Fibroblast growth factors, their receptors and signaling.
TL;DR: FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
Abstract: Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.
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01 Jan 2016
TL;DR: The inhibition of VEGF-A, V EGF-C, VEGf-D, and VEGFRs might be used in cancer treatment for the reduction in cancer metastasis.
Abstract: Cancer metastasis is one of the leading causes of death in humans and animals diagnosed with cancer. It is a complex process that involves the spread of cancer cells from the primary cancer to another parts of the body through lymphatic and blood vessels. Cancer angiogenesis and lymphangiogenesis have been considered as essential processes in the cancer metastasis because the new formation blood and lymphatic vessels occur, thereby creating new route for cancer cells to metastasize. Vascular endothelial growth factors (VEGF) is a protein previously known for the role in promoting vasculogenesis and angiogenesis. Overexpression of VEGF is known to be implicated in a wide variety of disease processes, especially cancer metastatic process. At present, there are 7 members of the VEGF family, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PlGF. Among all VEGF members, VEGF-A, VEGF-C and VEGF-D have been reported to be capable to promote cancer angiogenesis and lymphangiogenesis. Moreover, the molecular mechanism of VEGFs and their interaction with the VEGF receptors (VEGFRs) which involve in the processes of cancer metastasis has been extensively described in details. The previous research has shown that VEGF-A plays a major role in angiogenesis through the interaction with VEGFR1 and VEGFR2 receptors as well as with neuropilins presented on the endothelial cells. Following the stimulation of several signal transduction pathways, these interaction result in the endothelial cell proliferation and migration, by which subsequently leads to finally the neovascularization. Apart from the role of VEGF-A, in addition to the role of VEGF-A associated with angiogenesis, VEGF-C and VEGF-D have also been recently reported for their major roles in lymphagiogenesis through the interaction with VEGFR3 which is mostly present in lymphatic endothelial cells. Moreover, VEGF-C and VEGF-D are able to promote angiogenesis. Therefore, the inhibition of VEGF-A, VEGF-C, VEGF-D, and VEGFRs might be used in cancer treatment for the reduction in cancer metastasis.
Cites background from "Fibroblast growth factors, their re..."
...Thus, VEGF is a major growth factor for cancer metastasis (Powers et al., 2000)....
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01 Sep 2014
TL;DR: It is suggested that osteoblastic TGF- signaling inhibits PCa bone lesions development, but myeloid TGF - signaling promotesPCa bone lesion development.
Abstract: : Loss of the stromal TGF- signaling in the prostate has been shown to initiate prostate cancer (PCa), promote PCa progression, and facilitate the development of mixed osteoblastic/osteolytic bone lesions. However, the effects on bone lesions are found to be transient. We thus focused on delineating the context-dependent role of TGF- signaling in the bone microenvironment effects on PCa bone lesions. Using genetic engineered mouse models, TGF- signaling is cell-specifically knockout (KO) in the prostate fibroblasts and osteoblasts in the bone by Colcre/Tgfbr2 KO, or in the myeloid lineage cells, including osteoclasts in the bone by LysMcre/Tgfbr2 KO. Compared the PCa-induced bone lesions in the KO mice tibiae to the lesions in the Flox mice, we found that PC3-induced osteolytic bone lesions were significantly increased by Colcre/Tgfbr2 KO,but were significantly decreased by LysMcre/Tgfbr2 KO. Our findings suggested that osteoblastic TGF- signaling inhibits PCa bone lesions development, but myeloid TGF- signaling promotes PCa bone lesion development. We further found that basic FGF mediated the effect of increased PC3 bone lesions in Colcre/Tgfbr2 KO mice.
Cites background from "Fibroblast growth factors, their re..."
...[19] Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M....
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17 Feb 2012
01 Jan 2009
TL;DR: In this article, the in vitro effects of anti-bFGF on total embryonic development were investigated in 40 rat embryos (which were divided into four groups) (obtained from five pregnant females).
Abstract: In this study, we aimed at the in vitro effects of anti‐fibroblast growth factor‐2 (anti‐FGF‐2 or anti‐bFGF) on embryo culture in rats. In vitro effects of anti‐bFGF on total embryonic development were investigated in 40 rat embryos (which were divided into four groups) (obtained from five pregnant females) at 9.5 days of gestation that were cultured in whole rat serum (WRS), and in WRS+ 2.5, 5, and 10 μg/ml anti‐bFGF. After 48 h of culturing, the embryos from each group were harvested to be analysed morphologically according to a morphological scoring system and biochemically to obtain the embryo protein content. The morphological score, embryo protein content, somite number and crown‐rump length of embryos indicated that embryos cultured in WRS+ anti‐bFGF had significant embryonic retardation. Mean morphological scores for the embryos grown in WRS, in the presence of 2.5, 5 and 10 μg anti‐FGF‐2 were 61.4 ± 1.64, 46.3 ± 8.42, 27 ± 2.58 and13.6 ± 0.96 respectively. These results suggest that bFGF is very important for normal embryonic development and rat anti‐bFGF neutralizes bFGF effect.
References
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TL;DR: It is demonstrated that free heparin and heparan sulfate can reconstitute a low affinity receptor that is, in turn, required for the high affinity binding of bFGF.
2,448 citations
TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"Fibroblast growth factors, their re..." refers background in this paper
...One way these recruited target proteins may be localized to the activated receptor is through the interaction between their Src-homology 2 (SH2) domains and specific phosphotyrosine residues on the activated receptor (Pawson 1995)....
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...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
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TL;DR: Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of Thalidomid-treated embryos.
Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
2,364 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
"Fibroblast growth factors, their re..." refers background in this paper
...†From Ornitz et al. (1996), except where stated; ‡From Koga et al. (1995); §From Miralles et al. (1999); ¶From Xu et al. (1999). topologically identical to interleukin-1β (IL-1β) (Zhu et al. 1991), with which some members also share the feature of secretion by an endoplasmic reticulum…...
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...Mutation of all four cysteines to serines results in a protein with the same secondary structure and equally mitogenic for 3T3 cells as the wild-type FGF-2 (Foxet al. 1988), suggesting that the formation of disulfide bridges is not important for the secondary structure and mitogenic activity of…...
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...Ornitz et al. (1996) determined the specificity of different FGFs for different receptor isoforms by overexpressing these isoforms in Baf3 cells, which do not normally express FGFRs, and assaying for [3H]thymidine incorporation in these cells following treatment with different FGFs (see Table 2)....
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...1, IIIb 100 60 34 16 4 5 6 4 4 1, IIIc 100 104 0 102 59 55 0 1 21 2, IIIb 100 9 45 15 5 5 81 4 7 2, IIIc 100 64 4 94 25 61 2.5 16 89 3, IIIb 100 1 2 1 1 1 1 1 42 3, IIIc 100 107 1 69 12 9 1 41 96 4 100 113 6 108 7 79 2 76 75 Modified from Ornitz et al. (1996)....
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1,994 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Defining features of the FGF family are a strong affinity for heparin and HLGAGs (Burgess & Maciag 1989), as well as a central core of 140 amino acids that is highly homologous between different family members....
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