Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells.

Kuwabara, Kosuke; Ogawa, Satoshi; Matsumoto, Michihiro; Koga, Shin; Clauss, Matthias; Pinsky, David J.; Lyn, P; Leavy, J A; Witte, Larry; Joseph‐Silverstein, Jacquelyn

doi:10.1073/pnas.92.10.4606

Cited by 234 publications

(138 citation statements)

References 21 publications

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“…4). Inflammatory cells, including mononuclear phagocytes [204,205], CD4 + and CD8 + T lymphocytes [206,207], and mast cells [208] can express FGF2. Moreover, osmotic shock and shear stress induce the release of FGF2 from endothelial cells [209,210].…”

Section: Fgf-dependent Angiogenesis and Inflammationmentioning

confidence: 99%

“…Endothelial cell damage results in increased FGF2 production and release [217]; exudated fibrin(ogen) can bind FGF2 and enhances its biological activity (see above); hypoxia upregulates the production of angiogenic growth factor, including VEGF [218] and FGF2 [204]. Furthermore, hypoxia increases endothelial cell responsiveness to FGF2 by promoting HSPG synthesis [219] and upregulates FGF2 production also in vascular pericytes [220].…”

Section: Fgf-dependent Angiogenesis and Inflammationmentioning

confidence: 99%

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Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,130

870

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Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization. #

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Section: Fgf-dependent Angiogenesis and Inflammationmentioning

confidence: 99%

Section: Fgf-dependent Angiogenesis and Inflammationmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,130

870

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“…VEGF receptors are expressed only on endothelial cells (Keck et al, 1989). Low oxygen tension induces the expression of bFGF and VEGF in host-derived cells and in tumour cells (Shweiki et al, 1992;Kuwabara et al, 1995).…”

mentioning

confidence: 99%

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients

Dirix

Vermeulen²,

Pawinski³

et al. 1997

Br J Cancer

253

128

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Summary The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml-' for bFGF and 500 pg ml-1 for VEGF, were identified as 'elevated'. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.

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“…The production of several angiogenic factors, including VEGF, bFGF and PDGF (Minchenko et al, 1994;Gleadle et al, 1995;Kuwabara et al, 1995), is upregulated by hypoxia. In solid tumours, a more rapid increase in the number of oxygen-consuming tumour cells than can be sustained by the oxygen supply to the cells from the microvasculature occurs, resulting in tissue hypoxia.…”

Section: Discussionmentioning

confidence: 99%

A novel hypoxia-dependent 2-nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors

et al. 2003

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Tumour angiogenesis is initiated by angiogenic factors that are produced in large amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour-specific antiangiogenesis because normal tissues are not usually hypoxic. On the other hand, blocking a biological function of endothelial cells is known to result in angiogenic inhibition. To produce a tumour-specific and powerful antiangiogenesis, we determined whether potent angiogenic inhibition could be achieved by inhibiting the production of angiogenic factors by hypoxic tumour cells and simultaneously blocking certain angiogenic steps in endothelial cells under normoxia. We focused on the 2-nitroimidazole moiety, which is easily incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic cytotoxin. We designed and synthesised 2-nitroimidazole derivatives designated as KIN compounds, and investigated their antiangiogenic activities under normoxia using a chick embryo chorioallantoic membrane. KIN-841 (2-nitroimidazole 1-acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent manner. This compound inhibited the proliferation of bovine pulmonary arterial endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation by KIN-841 under hypoxia increased about five-fold compared to that under normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive production of vascular endothelial cell growth factors induced by 3LL cells as determined by tritium-labelled thymidine ([ 3 H]thymidine) incorporation into BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL-cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These results indicate that the regulation of the production of angiogenic factors by hypoxic tumour cells is a useful target for tumour-specific angiogenesis inhibition, and that KIN-841, which causes simultaneous direct inhibition of endothelial cell function and production of angiogenic factors by hypoxic tumour cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the potential for clinical use of KIN-841 as an antitumour drug is very high.

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Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells.

Cited by 234 publications

References 21 publications

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients

A novel hypoxia-dependent 2-nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors

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