenvironment affects the angiogenesis [5, 6]. Leukemia is an aggressive malignancy characterized by the accumulation of immature leukemia blasts in the bone marrow. Bone marrow angiogenesis is therefore important for both leukemogenesis, and the leukemic bone marrow shows increased microvascular density [7]. Figure 1: Schematic representation of PI3K/AKT/PTEN signaling. Examples of molecules known to act on angiogenesis via PI3K/AKT regulatory pathways are shown. VEGF and VEGF receptor (VEGFR) are major angiogenesis inducer associated with tumor angiogenesis in numerous solid or hematological malignancies. VEGF binds to VEGF receptor, which leads to the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. In addition to the PI3K/Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) play an important role as a molecular inhibitor of PI3K/Akt signaling in multiple cellular functions such as cell proliferation,
Tumor-Associated Macrophage: Its Role in Tumor Angiogenesis  [PDF]
Chun-Chung Lee,Ko-Jiunn Liu,Tze-Sing Huang
Journal of Cancer Molecules , 2006,
Abstract: Macrophages are important cells in wound healing, providing aids for tissue cell growth, tissue matrix remodeling and angiogenesis. Solid tumor comprises not only tumor cells, but also tissue matrix and many stromal cells such as fibroblasts and macrophages. Accumulating research results have suggested tumor-associated macrophages (TAMs) functioning in tumor cell proliferation, tumor cell migration and invasion, and tumor angiogenesis. In this review article, we review data from clinical investigations and animal studies to demonstrate the association of TAMs with tumor angiogenesis. We also discuss results of several mechanistic studies to provide possible mechanisms for TAMs-associated angiogenesis. By interacting with cancer cells, TAMs can be induced to express more cytokines and tissue matrix-degrading enzymes, such as matrix metalloproteinases, plasminogen activators and cathepsin B, that are either direct angiogenic factors or tissue matrix modulators responsible for promoting tumor angiogenesis. The angiogenic effect of TAMs can be neutralized by antagonizing antibodies or competitive soluble receptors of interleukin-6, interleukin-8 and tumor necrosis factor-alpha, suggesting the involvement of these cytokines in TAMs-associated angiogenesis. With evidence indicating TAM’s tumor-promoting roles, many investigations have been undertaken to study the potential of using TAMs as the therapeutic target. Photosensitizer can be labeled to the scavenger receptor class A to target TAMs in cancer photodynamic therapy. In addition, macrophages can be engineered to serve as vehicles to carry drug or genes to the hypoxic areas of tumor. More detailed mechanisms regarding the interaction between TAMs and tumor still need to be explored, and a thorough understanding of this interaction will provide some helpful conceptual suggestions for the future cancer therapy.
The Role of TWIST in Angiogenesis and Cell Migration in Giant Cell Tumor of Bone  [PDF]
Shalini Singh,Isabella W. Y. Mak,Divya Handa,Michelle Ghert
Advances in Biology , 2014, DOI: 10.1155/2014/903259
Abstract: Giant cell tumor of bone (GCT) is a bone tumor consisting of numerous multinucleated osteoclastic giant cells involved in bone resorption and neoplastic osteoblast-like stromal cells responsible for tumor growth. The tumor occasionally metastasizes to the lung; however, factors leading to metastasis in this tumor are unknown. The TWIST-1 protein (also referred to as TWIST) has been suggested to be involved in epithelial-mesenchymal transition (EMT) and tumor progression in some cancers. In this study we investigated the functional role of TWIST in GCT cell angiogenesis and migration. Overexpression of TWIST in neoplastic GCT stromal cells significantly increased mRNA and protein expression of VEGF and VEGFR1 in vitro, whereas knockdown of TWIST resulted in decreased VEGF and VEGFR1 expression. A stable cell line with TWIST overexpression resulted in features of EMT including increased cell migration and downregulation of E-cadherin. The results of our study indicate that TWIST may play an important role in angiogenesis and cell migration in GCT. 1. Introduction Giant cell tumor of bone (GCT) is an aggressive bone tumor characterized by the presence of an abundance of reactive multinucleated giant cells surrounded by mesenchymal stromal cells. To date, the oncogenesis of GCT remains unknown as the neoplastic stromal cells appear to be preosteoblastic cells that do not undergo terminal osteoblastic differentiation [1–4]. GCT is a highly vascular tumor and in several cases metastasizes to the lungs [2, 5, 6]. Bone tumors recruit new blood vessels from preexisting vessels of the host through factors secreted from either the tumor itself or the surrounding stromal cells [7, 8]. Tumor growth is dependent upon the growth of these new blood vessels. Angiogenesis is the process of developing new capillaries from the existing circulation via a complex multistep system regulated by a delicate balance between various angiogenic inhibitors and activators [9]. Activators of angiogenesis include growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and hypoxic conditions that activate hypoxia-inducible factor-1 (HIF-1) which in turn upregulate angiogenic proteins as well as angiogenic oncogenes [9]. The transcription factor TWIST is known to induce an embryonic event termed epithelial-mesenchymal transition (EMT) in tumor cells [10]. EMT is a process initially observed in embryonic development in which the cells lose epithelial cell properties and gain mesenchymal cells characteristics [11]. In hepatocellular
The role IL-1 in tumor-mediated angiogenesis  [PDF]
Elena Voronov,Yaron Carmi,Ron N. Apte
Frontiers in Physiology , 2014, DOI: 10.3389/fphys.2014.00114
Abstract: Tumor angiogenesis is one of the hallmarks of tumor progression and is essential for invasiveness and metastasis. Myeloid inflammatory cells, such as immature myeloid precursor cells, also termed myeloid-derived suppressor cells (MDSCs), neutrophils, and monocytes/macrophages, are recruited to the tumor microenvironment by factors released by the malignant cells that are subsequently “educated” in situ to acquire a pro-invasive, pro-angiogenic, and immunosuppressive phenotype. The proximity of myeloid cells to endothelial cells (ECs) lining blood vessels suggests that they play an important role in the angiogenic response, possibly by secreting a network of cytokines/chemokines and inflammatory mediators, as well as via activation of ECs for proliferation and secretion of pro-angiogenic factors. Interleukin-1 (IL-1) is an “alarm,” upstream, pro-inflammatory cytokine that is generated primarily by myeloid cells. IL-1 initiates and propagates inflammation, mainly by inducing a local cytokine network and enhancing inflammatory cell infiltration to affected sites and by augmenting adhesion molecule expression on ECs and leukocytes. Pro-inflammatory mediators were recently shown to play an important role in tumor-mediated angiogenesis and blocking their function may suppress tumor progression. In this review, we summarize the interactions between IL-1 and other pro-angiogenic factors during normal and pathological conditions. In addition, the feasibility of IL-1 neutralization approaches for anti-cancer therapy is discussed.
Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx
Yurdanur Sullu, Seda Gun, Sinan Atmaca, Filiz Karagoz, Bedri Kandemir
Diagnostic Pathology , 2010, DOI: 10.1186/1746-1596-5-35
Abstract: We examined immunohistochemical expression of VEGF and PTEN and CD34 for microvessel density (MVD) in sections of formalin-fixed, paraffin embedded tissue blocks of 140 patients with squamous cell carcinoma of the larynx. The intensity of VEGF and PTEN staining and the proportion of cells staining were scored.The tumor grade was not significantly related to PTEN expression, but it was to VEGF expression (p = 0.400; p = 0.015, respectively). While there was no significant relationship between PTEN expression and tumor size and cartilage invasion (p = 0.311, p = 0.128), there was a significant relationship between the severity of VEGF expression and tumor size (p = 0.006) and lymph node metastasis (p = 0.048) but not cartilage invasion (p = 0.129). MVD was significantly higher in high-grade tumors (p = 0.003) but had no significant relationship between MVD, lymph node metastasis, and cartilage invasion (p = 0.815, p = 0.204). There was also no significant relationship between PTEN and VEGF expression (p = 0.161) and between PTEN and VEGF expression and the MVD (p = 0.120 and p = 0.175, respectively).Increased VEGF expression may play an important role in the outcome of squamous cell carcinoma of the larynx. PTEN expression was not related to VEGF expression and clinicopathological features of squamous cell carcinoma of the larynx.Although tumor development is a multi-stage process, angiogenesis is essential to tumor growth and metastasis. Angiogenesis is regulated by the balance between positive and negative regulatory molecules released by tumor cells and other cells in the environment. The most important molecules positively affecting angiogenesis are basic fibroblast growth factor, vascular endothelial growth factor (VEGF), interleukin-8 platelet-derived growth factor, and hepatocyte growth factor. Thrombospondin 1, platelet factor-4, angiostatin, endostatin, IFN-α, and metalloproteinase tissue inhibitors are inhibitors of angiogenesis [1]. The VEGF gene is located
The Role of FoxC2 Transcription Factor in Tumor Angiogenesis
Tsutomu Kume
Journal of Oncology , 2012, DOI: 10.1155/2012/204593
Abstract: Much has been learned about the mechanisms underlying tumor angiogenesis, and therapies that target vascular endothelial growth factor (VEGF) to limit tumor angiogenesis and subsequent disease progression have recently been approved. However, the transcriptional mechanisms that regulate pathological angiogenesis remain largely unknown. FoxC2, a member of the Forkhead box (Fox) transcription factor family, is critical for vascular formation during development, and recent studies have shown that FoxC2 is expressed in the endothelium of tumors in both humans and mice. In a B16 mouse melanoma model, Foxc2 deficiency reduced tumor growth and neovascularization and was associated with impairments in mural-cell coverage and increases in endothelial-cell apoptosis in tumor blood vessels. FoxC2 is also expressed by tumor cells in human breast, colonic, and esophageal cancer and participates in the epithelial-mesenchymal transition (EMT), a key process that leads to the invasion and metastasis of aggressive tumors. Collectively, these observations suggest that FoxC2 is essential for tumor angiogenesis and disease progression and that FoxC2 may be a viable target for cancer therapy.
Angiogenesis and tumor
Kamran Mansouri,Ali Mostafaie,Hamid-Reza Mohammadi-Motlagh1
Behbood , 2010,
Abstract: Angiogenesis, the process of new blood vessel formation from existing ones, plays an important role in the physiologic circumstances such as embryonic development, placenta formation, and wound healing. It is also crucial to progress of pathogenic processes of a variety of disorders, including tumor growth and metastasis. In general, angiogenesis process is a multi-factorial and highly structured sequence of cellular events comprising migration, proliferation and differentiation of endothelial cells and finally vascular formation, maturation and remodeling.Thereby, angiogenesis inhibition as a helping agent to conventional therapies such as chemotherapy and radiation has attracted the scientists’ attentions studying in this field.
The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis  [PDF]
Krzysztof Fink,Janusz Boratyński
Post?py Higieny i Medycyny Do?wiadczalnej , 2012,
Abstract: Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs) are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN). MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs) and endothelial cells (ECs). MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT). MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM.
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