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Signaling Mechanisms of Endogenous Angiogenesis Inhibitors Derived from Type IV Collagen
Akulapalli Sudhakar,Chandra S. Boosani
Gene Regulation and Systems Biology , 2007,
Abstract: Vascular basement membrane (VBM) derived molecules are regulators of certain biological activities such as cell growth, differentiation and angiogenesis. Angiogenesis is regulated by a systematic controlled balance between VBM derived antiangiogenic factors and proangiogenic growth factors. In the normal physiological state, equilibrium is maintained between the antiangiogenic and proangiogenic factors. The antiangiogenic factors (molecules), which are generated by the proteolytic cleavage of the VBM, include; α1 chain non-collagenous (NC1) domain of type XVIII collagen (endostatin) and the NC1 domains from the alpha chains of Type IV collagen considered as endogenous angiogenesis inhibitors. These collagen derived NC1 domains have a pivotal role in the regulation of tumor angiogenesis, thus making them attractive alternate candidates for cancer therapies. In this review we illustrate a comprehensive overview of the knowledge gained from the signaling mechanisms of Type IV collagen derived endogenous inhibitors in angiogenesis.
Marine-Derived Angiogenesis Inhibitors for Cancer Therapy  [PDF]
Ying-Qing Wang,Ze-Hong Miao
Marine Drugs , 2013, DOI: 10.3390/md11030903
Abstract: Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs.
Proteolytically Derived Endogenous Angioinhibitors Originating from the Extracellular Matrix  [PDF]
Chandra Shekhar Boosani,Yakkanti A. Sudhakar
Pharmaceuticals , 2011, DOI: 10.3390/ph4121551
Abstract: Angiogenesis, a neovascularization process induced from the existing parent blood vessels, is a prerequisite for many physiological and pathological conditions. Under physiological conditions it is regulated by a balance between endogenous angioinhibitors and angioactivators, and an imbalance between them would lead to pathological conditions such as cancer, age-related macular degeneration (AMD), diabetic retinopathy, cardiovascular diseases, etc. Several proteolytically generated endogenous molecules have been identified which exhibit angioinhibition and/or antitumor activities. These angioinhibitors interact with endothelial and tumor cells by binding to distinct integrins and initiate many of their intracellular signaling mechanisms regulating the cell survival and or apoptotic pathways. The present review will focus on the extracellular matrix derived angioinhibitors, and their mechanisms of actions that point to the clinical significance and therapeutic implications.
Extra Cellular Matrix Derived Metabolite Regulates Angiogenesis by FasL Mediated Apoptosis  [PDF]
Raj K. Verma, Venugopal Gunda, Smita C. Pawar, Yakkanti Akul Sudhakar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080555
Abstract: Object Antiangiogenic treatments are beginning to give promising outcomes in many vascular diseases including tumor angiogenesis. In this current study the antiangiogenic and pro-apoptotic actions of α1(IV)NC1 and its N- and C- peptides α1S1(IV)NC1, α1S2(IV)NC1 were investigated in-vitro and in-vivo. Study Method Endothelial cells (ECs) were treated with α1(IV)NC1, α1S1(IV)NC1, α1S2(IV)NC1 and in-vitro proliferation, migration, tube formation and apoptotic assays were executed. FasL, Fas, Caspase-8, -3 and PARP activations were studied using immunoblotting analysis using specific antibodies. Also the in-vivo antiangiogenic and pro-apoptotic effects were tested using α1(IV)NC1 in a mice model. Results Like α1(IV)NC1, its N- and C- terminal α1S2(IV)NC1 and α1S1(IV)NC1 domains posses anti-proliferative, pro-apoptotic activity and inhibit ECs migration and tube formation in-vitro. Both α1S1(IV)NC1 and α1S2(IV)NC1 domains promote apoptosis by activating FasL and down stream apoptotic events including activation of caspase-8, -3 and PARP cleavage in a dose dependent manner in-vitro in ECs. Tumors in mice showed apoptotic TUNEL positive microvasculature upon α1(IV)NC1 treatment, indicating inhibition of tumor angiogenesis and tumor growth. Further, the antitumor activity of α1(IV)NC1 was abrogated when caspase-3 inhibitor was used. These results conform additional properties of α1(IV)NC1 as an endogenous angioinhibitor that induces apoptosis in-vitro and in-vivo by activating FasL mediated caspase-3. Significance α1(IV)NC1 and its N- and C- terminal α1S1(IV)NC1 and α1S2(IV)NC1 domains also posses pro-apoptotic and angioinhibitory activity in-vitro and in-vivo. α1(IV)NC1 regulates tumor angiogenesis by activating FasL mediated apoptosis in-vitro and in-vivo. These results demonstrate that α1(IV)NC1 and its peptides inhibit neo-vascular diseases.
Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix  [PDF]
Xiaodong Feng,Marcia G. Tonnesen,Shaker A. Mousa,Richard A. F. Clark
International Journal of Cell Biology , 2013, DOI: 10.1155/2013/231279
Abstract: Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors. 1. Introduction Angiogenesis, the development of new blood vessels from preexisting vessels, is critical for a wide array of complex normal and pathological processes including morphogenesis, wound healing, and tumor growth [1]. Under normal physiologic conditions, angiogenesis is well controlled by the local balance between endogenous angiogenesis stimulators and angiogenesis inhibitors, although the regulatory mechanism is still not clearly defined. Sustained tumor angiogenesis is one of the hallmark features of solid tumor development. It is essential for tumor development and tumor metastasis. Almost four decades ago Dr. Judah Folkman pioneered the strategy of stopping tumor growth and metastasis by blocking tumor angiogenesis. With the 2004 FDA approval of bevacizumab (Avastin), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), to treat metastatic colorectal cancer in combination with 5-fluorouracil (5-FU), antiangiogenesis therapy has emerged as an essential new strategy for cancer treatment [2]. Angiogenesis is a highly regulated event that involves complex, dynamic interactions between microvascular endothelial cells and ECM proteins. In developing capillary sprouts, endothelial cells digest the surrounding extracellular matrix (ECM) and invade the matrix as a cylindrical aggregate of cells. These events clearly require an integrated response of endothelial cells to angiogenic factors and ECM proteins [3]. Alteration of ECM
The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer  [cached]
Magdalena Groblewska,Maria Siewko,Barbara Mroczko,Maciej Szmitkowski
Folia Histochemica et Cytobiologica , 2012, DOI: 10.5603/18691
Abstract: Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized.
Apoptosis , Angiogenesis and Cancer Therapies
Manjul Tiwari
Journal of Cancer Therapeutics & Research , 2012,
Abstract: Angiogenesis, the growth of new blood vessels from the existing vasculature, and is maintained in adult tissues by the balanced presence of both angiogenic inducers and inhibitors in the tissue milieu. When inducers predominate, vascular endothelial cells (VECs) become activated and in this activated VECs, distinct cell signaling pathways are initiated providing the specificity of anti-angiogenic therapies to the tumor vasculature. VEC apoptosis has been well documented in regressing vessels, and it has been shown that, in addition to activating the VECs, some inducers such as vascular endothelial growth factor also up-regulate Fas expression, thus sensitizing the cell to apoptotic stimuli. Endogenous angiogenesis inhibitors, such as thrombospondin-1(TSP-1) and pigment epithelium-derived factor (PEDF), stimulate signaling cascades within the VECs and also induce the expression of Fas ligand in activated VECs. Therefore, when inhibitors predominate, the apoptotic cascade is initiated ,thus anti-angiogenic therapies can target the inducer supply or directly target the VECs. Although clinical studies suggest that anti-angiogenic therapies may prove to be most effective when used in combination with traditional therapies [1].
Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis
Alisa E Koch, Oliver Distler
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2187
Abstract: Angiogenesis, the process of new blood vessel formation, is controlled by a subtle balance between endogenous stimulators, which induce blood vessel growth, and inhibitors, which prevent growth. In processes such as wound healing, angiogenesis is a well programmed cascade of events that comprises a number of distinct steps. Angiogenic stimuli activate endothelial cells, which produce proteolytic enzymes that degrade the basement membrane and the perivascular extracellular matrix. Endothelial cells proliferate and migrate into the perivascular area, forming 'primary sprouts'. Subsequent lumenation of these primary sprouts leads to formation of capillary loops, which is followed by synthesis of a new basement membrane and blood vessel maturation to complete tube-like structures through which blood can flow [1] (Figure 1).Like any biological system, inducers of angiogenesis are counterbalanced by inhibitors. However, in angiogenesis the inhibitors often outweigh the inducers, resulting in a normal physiological balance. When the converse situation occurs, conditions characterized by angiogenesis, such as inflammatory angiogenesis or angiogenesis related to tumour growth, can develop. In this review we explore potential initiators of vascular injury in two example inflammatory rheumatic diseases, namely rheumatoid arthritis (RA) and scleroderma (systemic sclerosis [SSc]), in which the angiogenic process appears to be disrupted very differently. We also discuss how the angiogenic process might be manipulated for therapeutic benefit in the treatment of these debilitating diseases.The rheumatic diseases are a family of closely related disorders that includes RA, SSc and systemic lupus erythematosus. RA is characterized by excessive angiogenesis [2] and it has been studied extensively in this regard.Proangiogenic mediators associated with RA include the following (Table 1): growth factors such as vascular endothelial growth factor (VEGF); cytokines such as tumour necrosis f
Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro  [PDF]
Tina Friis,Anne-Marie Engel,Christine D. Bendiksen,Line S. Larsen,Gunnar Houen
Cancers , 2013, DOI: 10.3390/cancers5030762
Abstract: Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity in vivo since it inhibits ECs in vitro with a morphology resembling that obtained with antibodies to VEGF.
Arresten, a Collagen-Derived Angiogenesis Inhibitor, Suppresses Invasion of Squamous Cell Carcinoma  [PDF]
Mari Aikio, Ilkka Alahuhta, Sini Nurmenniemi, Juho Suojanen, Riitta Palovuori, Susanna Teppo, Timo Sorsa, Carlos López-Otín, Taina Pihlajaniemi, Tuula Salo, Ritva Heljasvaara, Pia Nyberg
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051044
Abstract: The turnover of extracellular matrix liberates various cryptic molecules with novel biological activity. Among these are the collagen-derived anti-angiogenic fragments, some of which are suggested to affect carcinoma cells also directly. Arresten is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of the basement membrane collagen IV α1 chain. As the mere prevention of tumor angiogenesis leads to hypoxia that can result in selection of more aggressive cell types and reduces the efficacy of chemotherapy, we aimed here to elucidate how arresten influences the aggressive human carcinoma cells. Arresten efficiently inhibited migration and invasion of HSC-3 tongue carcinoma cells in culture and in an organotypic model. Subcutaneous Arr-HSC xenografts grew markedly more slowly in nude mice and showed reduced tumor cell proliferation, vessel density and local invasiveness. In the organotypic assay, HSC-3 cells overproducing arresten (Arr-HSC) showed induction of cell death. In monolayer culture the Arr-HSC cells grew in aggregated cobblestone-like clusters and, relative to the control cells, showed increased expression and localization of epithelial marker E-cadherin in cell-cell contacts. Application of electric cell-substrate impedance sensing (ECIS) further supported our observations on altered morphology and motility of the Arr-HSC cells. Administration of a function-blocking α1 integrin antibody abolished the impedance difference between the Arr-HSC and control cells suggesting that the effect of arresten on promotion of HSC-3 cell-cell contacts and cell spreading is at least partly mediated by α1β1 integrin. Collectively, our data suggest novel roles for arresten in the regulation of oral squamous carcinoma cell proliferation, survival, motility and invasion through the modulation of cell differentiation state and integrin signaling.
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