Growth Factors and Cytokines

Growth factors and cytokines have historically been classified into 'families' based on their apparent activity and/or impact on a given cell type, system, or tissue. Lately however, there has been an effort to establish naming based upon growth factor and cytokine receptors. Growth factor and cytokine receptors are highly conserved, and by utilizing them as a key for developing a systematic naming process, the field of growth factor families has narrowed.

Naming based on the differentiation of the cytosolic receptor domains has resulted in several major 'families' of growth factors and cytokines. In addition, the extracellular domains of these receptors demonstrate considerable homologies. This degree of homology in the extracellular domain leads to the highly conserved structures of growth factors and cytokines. The conserved nature of these receptors accounts for multiple signal transduction pathways effecting or impacting similar processes.

The identification, origin, activity, and signal transduction pathways of growth factors and cytokines remains in the discovery phase, however some of the more established, influential, and common compounds have been characterized. In recent years, cell biologists have attempted to reach a consensus on naming and nomenclatures, however naming schemes previously have been rather chaotic, leaving some compounds in rather odd groups. For example, bone morphogenic proteins (BMP), which affect bone and cartilage formation, fall into the tumor growth factor-beta (TGF-b) super-family. Another example is the tumor necrosis factor (TNF) protein. It is not useful as an anti-tumor therapy, but is highly active in immune modulation and inflammation.

Cytokines are often referred to as “growth factors”, but the reverse is not necessarily the case. Historically, growth factors have been thought of as compounds that have a positive effect on cell growth and expansion while cytokines are typically considered to have an immunological or hematopoietic response. Cytokines such as interleukin-2 (IL-2), which promote long term growth of activated T cells and related cell types fit the 'growth factor' description, but are classified as cytokines for their immunological responses and molecules such as the FAS ligands, which are involved in the initiation of programmed cell death - certainly not a positive effect on cell growth and expansion -fall into the cytokine category.

Over the years these compounds have been categorized into various classes, families, and super families, including the bone morphogenic proteins, epidermal growth factors, fibroblast growth factors, interferons, transforming growth factors, tumor necrosis factors, and vascular endothelial growth factors. As new molecules and pathways are identified, the terms 'growth factor' and 'cytokine' have come to be used interchangeably.

The epidermal growth factor (EGF) family of growth factors is comprised of the normal mammalian gene products of EGF, amphiregulin, betacellulin, heparin-binding EGF (HB-EGF), and transforming growth factor-α (TGF-a), plus pox virus EGF-like protein (PVGF), lin-3 from Caenorhabditis elegans, and spitz from Drosophila. The neuregulin (NRG) or neu differentiation factor (NDF) family of growth factors includes the heregulins (HRG-a and HRG-β), acetylcholine receptor inducing activity (ARIA) and glial growth factor (GGF). The EGF and NRG families are similar in that all members contain one or more EGF-like motifs in the extracellular domain that interacts with a cell surface receptor. Many members of both families also undergo proteolytic cleavages in the region between the EGF-like motif and transmembrane domain and also further toward the N-terminus to release molecules that bind and activate one or more members of the EGF receptor (EGFR) family. Among the members of both families there is a great deal of variations in other extracellular and intracellular structures of the precursor forms. EGF family members all bind and activate EGFR. Members of the NRG family bind to one or more of the EGFR-related receptors designated as erbB-2, erbB-3 or erbB-4. Emphasizing the homologies among the two families, some authors designate the EGFR as HER1 (human EGF receptor-1) and erbB-2-4 as HER2-4.

View Epidermal Growth Factor Table

Fibroblast Growth Factors (FGFs) are potent regulators of cell proliferation, differentiation and function and are critically important in normal development, tissue maintenance and wound repair. FGFs are also linked with several pathological conditions.^1,2,3 There are at least 20 FGF members, designated FGF-1 through FGF-20, but acidic FGF and basic FGF are names commonly used for FGF-1 and FGF-2, and keratinocyte growth factor (KGF) for FGF-7. Although FGF was originally named after its fibroblast mitogenicity,⁴ some FGFs do not induce fibroblast growth at all. Members of the FGF family generally share 30-50% amino acid sequence homology, have two conserved cysteine residues, and bind with high affinity to heparin. Several FGF members are oncogene products, e.g., FGF-3 (int-2), FGF-4 (hst-1, K-FGF), FGF-5 and FGF-6 (hst-2). FGFs interact with four distinct FGF receptors on cells of mesodermal, ectodermal and endodermal origin, eliciting changes in migration, morphology, function or proliferation. FGFs play several roles, including angiogenesis, wound healing, tissue regeneration, embryonic development, endocrine modulation and neurotrophic support.³

Acidic FGF (aFGF) and basic FGF (bFGF) are the prototypic FGF members named because of their different isoelectric points. They share a 55% homology in amino acid sequence and similar size, depending on translation extensions and truncations (15-18 kDa for aFGF and 16-24 kDa for bFGF). Neither aFGF nor bFGF genes include a secretory signal sequence and the prinicple mechanism of their release into extracellular fluid has not yet been resolved. Acidic FGF has high expression levels in brain, retina, bone matrix and osteosarcomas. Basic FGF is found in a variety of tissues, including pituitary gland, neural tissue, adrenal cortex, corpus luteum, and placenta. Acidic and basic FGFs stimulate proliferation in all cells of mesodermal origin, and many cells of neuroectodermal, ectodermal, and endodermal origin. They are chemotactic and mitogenic for endothelial cells and induce the release of agents that break down basement membranes. These two FGFs appear to play significant roles in modulating such normal processes as angiogenesis, tissue repair, embryonic development, and neural function. They also appear to participate in some pathological conditions that involve excessive cell proliferation or angiogenesis, such as tumor production.

1. Galzie, Z., et al., Fibroblast growth factors and their receptors, Biochem. Cell Biol., 75, 669-685 (1997).
2. Vainikka, S., et al., Fibroblast growth factors (FGFs), in Guidebook to Cytokines and Their Receptors, Nicola, N., ed., Oxford Press (New York, NY: 1994), pp. 214-217.
3. Baird, A., and Bohlen, P., Fibroblast growth factors, in Peptide Growth Factors and their Receptors, Sporn, M., and Roberts, A, eds., Springer-Verlag, (New York, NY: 1991), pp. 369-418.
4. Gospodarowicz, D., et al., Structural characteriztion and biological functions of fibroblast growth factor. Endocrinol. Rev., 8, 95-114 (1987).
5. Callard, R., and Gearing, A., The Cytokine Facts Book, Academic Press (New York, NY: 1994).

Numerous cytokines are involved in the regulation of hematopoiesis within a complex network of positive and negative regulators. Some cytokines have very narrow lineage specificities of their actions, while many others have rather broad and overlapping specificity ranges. Listed within this section include the cytokines whose predominant action appears to be the stimulation or regulation of hematopoietic cells. The term ''colony stimulating factor'' (CSF) was a designation originally given to agents discovered to stimulate growth of colonies containing differentiated myeloid cells from single bone marrow-derived precursor cells plated in semisolid medium. The glycoproteins considered to be CSFs include granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), interleukin-3 (multi-CSF or IL-3), interleukin-5 (IL-5), erythropoietin (EPO), ¹ and thrombopoietin (TPO). ²

A number of other cytokines exert profound effects on the formation and maturation of hematopoietic cells, with most of these belonging to the structural class known as the ''4-α-helical bundle'' family of cytokines, ³ which include stem cell factor (SCF), flt-3/flk-2 Ligand (FL) and leukemia inhibitory factor (LIF). Other cytokines or ligands, such as jagged-1, transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) also play significant roles in modulating hematopoiesis. Descriptions and listings of IL-3, IL-5, TGF-β and TNF-α products are listed in other sections by name.

References
1. Brugger, W., et al., Clinical role of colony stimulating factors. Acta Haematol. , 86, 138-147 (1991).
2. Lok, S., and Foster, D., The structure, biology and potential therapeutic applications of recombinant thrombopoietin. Stem Cells , 12, 586-598 (1994).
3. Nicola, N., An introduction to the cytokines, in Guidebook to Cytokines and Their Receptors, Nicola, N., ed., Oxford Press (New York, N.Y.: 1994), pp. 1-7.

 Cells derived from the culture of neural stem cells grown in the presence of EGF ( Cat. No. E9644 ) and LIF ( Cat. No. L5283 ). The cells were expanded in ( Cat. No. S3194 ) and then moved to conditions to allow them to differentiate. This image shows differentiated cells fixed and stained with an antibody for GFAP (an astrocyte marker in green, Cat. No. G9269 ). The cells are also stained with ( Cat. No. P1951 and Cat. No. D8417 ).

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Growth factors are naturally occurring regulatory molecules, which bind to receptors on the cell surface. They stimulate cell and tissue function through influencing cell differentiation by changing their biochemical activity and cellular growth, and regulating their rate of proliferation. Numerous families of growth factors have already been identified and remarkable advancements have been made in understanding the pathways growth factors use to activate cellular proliferation and differentiation.

Medical researchers recognize the important role growth factors play in stem cell therapy and regenerative medicine. Stem cell research has the potential to dramatically change the treatment of human disease and serious injuries by providing a platform for deciphering the secrets surrounding the cellular processes controlling development, aging, and tissue regeneration. Regenerative medicine shows promise for repair of damaged tissues and organs, deliver safer and more efficient drugs, better disease models, and cures for numerous devastating diseases.

Stem cell treatment could put an end to inefficient disease treatments and lack of organ donations for organ transplants. Much is expected from Embryonic Stem Cell (ESC) research, due to their ability to differentiate into all possible cell types in the body and their potentially unlimited capacity for self-renewal. However, no approved medical therapies have been developed using ESC, due to the lack of understanding these cells and how are they influenced. Once growth factors are added to pluripotent stem cells under certain conditions, they are able to direct differentiation into three different germ layers, endoderm, mesoderm, and ectoderm, from which various cell types are derived. Endodermal cells develop into the liver and pancreas, mesodermal cells give rise to muscles and red blood cells, and ectodermal cells become the brain and skin. Tremendous progress has been made in understanding which growth factors manipulate the different lineage pathways. However, complete control of stem cell differentiation, from pluripotent to fully specialized cell, needs further investigation since it requires multiple growth factors in defined order and quantity and at defined time intervals.

A recent advancement in the field of regenerative medicine is the production of induced pluripotent stem (iPS) cells. iPS cells are embryonic-like stem cells, derived from reprogrammed adult cells. The use of iPS cells in place of embryonic stem cells from human embryos provides an avenue for creating an unlimited supply of embryonic-like stem cells generating a tremendous enthusiasm in this field. Induced pluripotent stem cell technology has enormous possibilities for safe treatment of numerous diseases, bypassing the current ethical and political issues of embryonic stem cells. Also, iPS cells allow for personalized medicine as both the nuclear and the mitochondrial DNA matches the donor. Furthermore, using iPS cells would not require any immune suppression, making them a superior choice over donor embryonic stem cells for therapeutic uses. Researchers are daily enhancing their already significant understanding of how growth factors affect both somatic and embryonic stem cell expansion and differentiation. However, they have only begun to explore the effects of growth factors on iPS cells and how they differ, if at all, from embryonic stem cells. Once they can completely control the fate of pluripotent stem cells, which is influenced by a number of cellular signals including growth factors, they will be able to direct these cells, both in vivo and in vitro, to become the specialized cells that make up all the tissue in the body and enable subsequent use in cell-based therapies, drug development, and disease modeling.

Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes and a variety of other cells, including endothelial and epithelial cells, melanocytes, and keratinocytes. It also mediates epithelial morphogenesis. HGF is the ligand for a receptor encoded by the c-met proto-oncogene. c-Met expression has been observed in tumors from many sources, including stomach, lung, breast, kidney colon, liver, and melanoma, and is associated with tumor progression and metastasis.

References
1. Birchmeier, C., et al., Met, metastasis, motility, and more. Nat. Rev. Mol. Cell Biol. 4, 915-925 (2003).
2. Ma, P.C., et al., c-Met: structure, functions and potential for therapeutic inihibition. Cancer Metastasis Rev. 22, 309-325 (2003).
3. Zhang, Y.W., and Vande Woude, G.F., HGF/SF-met signaling in the control of branching morphogensis and invasion. J. Cell Biochem. 88, 408-417 (2003).

Insulin-like growth factors (IGF-I and IGF-II) are mitogenic and anabolic peptides structurally homologous to insulin. IGF-I and -II are single polypeptide chains of approximately 7.5 kDa comprised of 70 and 67 amino acid residues, respectively. IGF-I and -II share 70% homology in amino acid sequence, while IGF-I and proinsulin share 48% homology. Both IGFs are highly conserved between species, with 100% identity among human, bovine and porcine IGFs. Unlike insulin, IGF-I and -II are primarily involveto the insulin receptor (IR) and is comprised of two 130-kDa ligand-binding a-subunits and two 95-kDa transmembrane b-subunits. IGF-IR binds IGF-I d in normal growth and development. Circulating IGF is mainly secreted from the liver and acts as an endocrine to distant cells

Many other tissues also make IGFs, where they act with autocrine and paracrine functions to regulate a number of different cellular functions.IGF-I receptor (IGF-IR) is homologous with highest affinity, IGF-II with somewhat lower affinity, and insulin with rather weak affinity. IGF-IR is a tyrosine kinase receptor with signal transduction pathways that include substrates IRS-1, IRS-2, Shc, and Grb10. IGF-IIR has anabolic functions (like IR) but also shows three distinguishing qualities concerned with growth: 1) It signals mitosis in a variety of cells. 2) It is a necessary factor in establishing and maintaining cells in a transformed phenotype. 3) It protects cells from apoptosis, both in vitro and in vivo. This last quality is the subject of considerable interest, as it was found that IGF-I administration to cells stimulates the formation of bcl-2, a prominent anti-apoptotic intracellular messenger. While other known anti-apoptosis treatments inhibit apoptotic pathways without actually preventing cell death, IGF-I stimulation may actually decrease the probability of apoptosis initiation. Read More...

The Interleukins comprise a disparate group of cytokines and growth factors that are produced by and released from leukocytes. Interleukin-1β (1L-1β) is released primarily from stimulated macrophages and monocytes and plays a key role in inflammatory and immune responses and may induce anti-tumor immunity. It activates T cells to proliferate and secrete IL-2. IL-2 is also known as T cell growth factor since it promotes long-term growth of activated T cells, activation and proliferation of natural killer (NK) cells and induction of IFN-γ and B cell growth factor secretion. IL-3 is a colony-stimulating factor that induces colony formation of macrophages, neutrohils, mast cells, and megakaryocytes from hematopoietic progenitor cells. IL-3 also interacts with IL-2 to stimulate growth of T cells and to induce IgG secretion from activated B cells. IL-4 is produced by T cells and stimulates the growth and differentiation of immunologically competent cells and activates helper T cell (Th2) function. IL-5 is a hematopoietic cytokine that stimulates the proliferation, differentiation, and survival of eosinophils. It is also involved in B cell growth and antibody production and in the generation of cytotoxic T cells. IL-6 is a multifunctional cytokine that is involved in the regulation of the acute-phase immune system response to infection and injury. IL-7 is a lymphoid cell growth factor that induces proliferation of pre-B, pro-B, and early T cells as well as certain leukemia and lymphomas. IL-8 is a chemokine of the CXC family that is chemotactic for neutrophils and induces the release of hematopoietic progenitor cells from bone marrow. IL-10 is produced by the Th2 cells, B cells, macrophages and keratinocytes. It is anti-inflammatory in that it inhibits the synthesis of cytokines in target cells at the mRNA transcription or translation level. However, it also enhances the function of B cells and cytotoxic T cells. IL-12 is produced predominantly by monocytes and NK cells and induces T cells and NK cells to produce IFN-γ. IL-12 has anti-angiogenic properties. IL-13 is produced predominantly by Th2 cells and induces B cell proliferation and differentiation. IL-15 is a cytokine produced in macrophages and T cells that enhances T cell proliferation and maintains CD8 (+) cytotoxic T cell survival.

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Neurotrophic factors are agents that are important for survival, growth, or differentiation of discrete neuronal populations. Based on amino acid sequence homologies of cytokines and receptors and based on similarities in cytokine-receptor binding characteristics, neurotrophic factors can be divided into three general families. The ''neurotrophin family'' includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrohin-3 (NT-3) and neurotrohin-4 (NT-4). The ''CNTF family'' includes ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). Due to their boad biological actions, LIF and IL-6 are listed in separate sections. The ''GDNF family'' includes glial cell linederived neurotrophic factor (GDNF), neurturin (NTN), artemin(ART) and persephin (PSP).

Platelet-Derived Growth Factor is the principal mitogen found in mammalian serum and is released from platelets during clot formation.PDGF elicits multifunctional actions with a variety of cells, including mitogenesis of mesoderm-derived cells, increased extracellular matrix synthesis, and chemotaxis and activation of neutrophils, monocytes and fibroblasts. PDGF is mitogenic for dermal and tendon fibroblasts, vascular smooth muscle cells, glial cells and chondrocytes. PDGF appears to interact with Transforming Growth Factor-1 in acceleratting wound healing. However, PDGF may also be pathogenic in arteriosclerosis and neoplasia.

The mitogenic activities of all PDGF products are tested in culture using Swiss 3T3 cells or NR6-3T3 fibroblasts.

The transforming growth factor-β (TGF-β ) superfamily of cytokines include the structurally related subfamily of TGF-β s, the subfamily of bone morphogenic proteins (BMP), decapentaplegic (dpp) and Vg1, the subfamily of Mullerian inhibitory substances (MIS), and the subfamily of activins and inhibins.In general, individual members of this superfamily were originally purified and characterized with a specific functional assay, but most of these have broader biological activities that are particularly relevant in development. TGF-β superfamily members have a conserved set of six cysteine residues that form a rigid ''cysteine knot'' in the carboxyterminal region. They are all secreted as large propeptide molecules which then form homodimers (or sometimes heterodimers with certain other superfamily members). Because TGF-β s and BMPs receptors share close similarities, these two subfamilies are grouped together in this section.

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Understanding cancer has been similar to the parable of the blind men describing an elephant based on touch. Depending on what part of the elephant each blind man touched, one would get a different description of the beast. So it is with cancer. The causes of cancer have at various times been described as a series of mutations, viral infections, failures of apoptosis, and failures of the immune system. Cancer is all of these and more; however, simply put, cancer is cells out of control. The question is, how do these cells get out of control?

Normal cells of multicellular organisms are constantly signaling to one another via molecules called growth factors and cytokines. The signals released by growth factors and cytokines can tell individual cells whether to divide or not. Cytokines also signal the immune system, triggering white blood cells to mount coordinated attacks on invading bacteria, viruses, and fungi.

One of the first hints of a connection between cancer and growth factors came from the observation that normal cells in culture required...Read More

Vascular endothelial growth factor (VEGF) is a family of closely related growth factors having a conserved pattern of eight cysteine residues and sharing common VEGF receptors. Originally known simply as VEGF, vasculotropin (VAS) or vascular permeability factor (VPF), this factor is now sometimes called VEGF-A. Four additional family members (placental growth factor, PlGF; VEGF-B; VEGF-C; and VEGF-D) have been identified to date.

VEGF-A (VEGF) is a potent growth factor for blood vessel endothelial cells, showing pleiotropic responses that facilitate cell migration, proliferation, tube formation, and survival. It is also one of the most potent permeability factors, so that VEGF-A is a common link of inflammation, permeability and angiogenesis. VEGF-A mRNA expression patterns are closely related to proliferation of blood vessels during the developing embryo and wound healing or in the ovary. Local hypoxia is a potent inducer of VEGF-A expression from adjacent cells but it is not synthesized in endothelial cells, indicating a paracrine regulation of vessel formation. In the developing embryo VEGF-A mRNA is expressed by cells within tissues undergoing capillarization. In most adult tissues the level of VEGF-A expression is low except in the kidney (Bowman's capsule podocytes). Expression of VEGF-A can be induced in macrophages, T cells, astrocytes, osteoblasts, smooth muscle cells, fibroblasts, endothelial cells, cardiomyocytes, skeletal muscle cells and keratinocytes. It is also expressed in a variety of human tumors. Due to alternative splicing of a single gene, VEGF-A may exist in four isoforms, designated by their expected final amino acid length (VEGF121, VEGF165, VEGF189 and VEGF206). These isoforms show similar biological activities but bind with different affinities to the heparin and result in different secretion patterns. The smallest isoform (VEGF121) is secreted and completely diffusible, the largest (VEGF206) is almost completely attached to the extracellular matrix, and the other two show intermediate heparinbinding affinities. VEGF-A exerts its actions through two receptors (VEGFR-1 and VEGFR-2).

PlGF is expressed in the placenta and somewhat less in the heart, lung and thyroid gland. Placentally expressed PlGF may act as an autocrine on trophoblasts, which express both PlGF and its receptor (VEGFR-1). Since these cells also make VEGF-A, natural heterodimers (PlGF/VEGF-A) have also been detected. Two alternatively spliced isoforms of PlGF have been identified. Hypoxia does not induce PlGF synthesis, but the formation of heterodimers would be affected due to hypoxic control over VEGF-A expression.VEGF-B is largely cell-associated and expressed mostly in the heart, skeletal muscle, brain and kidney. It is often co-expressed with VEGF-A and heterodimers of A/B have been detected. VEGF-B expression is not regulated by hypoxia. The long half-life of its mRNA (>8 hours) suggests a chronic rather than acute regulation. VEGF-B exerts its actions through one receptor (VEGFR-1).VEGF-C, also called VEGF-related factor (VRP) or VEGF-2, in the adult is expressed primarily in the heart, placenta, lung, kidney, muscle, ovary and small intestine. During embryo development it is expressed in the cephalic mesenchyme, tail region and allantois and along the somites. VEGF-C may play roles in the development of the veinous and lymphatic vasculature systems. VEGF-C exerts its actions through two receptors (VEGFR-2 and VEGFR-3). VEGF-D, also called c-fos induced growth factor (FIGF), is a VEGF homologue induced by c-fos. It is expressed in adult lung, heart and small intestine and in fetal lung. It is reported mildly mitogenic for endothelial cells. VEGF-D and VEGF-C share 23% amino acid sequence homology. VEGF-D exerts its actions through two receptors (VEGFR-2 and VEGFR-3).

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Fetal bovine serum (FBS) is the most widely used growth supplement for cell culture media because of its high content of embryonic growth promoting factors. When used at appropriate concentrations it supplies many defined and components that have been shown to satisfy specific metabolic requirements for the culture of cells in vitro.

Sigma-Aldrich continues its commitment to the life science researcher by providing over 30 years of fetal bovine serum production and manufacturing. We offer a variety of origins with special treatments and specifications along with a dependable, consistent supply that is ISO certified quality from collection to finished product.