Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Vascular endothelial growth factor: basic science and clinical progress.

Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...

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Regulation of Wound Healing by Growth Factors and Cytokines

https://www.gastrojournal.org/article/S0016-5085(08)00429-0/pdf

Mechanisms of Hepatic Fibrogenesis

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the FGF family range in molecular mass from 17 to 34 kDa and share 13-71% amino acid identity. Between vertebrate species, FGFs are highly conserved in both gene structure and amino-acid sequence. FGFs have a high affinity for heparan sulfate proteoglycans and require heparan sulfate to activate one of four cell-surface FGF receptors. During embryonic development, FGFs have diverse roles in regulating cell proliferation, migration and differentiation. In the adult organism, FGFs are homeostatic factors and function in tissue repair and response to injury. When inappropriately expressed, some FGFs can contribute to the pathogenesis of cancer. A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.

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Fibroblast growth factors

Fibroblast growth factor 1 (FGF1) and FGF2, the prototypic members of the FGF family of growth factors, have been implicated in a variety of physiological and pathological processes. Unlike most other FGFs, FGF1 and FGF2 are ubiquitously expressed and are not efficiently secreted. Gene knockouts in mice have previously demonstrated a role for FGF2 in brain development, blood pressure regulation, and wound healing. The relatively mild phenotypic defects associated with FGF2 deletion led to the hypothesis that the continued expression of other FGFs partially compensated for the absence of FGF2 in these mice. We now report our generation of mice lacking FGF1 and their use, in combination with our previously described FGF2 null mice, to produce mice lacking both FGF1 and FGF2. FGF1-FGF2 double-knockout mice are viable and fertile and do not display any gross phenotypic defects. In the double-knockout mice we observed defects that were similar in extent to those previously described for the FGF2 null mice. Differences in the organization of neurons of the frontal motor cortex and in the rates of wound healing were observed. We also observed in FGF2−/− mice and in FGF1-FGF2 double-knockout mice novel impairments in hematopoiesis that were similar in severity. Essentially no abnormalities were found in mice lacking only FGF1. Our results suggest that the relatively mild defects in FGF2 knockout animals are not a consequence of compensation by FGF1 and suggest highly restricted roles for both factors under normal developmental and physiological conditions.

Compensation by Fibroblast Growth Factor 1 (FGF1) Does Not Account for the Mild Phenotypic Defects Observed in FGF2 Null Mice

Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl4) in the livers of FGF1- and FGF2-deficient mice. After acute CCl4 exposure, FGF1(−/−)FGF2(−/−) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(−/−)FGF2(−/−) mice exhibited a normal increase in α-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen α1(I) synthesis. Liver fibrosis resulting from chronic CCl4 exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis.

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Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Moyamoya disease (MMD) is a rare cerebral vasculopathy characterized by occlusion of the supraclinoid portion of the internal carotid artery and proximal portions of the anterior and middle cerebral arteries. Patients develop an extensive collateral network of parenchymal, transdural and leptomeningeal vessels to supply the compromised brain. These collateral channels, also known as “moyamoya vessels,” may be seen in a number of disorders which lead to intracranial vascular occlusion. We report a case of MMD in a child with hereditary spherocytosis.

Moyamoya disease in a patient with hereditary spherocytosis.

From the Department of Biochemistry and Biophysics,* Texas AM the Graduate School of Biomedical Sciences, The University of Texas–Houston Health Science Center, Houston, Texas; and the Department of Microbiology, New York University School of Medicine, New York, New York

Animal Model Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Publisher Summary This chapter describes the growth factor signal transduction and hormone independence in breast cancer. Mitogenesis in breast tissue is mediated in part through the interaction of the steroid hormone estrogen, denoted E2 or 17-β-estradiol, with an intracellular protein, the estrogen receptor (ER). The E2–ER complex acts as a transcription factor to induce expression of specific genes. Hormone-dependent breast cancers express ER and are stimulated by E2, which acts in these cells in part through induction of genes coding for polypeptide growth factors that in turn promote cell growth. The E2-mediated growth stimulation of these cells leads to the use of antiestrogenic drugs to inhibit the growth of these tumors. Hormone-independent breast cancers are not stimulated by E2 and may have no detectable ER expression and are therefore insensitive to antiestrogen treatment. These tumors often express growth factors at high levels. This inverse correlation between ER and over expression of growth factors suggests that the expression of such proteins in an unregulated manner by hormone-dependent breast cancer may contribute to its growth in the absence of E2. It leads to the hypothesis that the constitutive expression of growth factors by a hormone-dependent cancer may contribute to the development of hormone independence.

David L. Miller

Papers

Compensation by Fibroblast Growth Factor 1 (FGF1) Does Not Account for the Mild Phenotypic Defects Observed in FGF2 Null Mice

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Moyamoya disease in a patient with hereditary spherocytosis.

Animal Model Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Growth factor signal transduction and hormone independence in breast cancer