Growth Factors

Growth Factors Overview

• Growth factors are diffusible signaling proteins
• They stimulate cell growth, differentiation, survival, inflammation, and tissue repair
• Normal cells require several growth factors to maintain proliferation and viability
• Growth factors are secreted by cells through autocrine, paracrine, or endocrine actions, including by tumor cells
• They generally have short half-lives and diffuse slowly in intercellular spaces, acting locally
• Signal transduction is initiated when growth factors bind to receptors on the surface of target cells

Growth Factor Families

• Nerve growth factor family was the first discovered in 1952
• Other families include Fibroblast growth factor (FGF), Vascular endothelial growth factor (VEGF), Insulin-like growth factor (IGF), Epidermal growth factor (EGF), Platelet-derived growth factor (PDGF), Hepatocyte growth factor (HGF), Hepatoma-derived growth factor (HDGF), Connective tissue growth factor (CTGF), and Transforming Growth Factors α and β (TGFα, TGFβ)

Cytokines

• Cytokines are a class of growth factors involved in cellular communication, immune function, and embryogenesis
• They are produced by hematopoietic and non-hematopoietic (adipocytokines) cells
• Cytokines exert autocrine, paracrine, and endocrine effects, similar to hormones
• Lymphokines are cytokines secreted from lymphocytes, many of which are also interleukins (ILs).
• Interleukins are growth factors that target hematopoietic cells

Adipocytokines

• Adipocytokines are bioactive products produced by adipose tissue, an endocrine organ
• Examples include inflammatory mediators (IL-6, IL-8), angiogenic proteins (VEGF), and metabolic regulators (adiponectin, leptin)

Adiponectin

• Adiponectin, also known as Adipocyte complement-related protein of 30 kDa (Acrp30), is derived from adipocytes
• It has wide-ranging paracrine and endocrine effects on metabolism and inflammation
• Adiponectin promotes adipocyte differentiation, fatty acid catabolism, and insulin sensitivity
• Adiponectin levels are negatively correlated with obesity, type 2 diabetes, and atherogenesis

Leptin

• Leptin is an adipose-secreted hormone (adipokine) that exhibits potent anorexic effects

Growth Factors, Sources, and Activities

• Platelet-Derived Growth Factor (PDGF) is sourced from platelets, endothelial cells, and the placenta; it promotes the proliferation of connective tissue, glial cells, and smooth muscle cells
• Epidermal Growth Factor (EGF) is sourced from the submaxillary and Brunner's glands; it promotes the proliferation of mesenchymal, glial, and epithelial cells
• Insulin-like Growth Factor-1 (IGF-1, somatomedin C) is sourced from the liver and promotes the proliferation of many cell types
• Insulin-like Growth Factor-2 (IGF-2) is sourced from a variety of cells and primarily promotes proliferation during fetal development
• Transforming Growth Factor-alpha (TGF-α) is sourced from transformed cells and may be important for normal wound healing
• Fibroblast Growth Factor (FGF) is sourced from a wide range of cells and promotes the proliferation of many cells, inhibits some stem cells, and induces mesoderm formation in early embryos
• Nerve Growth Factor (NGF) is sourced from mast cells, eosinophils, bone marrow stromal cells, and keratinocytes; it promotes neurite outgrowth and neural cell survival
• Erythropoietin is sourced from the kidney and promotes the proliferation and differentiation of erythrocytes
• Transforming Growth Factor-beta (TGF-β) is sourced from activated Th1 and NK cells, has anti-inflammatory effects, promotes wound healing, and inhibits macrophage and lymphocyte proliferation

Growth Factors and Medical Associations

• IGF-1 is associated with T2 diabetes and kidney issues
• EGF is associated with wound healing
• PDGF is associated with diabetic ulcers
• TGF-β is associated with bone and skin ulcers
• FGFs are associated with skin ulcers and wounds
• NTs are associated with neurodegeneration

Wound Healing and Growth Factors

• Wound healing is a natural body function for repairing itself after injury
• Wound healing has four basic stages: hemostasis, inflammation, proliferation, and remodeling and maturation
• Post-wound activation involves vascular constriction, fibrin clot formation, and the release of pro-inflammatory cytokines and growth factors like TGF-β, PDGF, FGF, and EGF

Wound Healing Components

• Fibroblasts produce collagen and elastin
• Epidermal cells grow over connective tissue to close the wound
• PMNs (polymorphonuclear leukocytes) are immune cells with granules containing enzymes released during infections, allergic reactions, and asthma; examples include neutrophils, eosinophils, and basophils

Insulin-like Growth Factors (IGFs)

• IGFs consist of two peptides: IGF-1 and IGF-2
• They have a chemical structure similar to proinsulin
• Insulin-like growth factor-I (IGF-I) is a hormone serving as a major mediator of growth hormone (GH)-stimulated somatic growth and of GH-independent anabolic responses
• IGFs are synthesized in the liver and secreted into the bloodstream

IGF Biological Effects

• IGFs have biological effects that promote cell cycle progression
• They play a role in organogenesis during the fetal development of IGF-2
• IGFs contribute to longitudinal body growth and increased body weight
• They affect male and female reproductive tissue function
• IGFs promote neuronal tissue growth and differentiation
• Present in maternal milk, IGFs are also found

IGF and Cancer

• IGFs can sustain uncontrolled cell growth in cancer
• Transformed cells often have high levels of IGF receptors
• Blocking the IGF receptor can slow down the growth of these cells, making it a therapeutic target

Other Uses for IGF

• IGF can be used for cachexia (wasting disease)
• It can be used for type II diabetes (helps cells uptake more glucose)
• IGF can be used for dwarfism (as part of GH-IGF pathway)
• It can be used for tissue repair in adults
• IGF has applications of reproductive disorders
• It can be used for peripheral nerve damage

Epidermal Growth Factor (EGF)

• EGF was one of the first growth factors identified
• Skin is its major target
• EGF is important in the wound healing process
• EGF is synthesized by monocytes, kidney, and duodenal cells
• It plays an important role in cell proliferation, differentiation, and maturation of the newborn's intestinal epithelium when found in maternal milk

Platelet-Derived Growth Factor (PDGF)

• Platelet-Derived Growth Factor (PDGF) is synthesized by platelets, endothelial cells, and the placenta
• It has effects on fibroblasts and smooth muscle cells
• PDGF is released by activated platelets at the damage site during wound healing and acts as a chemoattractant for cells that initiate tissue repair
• Human trials with topical PDGF showed higher healing rates, especially in some diabetic ulcers

Fibroblast Growth Factors (FGFs)

• FGFs are a family of 20 proteins (FGF 1-20)
• These proteins range in response, can be mitogenic, chemotactic and angiogenic
• Fibroblast Growth Factors(FGFs) promote the proliferation of many cells, they also inhibit some stem cells; induces mesoderm to form in early embryos
• Earlier ones work directly on fibroblasts, newer members do not
• They tightly bind heparin molecules for wound repair in the extracellular matrix (ECM), which is an external lattice including proteins and polysaccharides secreted by surrounding cells in most tissues

Transforming Growth Factors (TGFs)

• Transforming Growth Factors has α and β forms
• They bind the transmembrane glycoproteins receptors

TGF- α

• Transforming Growth Factors(TGFs): TGF- α are membrane proteins
• They are homologous to EGF
• Transforming Growth Factors(TGFs): TGF- α bind the EGF receptor
• Transforming Growth Factors(TGFs): TGF- α are produced by many tissues

TGF- β

• Transforming Growth Factors(TGFs): TGF- β are identified by the ability to transform some fibroblast cell lines
• They inhibit the cell cycle, more specifically hemopoietic and epithelial cells
• Transforming Growth Factors(TGFs): TGF- β stimulate growth of other cells such as connective tissue, bone and cartilage
• Transforming Growth Factors(TGFs): TGF- β involves tissue remodeling, wound repair, and hemopoiesis
• They are drug targets for different cancer types, more specifically leukemia

Neurotrophic Factors (NTs)

• Neurotrophic Factors-NTs promote neuron development and neural cell survival in both the CNS and PNS
• The first member is Nerve Growth Factor (NGF), just known as nerve growth factor
• Neurotrophins all belong to the same gene family, examples include NGF, BNDF (Brain-derived neurotrophic factor, NT-3, NT-4/5 and NT-6)

NTs and Disease

• Death of neurons occurs; in vitro studies show response of neurons to NTS
• NTs are associated with Amyotrophic Lateral Sclerosis (ALS) Lou Gehrig's disease which causes progressive degeneration of the motor neurons, degeneration of the brainstem and spinal neurons (muscle wasting, paralysis and death)
• IGF-1 and NT's can improve motor neuron function in vitro and in vivo (animal studies) with human trials now underway
• NTs show promise in the treatment of Alzheimer's, Parkinson's and Huntington's diseases.

Growth Factors & Receptors in Clinical Use

• Growth factors play an important role in various cellular processes
• Growth factors, in addition to inhibitors or antibodies, have a use in disease therapy
• Researches have made great progress in cancer, cardiovascular diseases, and diabetic mellitus treatment

Herceptin

• Her2 antibody known as Herceptin, aids in curing breast cancer,
• Iresa, a tyrosine kinase inhibitor prevents colon cancer and non-small cell lung carcinoma when aimed at EGFR,
• Hepatocyte growth factor enhances the ability of cardiac stem cells to promote myocardial regeneration.

Clinical Uses

• Insulin-like growth factor-1 (increases cellular glucose uptake) treats diabetes mellitus
• Epidermal growth factor alleviates diabetic foot ulcers