The fibroblast growth factor-binding protein FGF-BP

Fibroblast growth factors (FGFs) are important regulators of cell migration, proliferation and differentiation, e.g., during embryogenesis and wound healing, and under several pathological conditions including tumor growth and tumor angiogenesis. Since heparin-binding FGFs are tightly bound to heparansulfate proteoglycans, and therefore, trapped in the extracellular matrix, their release through the action of an FGF-binding protein (FGF-BP) is one of the critical steps in FGF bioactivation. FGF-BP expression is highly tissue specific and strictly regulated through different promoter elements. Besides its role in embryogenesis and wound healing, FGF-BP is upregulated in several tumors and it is associated especially with early stages of tumor formation, where angiogenesis plays a critical role. Concomitantly, in several mouse tumor models, targeting of FGF-BP by ribozymes or RNA interference (RNAi) abolishes or reduces tumor growth and tumor angiogenesis. This indicates that FGF-BP can be rate-limiting for tumor growth and serves as an angiogenic switch molecule, and that it represents an increasingly promising target molecule in anti-tumor therapy.     

Polypeptide growth factors in animal embryogenesis

Data about polypeptide growth factors in animal cells during embryogenesis and about the sensitivity of these cells to regulatory effect of the factors have been systematically reviewed. The conclusion was drawn that they play an important role in molecular mechanisms controlling cell proliferation and differentiation at the early embryonic stages. Information has also been provided about transforming growth factors and about the products of some proto-oncogenes, which are detected in the embryonic cells in amounts comparable with those in the transformed cells. However, this does not lead to malignant growth. Moreover, microenvironment of an intact embryo exerts an antitransforming influence on tumor cells. Studies of the "normalizing" effect of the embryonic cells may help in developing new methods of suppression of the malignant growth.     

Polypeptide Growth Factors in Embryogenesis and Tumor Growth

Polypeptide growth factors belonging to different families (epidermal growth factors, insulin-like growth factors, fibroblast growth factors, transforming growth factors-, and some others), were characterized regarding their specific role in embryogenesis and tumor growth. Differences and parallels in the functioning of growth factors in these processes have been noted. The potential significance of the described characteristics of growth factors for directed modulation of embryogenesis and tumor growth is discussed.     

Embryonic growth factors.

The role of growth factors in development is under analysis on three main fronts: examination of patterns of growth factor expression in embryogenesis, studies of biological activity in vitro, and mutational analysis in vivo. Recent findings indicate that growth factors control developmental decisions, are strictly controlled in their delivery to responding cells, and act in conjunction to create tissue-specific regulatory networks.     

A critical role of vascular endothelial growth factor D in zebrafish embryonic vasculogenesis and angiogenesis

The VEGF family comprises seven members that are designated VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF), and VEGF-F. Of these factors, VEGF-D plays important roles for angiogenesis and lymphangiogenesis, and could promote tumor growth and lymphatic metastasis. In this study, we identified a zebrafish VEGF-D homolog that encodes a 272 amino acid protein including a PDGF (platelet-derived growth factor) domain characteristic to VEGF family. Expression profile demonstrated that the VEGF-D began expressed from 13 somite stage. Microinjecting zVEGF-D mRNA into zebrafish 1-cell stage embryos resulted in severe misguidance of intersegmental vessels (ISV) and abnormal connection between dorsal aorta and caudal vein. Microangiography indicated that these abnormal ISVs were not functional. Our studies therefore identified the first non-mammalian VEGF-D and established its in vivo role for vascular system development during vertebrate embryogenesis and provided an alternative animal model to further reveal functions of VEGF-D.     

柑橘愈伤组织生长速度与体细胞胚胎发生的关系

为了探讨柑橘愈伤组织不能再生的原因,试图寻找柑橘愈伤组织生长速度与其体细胞胚胎发生之间的关系,对7种柑橘类型的29种基因型的愈伤组织的生长速度进行了测定,并对愈伤组织生长速度与体细胞胚胎发生之间的相关性进行了统计分析。结果表明,柑橘愈伤组织生长速度与体细胞胚胎发生之间的相关系数为r=-0.3683。由此推断在这两者之间还存在其它影响因素。     

Angiogenesis and organ transplantation

Angiogenesis is a vessel development process that maintains the vascular supply for organ function. Regulation of angiogenesis is provided by positive factors, such as vascular endothelial or basic fibroblast growth factors, and negative factors, such as thrombospondin and macrophage-derived inflammatory cytokines. While the role of angiogenesis in the wound healing, embryogenesis, tumor growth and proliferative diseases is clear, in organ transplantation it is not yet well established. Herein we discuss the potential role of angiogenesis in chronic renal disease and in transplant settings.     

血管内皮生长因子的脑保护及其机制研究进展

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管发育调节因子,最早发现于肿瘤细胞。上世纪90年代,人们发现VEGF在神经细胞上也有广泛表达,并具有神经细胞保护作用。此外,VEGF显著促进成年哺乳动物结构性神经元再生区(constitutive neurogenic regions)和非神经元再生区(non-neurogenic regions)的神经元再生/更新(neurogenesis/regenera-tion),显示了VEGF在神经损伤性及退行性疾病治疗中的潜在意义。本文着重讨论VEGF在脑缺血损伤中的神经保护(neuroprotection)和神经修复(neural repair)及其细胞和分子机制研究进展。     

Parallels and Antagonisms of Embryogenesis and Carcinogenesis

The main similarities of embryonic and tumor cells, as well as the mechanisms preventing the malignant transformation of embryonic cells, are presented in this review. Special attention is paid to the role of specific polypeptide growth factors in reciprocally excluding processes: embryogenesis and carcinogenesis. Based on the presented analysis, new potential targets for antitumor drugs are considered.     

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

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.     

The similarities and the differences of embryogenesis and carcinogenesis

The main similarities and embryonic and tumor cells, as well as the mechanisms preventing the malignant transformation of embryonic cells, are presented in this review. Special attention is paid to the role of specific polypeptide growth factors in reciprocally excluding processes: embryogenesis and carcinogenesis. Based on the presented analysis, new potential targets for antitumor drugs are considered.     

Signal transduction by vascular endothelial growth factor receptors

VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.     

Heparin-binding growth factor/prostatropin attenuates inhibition of rat prostate tumor epithelial cell growth by transforming growth factor type beta

Summary Normal rat prostate epithelial cell growth requires both epidermal growth factor and heparin-binding growth factor/prostatropin. In contrast, epithelial cells derived from the transplantable Dunning R3327H rat tumor require either epidermal growth factor or heparin-binding growth factor/prostatropin. Transforming growth factor type beta inhibited normal epithelial cell growth. Transforming growth factor beta inhibited epidermal growth factor-dependent growth of tumor epithelial cells, independent of epidermal growth factor concentrations. Transforming growth factor beta increased the effective dose of heparin-binding growth factor type 1 required to support tumor epithelial cell growth by 10-fold but saturating levels of heparin-binding growth factor type 1 (290 pM) completely attenuated the inhibitory effect of transforming growth factor beta. These results suggest that prostate tumor epithelial cells may escape the inhibitory effect of transforming growth factor beta as a consequence of alteration of the concurrent requirement for both epidermal growth factor (or homologues) and heparin-binding growth factors. This work was supported by NCI Grant CA37589. Editor’s Statement The observation that heparin-binding growth factor/prostatropin can counteract the inhibitory effect of transforming growth factor beta in prostate epithelial cells may help explain how some cancers avoid the action of growth inhibitors and provides a model for studying how inhibitory peptides overcome the stimulatory signals generated by growth factors.     

Comparison of exogenous growth stimuli for chemically transformed cells: growth factors, serum and cocultures

Rat tumor cells isolated from 2 fibrosarcomas which differed in their degree of differentiation were exposed to growth-stimulating influences in soft agar. The effects of growth factors (epidermal growth factor, fibrosarcoma growth factor and insulin), of fetal calf serum and of cocultured normal mesenchymal cells of rats and nude mice were compared. Each of the 3 growth factors exerted a specific response and dose dependence. Increasing concentrations of serum stimulated the number of cells which formed clones in soft agar. Experiments using combinations of growth factors and fetal calf serum demonstrated that a complex optimal mixture of growth stimuli was responsible for the efficient growth-promoting activity of the serum. In cocultures with normal cells, cloning efficiency of tumor cells was enhanced and growth of tumor cells was accelerated. This stimulus was due to the constant release of an agar-diffusible growth-stimulating factor by the normal, nondividing cells. Cocultured mouse cells showed an even higher growth-stimulating activity than rat fibroblasts. Cells obtained from the poorly differentiated fibrosarcoma responded, in relative terms, better to all growth-stimulating influences, than those derived from the well-differentiated tumor.     

Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis

Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.     

Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian embryogenesis

During mouse embryogenesis, diffusible growth factors, i.e. fibroblast growth factors, Wnt, bone morphogenetic protein and Hedgehog family members, emanating from localized areas can travel through the extracellular space and reach their target cells to specify the cell fate and form tissue architectures in coordination. However, the mechanisms by which these growth factors travel great distances to their target cells and control the signalling activity as morphogens remain an enigma. Recent studies in mice and other model animals have revealed that heparan sulfate proteoglycans (HSPGs) located on the cell surface (e.g. syndecans and glypicans) and in the extracellular matrix (ECM; e.g. perlecan and agrin) play crucial roles in the extracellular distribution of growth factors. Principally, the function of HSPGs depends primarily on the fine features and localization of their heparan sulfate glycosaminoglycan chains. Cell-surface-tethered HSPGs retain growth factors as co-receptors and/or endocytosis mediators, and enzymatic release of HSPGs from the cell membrane allows HSPGs to transport or move multiple growth factors. By contrast, ECM-associated HSPGs function as a reservoir or barrier in a context-dependent manner. This review is focused on our current understanding of the extracellular distribution of multiple growth factors controlled by HSPGs in mammalian development.     

Transformation-related growth factors and their receptors

Cellular transformation may be accomplished in vitro and in vivo through the concerted action of growth factors and oncogenes. This association has demonstrated that malignant growth results from aberrations in growth factor-signal transduction pathways that normally operate to control proliferation. Activation of genes that code for growth factors and/or their receptors provides tumor cells with potential mechanisms to maintain their proliferative state. Tumor cells have been shown to produce endogenous substances that augment their growth (autocrine stimulation), as well as responding to exogenous substances (paracrine stimulation). With solid tumor cells these responses have been shown to involve aberrant expression of growth factor and/or receptor genes. The study of the interrelationship of these various growth regulatory molecules is important not only in the identification of gene products essential to cellular proliferation, but also in providing clues as to what forces are driving tumor cell growth.     

From growth arrest to growth suppression.

Since the introduction of the cell cycle concept two approaches to study growth regulation of cells have been proposed. One claims that cells are naturally quiescent, requiring a stimulatory encouter with growth factors for induction of cell division. The other considers cellular multiplication as the natural steady-state; cessation of multiplication is thus a restriction imposed on the system. In the latter case emphasis is mainly on the signals involved in arrest of multiplication. This Prospect focuses on specific events occurring in mammalian cells at growth arrest, senescence, and terminal differentiation, specifically emphasizing the growth inhibitory factors, tumor suppressor genes, and other signals for growth suppression.