Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: potential mechanism for maintenance of an avascular environment

Fannon, Michael; Forsten-Williams, Kimberly; Dowd, Christopher J.; Freedman, Deborah A.; Folkman, Judah; Nugent, Matthew A.

doi:10.1096/fj.02-0935fje

Cited by 40 publications

(28 citation statements)

References 43 publications

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“…Hepatocytes surrounding the central vein have been shown to be hypoxic 19,20 , and their location coincides with overexpression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF, also known as FGF2) 21 . In an unperturbed state, there is no angiogenesis, so the cytokines are probably bound to proteoglycans, which maintain them in an inactive state 22,23 . However, the inactive forms can be rapidly released after injury or stress to promote angiogenesis.…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Mast cells were thought to be detrimental to tumor cells by releasing IL-4, TNF-␣, and others to induce the apoptosis of tumor cells. [42][43][44] However, much evidence obtained in recent years indicates that these inflammatory cytokines are beneficial to tumors. [18][19][20] In addition, other proinflammatory factors and inflammation-related enzymes also benefit tumor development.…”

Section: Discussionmentioning

confidence: 99%

SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment

Huang

Zhang

et al. 2008

Blood

295

260

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Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here IntroductionChronic inflammation, a "promoting force" in the tumor microenvironment, has long been known to be commonly braided with the initiation, promotion, and progression of tumorigenesis. [1][2][3][4][5] To date, however, it is still incompletely understood how the inflammation in the tumor microenvironment is orchestrated by inflammatory cells. Recently, mast cells were highlighted as not only a major participator but also an important regulator of inflammation, 6,7 and their accumulation in tumors has also been well documented, [8][9][10][11][12][13] implying that mast cells may possibly play an important role in orchestrating the inflammation in tumors.The tumor microenvironment is regarded as a "smoldering" inflammation site in which a lot of cytokines, chemokines, and enzymes mediate the inflammatory process and drive malignant progression. 14,15 Among them, TNF-␣, IL-6, VEGF, iNOS, Cox-2, and MMP-9 are of particular interest. [15][16][17][18] Coincidentally, all of them can be produced by mast cells. However, the tumor microenvironment is also characterized by its immunoediting from immunosurveillance to immunosuppression. 19 Mast cells have been found to play a critical role in the suppression of immune reactions. 20 They not only produce inhibitory cytokine IL-10, 21 but they also are essential for the immune tolerance mediated by regulatory T (Treg) cells. 22 Thus, mast cell infiltration into tumor may possibly remodel tumor microenvironment and profoundly influence tumor behavior by participating and regulating inflammatory and immune reactions. However, although some studies have shown that mast cells promote tumor angiogenesis and tumor growth because of their properties as inflammatory cells, [23][24][25] the roles of mast cells in tumor progression have been incompletely understood so far. Several key questions remain unclear, especially how mast cells are recruited into the tumor site and whether they can remodel the tumor microenvironment.Mast cell migration to the tumor site and the following activation may be the prerequisite for their promoting effect on tumors. In this regard, stem cell factor (SCF) is possibly involved, because SCF triggers the c-Kit signaling pathway for the differentiation, migration, maturation, and survival of mast cells. 26 In the present study, we investigated the relation of mast cells and SCF in tumor progression and showed that SCF recruited and activated mast cells, the activated mast cells remodeled the tumor microenvironment by intensifying inflammation and immunosuppression, the tumor cell NF-B and AP-1 activities were augmented, and the suppression of T cells and natural killer (NK) cells was exacerbated in such remodeled microenvironments. These findings provide a new insight into the role of mast cells in tumors and the relati...

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“…DS chains purified from endocan mimicked the biological activity of native endocan. Moreover, HS proteoglycans contributed to preserve an avascular environment in aqueous humor (42). Thus, many of the effects of HS or DS may be related to regulation of the bioavailability of heparin-binding growth factors.…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis

Rouet

Hamma-Kourbali

Petit

et al. 2005

Journal of Biological Chemistry

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In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dosedependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF 165 ). OTR4120 showed high affinity binding to VEGF 165 (K d ‫؍‬ 2.2 nM), as compared with heparin (K d ‫؍‬ 15 nM), and potentiated the affinity of VEGF 165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF 165 -induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel TM plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF 165 -induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel TM sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF 165 -induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.

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Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: potential mechanism for maintenance of an avascular environment

Cited by 40 publications

References 43 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment

A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis

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