Handbook of Growth Factors (1994)

Volume 1

Enrique Pimentel

• Publisher: CRC Press
• Year: 2017
• eBook ISBN: 9781351363174
• Topic: Biological Sciences
• Subtopic: Endocrinology & Metabolism
• Index: Biological Sciences

Volume I of this book provides a comprehensive discussion of the factors involved in regulation of the cell cycle, the general biological properties of growth factors, and the receptor and postreceptor mechanisms of action of these signaling agents. It evaluates the possible role of growth factors in the regulation of proto-oncogene and tumor suppressor gene expression, and the development of neoplastic processes is discussed in detail.

Chapter 1

Regulation of Cell Functions

I. Introduction

Hormones and peptide growth factors are important regulatory substances present in metazoan organisms. They represent biological signals involved in the regulation of cell growth and differentiation as well as in the control of specific metabolic processes during both pre- and postnatal life. Certain hormones and peptide growth factors act in a restricted manner on specific types of cells, whereas others may have a broad, perhaps universal, spectrum of activity for different types of cells and tissues.

Hormones are defined as chemical messengers synthesized in the endocrine glands of multicellular organisms and secreted into the extracellular body fluids, which transport them to more or less distantly located target cells (hormone-responsive cells), where they can exert important regulatory actions. Upon arrival to its target cell, the hormone is recognized by and binded to a specific site, the hormone receptor. The formation of a hormone-receptor complex determines the response that is specific for both the hormone and the cell.^1,2 Hormones are involved in the integrated regulation and modulation of the differentiated functions of multicellular organisms. The neural system and the endocrine system have partially overlapping and complementary functions related to the integration and coordination of complex biological processes. They constitute a functionally important integrative structure of the organism, the neuroendocrine system.

In contrast to the classical hormones, the peptide growth factors (usually called in an abbreviated manner “growth factors”) are not necessarily synthesized in specialized endocrine organs but are produced and secreted by cells from a wide variety of tissues, and their target cells are frequently located not far from the site of release (paracrine response). Even the cell producing a growth factor may in some cases (when it is endowed of the specific receptor) respond to the factor (autocrine response).^4-8 Certain growth factors remain anchored to the cell membrane.⁹ The distinction between peptide hormones and growth factors may be a subtle one, however. Many growth factors, or proteolytic products of growth factors, circulate in the blood and may act at sites far away from the place of their secretion or may display specific regulatory functions. Growth factors, or substances with growth factor-like activities, have been found not only in vertebrates but also in invertebrates and even in plants, where they are represented by biologically active agents called cytokinins.

Growth factors are produced by normal and neoplastic cells in vitro and in vivo. They are essential components of the media required for the survival and growth of cells cultured in vitro and afford protection of cells against death. Growth factors are involved in cell survival in vivo and have a crucial role in the control mechanisms of the development of organs and tissues. In addition to their growth-promoting and differentiation-inducing activities, growth factors are able to elicit a wide variety of effects in their target cells, including diverse metabolic effects. Growth factors are importantly involved in physiological processes such as inflammation, immune reactions, and tissue repair.^10-12 Wound repair requires close control of both degradative and regenerative processes. It involves numerous types of cells and complex interactions between multiple biochemical pathways and growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF), which when released in the traumatized area have a crucial role in the regulation of these processes.¹³ The effects of growth factors in relation to wound healing include promotion of cell migration into the wound area (chemotaxis), stimulation of the proliferation of epithelial cells and fibroblasts (mitogenesis), formation of new blood vessels (angiogenesis), and formation of matrices and remodeling of the affected region. Growth factors produced by a subpopulation of dermal fibroblasts contribute to the excessive accumulation of extracellular matrix that occurs in scleroderma.¹⁴

Growth factors are importantly implicated in the development of common human diseases such as atherosclerosis and cancer.^15-18 There are numerous structural and functional relationships between extracellular signaling agents, such as hormones, growth factors, and regulatory peptides, and intracellular signaling molecules, such as oncogene products (oncoproteins) and tumor suppressor gene products (onco-suppressor proteins).^19,20 Expression of growth factors, oncoproteins, and onco-suppressor proteins is altered in a diversity of benign and malignant tumors.^{21, 22 and 23} Quantitative and/or qualitative alterations of hormones and growth factors can be profitable as valuable markers for the diagnosis and follow-up of various human tumors.^24,25 In general, tumor growth depends on complex interactions between hormones and growth factors,²⁶ but malignant cells may depend less than normal cells on the exogenous supply of these agents, and some tumor cells are able to produce and utilize them by an autocrine or paracrine mechanism. The altered growth of tumor cells depends, at least in part, on the action of certain growth factors that are produced and utilized in inappropriate amounts by the tumor cells themselves.

The biological properties of growth factors can be studied either in vitro or in vivo. The isolation and characterization of growth factors are facilitated by culturing cells in a defined protein-free medium.²⁷ The undefined serum component of the medium can be replaced by specific mixtures of nutrients, hormones, growth factors, and metal ion transporting proteins.²⁸ Bioassay can be used as the initial method for the detection and measurement of growth factors. It requires the discovery and characterization of a factor-dependent morphological, physiological, or biochemical event in whole animals, tissue fragments, or cultured cells. The biological activity of growth factors can be examined in organ culture assays or in colony assay systems in agarose culture. Each of these methods has some advantages and disadvantages.²⁹ While the organ culture may be a better method for screening possible growth factors, the colony assay may provide quantitative results for statistical analysis. Growth factors are defined by their ability to induce stimulation of target cell proliferation, and their activity is measured by assays where the increase of cell number is estimated or the incorporation of radioactively labeled thymidine into DNA is determined by autoradiography and counting of the labeled cells or by determination of radioactivity in liquid scintillation vials. The most suitable routine test for detection of growth factor activity in a biological sample may lie on measuring the incorporation of tritiated thymidine into DNA of target cells with a scintillation counter.³⁰ After isolation guided by bioassay, the purified growth factor peptide can be used to develop antisera for detection and measurement of the growth factor by immunodiffusion or radioimmunoassay procedures, as well as by enzyme-linked immunoassay (ELISA) and membrane receptor assay. Polyclonal or monoclonal antibodies can be developed by using synthetic oligopeptides corresponding to specific amino acid sequences of the growth factor. A list of growth factors and other peptides with growth factor-like properties appears in Table 1.1 The chromosomal localization of genes coding for hormones and growth factors or their respective receptors is indicated in Table 1.2 and Figure 1.1.

II. The Cell Cycle

Depending on the cell type and the physiological conditions, cells may be engaged in proliferation and may continuously traverse the different phases of the cell cycle or may not divide and remain in a quiescent state. In general, there is an antagonism between the rapid proliferation of cells and the expression of highly differentiated functions by the cells. Cultured cells have been extensively used in the past decades for the analysis of the different phases of the cell cycle and the evaluation of exogenous factors capable of altering them. Serum contains a complex mixture of mitogens; cultured fibroblasts from mouse and other rodent species are widely used as a simple system for evaluating the influence of purified hormones, growth factors, and other mitogens on cell proliferation. Fibroblastic cells whose growth has been arrested by serum starvation (quiescent cells...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• The Author
• 1. Regulation of Cell Functions
• 2. Growth Factor Receptors
• 3. Postreceptor Mechanisms of Growth Factor Action
• 4. Cyclic Nucleotides
• 5. Guanosine Triphosphate-Binding Proteins
• 6. The Calcium-Calmodulin System
• 7. Phosphoinositide Metabolism
• 8. Protein Phosphorylation
• 9. Proto-Oncogene and Onco-Suppressor Gene Expression
• 10. Role of Growth Factors in Neoplastic Processes
• Index