Fibroblast Growth Factors: Biology and Clinical Application

FGF Biology and Therapeutics

Michael Simons

• Publisher: WSPC
• Year: 2016
• eBook ISBN: 9789813143388
• Topic: Medicine
• Subtopic: Cardiology

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The fibroblast growth factor (FGF) family of ligands and the corresponding family of FGF receptor tyrosine kinases comprise one of the most versatile and diverse growth factor signaling families in vertebrates, found virtually in every tissue and cell type where they regulate metabolic and physiologic function, maintain tissue homeostasis, and mediate injury response, tissue repair, and regeneration. As a result, FGFs play critical roles in a wide variety of normal biological and abnormalities in FGF signaling can lead to a variety of disease states from developmental malformations, to atherosclerosis, pulmonary hypertension and cancer among many others. A thorough understanding of this system is necessary for critical insights into both normal and disease biology and is essential to development of rationale therapeutic strategies aimed at treatment of FGF-dependent diseases states.

Recent years have seen advances in our understanding of FGFs role in endothelial and, more general, vascular biology, the subject of this book. In particular, FGFs have been implicated in the maintenance of vascular homeostasis and control of blood vessel permeability while aberrant FGF signaling has been shown to be central to the development of pulmonary hypertension, and endothelial-to-mesenchymal transition, a process implicated in the development of atherosclerosis. Finally, FGFs ability to stimulate blood vessel growth has been explored in therapeutic angiogenesis approaches.

With this in mind, the present monograph is structured to provide comprehensive information to a reader interested in FGFs in general and vascular biology in particular. To this end, we explore everything from the structure and signaling of FGFs and their receptors (Chapters 1, 2 and 3) to their role in the regulation of vascular homeostasis (Chapter 4) and cardiovascular diseases (Chapters 5 and 6). We then address new developments in FGF therapeutics (chapter 7) and explore FGF biology in the epithelium (Chapter 8) thereby providing a complete analysis of this growth factor family biology in two closely related but distinctly different environments — endothelium and epithelium. Finally, we examine FGF biology in eye disease and in cancer.

It is our hope that this comprehensive treatment of FGF vascular biology and its application will provide the reader with the accurate and timely summary of this rapidly moving field.

--> Contents:

• An Introduction to the Fibroblast Growth Factors (David M Ornitz and Nobuyuki Itoh)
• Regulation of FGF Signaling (Robert E Friesel)
• FRS2α At the Center of FGF Signaling (Cong Wang, Wallace L McKeehan and Fen Wang)
• Fibroblast Growth Factor Signaling, Endothelial Homeostasis, and Endothelial Cell to Mesenchymal Transition (Pei-Yu Chen and Michael Simons)
• FGF in Cardiovascular Disease (Surovi Hazarika and Brian H Annex)
• FGF Signaling in Pulmonary Hypertension (Irinna Papangeli and Hyung J Chun)
• Therapeutic Potential of Allosteric Modulation of FGF Receptors (Frederik De Smet and Peter Carmeliet)
• Fibroblast Growth Factors in Epithelial Homeostasis and Repair (Michael Meyer, Luigi Maddaluno and Sabine Werner)
• Growth Factors in the Eye (Rong Ju, Chunsik Lee, Weisi Lu and Xuri Li)
• FGF Ligand Traps for the Therapy of FGF-Dependent Tumors (Marco Rusnati, Marco Presta and Roberto Ronca)

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Readership: People working in the field of FGF/FGF signaling: investigators, students and clinicians; vascular biologists and trainees in vascular biology. The book is also suitable for graduate courses on FGF biology, RTFs or vascular biology.
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Chapter 1

An Introduction to the Fibroblast Growth Factors

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David M. Ornitz^*,‡ and Nobuyuki Itoh^†

Abstract

Fibroblast growth factors (FGFs) comprise a family of twenty-two evolutionarily conserved molecules. Eighteen of the FGFs are secreted signaling molecules that interact with four tyrosine kinase FGF receptors (FGFRs), other FGF binding proteins, and heparan sulfate proteoglycans or Klotho family proteins. FGFs and FGFRs are present in nearly every tissue of a developing vertebrate and consequently a wide spectrum of developmental defects result from mutations in FGF ligands, receptors, interacting proteins, and downstream mediators and effectors of the signaling pathway. FGFs and FGFRs are also present in adult tissues where they regulate metabolic and physiologic function, maintain tissue homeostasis, and mediate injury response, tissue repair, and regeneration. Mutation, gene amplification, and ectopic expression of FGFs and FGFRs can also lead to the initiation or progression of cancer. Four members of the FGF family are intracellular molecules that interact with and regulate the activity of voltage-gated sodium channels, to regulate cell excitability.

1.Introduction to the FGF Family

The mammalian FGF family contains twenty-two genes; eighteen encode secreted molecules that signal through tyrosine kinase FGF receptors (FGFRs) and four encode intracellular molecules (iFGFs) that regulate voltage-gated sodium (Nav) channels.^1,2 Based on biochemical function, sequence similarities, and evolutionary conservation, FGFs can be grouped into seven subfamilies. The secreted FGFs are categorized into five subfamilies of locally acting (autocrine or paracrine) FGFs and one subfamily of endocrine FGFs, and the intracellular FGFs are categorized into a separate subfamily (Fig. 1).^1–9 FGF15 in rodents, and FGF19 in other vertebrates, are thought to be orthologs and are referred to as FGF15/19.

2.Discovery of FGFs

The concept that a soluble factor that could promote the growth of tissues or cells was developed in the early 1900’s using extracts from tissues or embryos to promote the growth of primary fibroblasts.^10–12 It was not until the 1970’s that an extract from bovine pituitary was shown to stimulate the proliferation of 3T3 fibroblasts at nanogram per ml concentrations of protein. Protease sensitivity and thermolability suggested that this “Fibroblast growth factor” activity was contained within a protein,¹³ partial purification of this activity was achieved in 1975 by Gospodarowicz,¹⁴ and a homogeneous preparation was isolated by Lemmon in 1983.¹⁵ This protein was referred to as basic FGF (bFGF or FGF2) due the overall basic composition of amino acids and high isoelectric point. A second Fibroblast growth factor-like activity with a low isoelectric point was purified from bovine brain. This factor was referred to as acidic FGF (aFGF or FGF1).^16-21 FGF1 turned out to be identical to a factor called ECGF (endothelial cell growth factor), which was consistent with its potent mitogenic activity towards endothelial cells.^{15,18,22–24} FGF1 was first cloned from a human brain cDNA library²⁵ and FGFs 1 and 2 were cloned from bovine pituitary cDNA libraries²⁶ in 1986. The remaining members of the FGF family were identified based on oncogenic properties activated by retroviral insertions, as growth factors for cultured cells or tissues, as genes that were mutated in genetic diseases, by homology-based cloning, or homology-based database searches.^1,3,27,28

Fig. 1. Phylogenetic analysis segregates the twenty-two FGF genes into seven subfamilies that contain two to four members each. Branch lengths are proportional to the evolutionary distance between each gene. Canonical FGFs, which bind to and activate FGFRs with heparin/HS as a co-factor, include the FGFs 1, 4, 7, 8, and 9 subfamilies. Endocrine FGFs include the FGF15/19 subfamily. These FGFs bind and activate FGFRs but use Klotho family proteins as a co-factor. Intracellular FGFs (iFGFs) are also referred to as fibroblast growth factor homologous factors (FHFs) and include the FGF11 subfamily. These are non-signaling proteins that regulate Nav channels and other cellular proteins.

3.Molecules that Mediate the Function of FGFs

Secreted FGFs transmit their signal to cellular targets through four FGFRs (detailed in chapter 2) (reviewed in Ornitz and Itoh, 2015).¹ The ligand binding affinity and specificity of FGFRs is regulated through alternative splicing of the FGFR mRNAs, and interactions with co-factor molecules. Several alternative splicing events occur in various extracellular and intracellular encoding regions; however, alternative splicing in the third immunoglobulin-like domain of FGFRs 1-3 generating b and c variants are particularly important determinants of ligand binding specificity. Interestingly, FGF1 is the only ligand that can activate all FGFRs irrespective of alternative splicing.²⁹ Ligand binding specificity assays show that the FGF7 subfamily preferentially binds and activates b splice variants while the other subfamilies activate c splice variants. The FGF9 subfamily also uniquely activates FGFR3b.^29,30 For the canonical FGF subfamilies, (FGF1, 4, 7, 8, and 9 subfamilies) heparan sulfate (HS) serves as the primary endogenous co-factor for ligand binding and receptor activation (Fig. 1).^31–33 For endocrine FGFs (FGF15/19 subfamily), aKlotho and bKlotho function as co-factors.³⁴ Intracellular FGFs (FGF11 subfamily) directly bind and regulate Nav channels and do not activate FGFRs.^35,36.

4.The FGF Subfamilies

4.1.FGF1 subfamily

FGFs 1 and 2 were the first identified FGFs and now comprise the FGF1 su...

Table of contents

• Cover Page
• Title
• Copyright
• Contents
• Preface
• Chapter 1 An Introduction to the Fibroblast Growth Factors
• Chapter 2 Regulation of FGF Signaling
• Chapter 3 FRS2α: At the Center of FGF Signaling
• Chapter 4 Fibroblast Growth Factor Signaling, Endothelial Homeostasis, and Endothelial Cell to Mesenchymal Transition
• Chapter 5 FGF in Cardiovascular Disease
• Chapter 6 FGF Signaling in Pulmonary Hypertension
• Chapter 7 Therapeutic Potential of Allosteric Modulation of FGF Receptors
• Chapter 8 Fibroblast Growth Factors in Epithelial Homeostasis and Repair
• Chapter 9 Growth Factors in the Eye
• Chapter 10 FGF Ligand Traps for the Therapy of FGF-Dependent Tumors
• Index