Cell Growth Factors

• 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 (autocrine), neighboring cells (paracrine), distant tissues (endocrine), or tumor cells.
• They have short half-lives and slow diffusion in intercellular spaces, acting locally
• Signal transduction begins by binding to receptors on the surface of target cells
• The nerve growth factor family was the first growth factor discovered in 1952
• Other growth factors include Fibroblast growth factor family (FGF), Vascular endothelial growth factor (VEGF) family, Insulin-like growth factor (IGF) family, Epidermal growth factor (EGF) family, Platelet-derived growth factor (PDGF), Hepatocyte growth factor (HGF)family, Hepatoma-derived growth factor (HDGF) family, Connective tissue growth factor (CTGF) family, Transforming Growth Factor a (TGFa) family, and Transforming Growth Factor β (TGFB) family

Cytokines

• They are a class of growth factors involved in cellular communication, immune function, and embryogenesis
• Cytokines are produced by hematopoietic and non-hematopoietic (adipocytokines) cells
• They exert autocrine, paracrine, and endocrine effects similar to hormones

Lymphokines and Interleukins

• Lymphokines are cytokines secreted from lymphocytes
• Many lymphokines are also interleukins (ILs)
• Interleukins are growth factors targeting hematopoietic cells

Adipocytokines

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

Adiponectin

• It's an adipocyte-derived protein with wide-ranging paracrine and endocrine effects on metabolism and inflammation
• Adiponectin promotes adipocyte differentiation, fatty acid catabolism, and insulin sensitivity
• Adiponectin is negatively correlated with obesity, type 2 diabetes, and atherogenesis in coronary artery heart disease

Leptin

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

Growth Factor Examples

• PDGF: Promotes proliferation of connective tissue, glial and smooth muscle cells, and is sourced from platelets, endothelial cells, and the placenta
• EGF: Promotes proliferation of mesenchymal, glial, and epithelial cells, and is sourced from the submaxillary gland and Brunners gland
• IGF-1 (somatomedin C): Promotes proliferation of many cell types, and is sourced primarily from the liver
• IGF-2: Promotes proliferation of many cell types primarily of fetal origin, and is sourced from various cells
• TGF-α: May be important for normal wound healing, and is sourced from common transformed cells
• FGF: Promotes proliferation of many cells, inhibits some stem cells, induces mesoderm to form in early embryos, and is sourced from a wide range of cells associated with the ECM
• NGF: Promotes neurite outgrowth and neural cell survival, and is sourced from mast cells, eosinophils, bone marrow stromal cells, and keratinocytes
• Erythropoietin: Promotes proliferation and differentiation of erythrocytes, and is sourced from the kidney
• TGF-β: Anti-inflammatory, promotes wound healing, inhibits macrophage and lymphocyte proliferation, and is sourced from activated Th1 cells (T-helper) and natural killer (NK) cells

Growth Factor Medical Applications

• IGF-1: Used in T2 diabetes and kidney treatments
• EGF: Used in wound healing
• PDGF: Used in treating diabetic ulcers
• TGF-β: Used in treatments for bone and skin ulcers
• FGFs: Used in treating skin ulcers and wounds
• NTs: Used in treating neurodegeneration

Wound Healing

• It is a natural body function by which the body repairs itself after injury
• The four basic stages are hemostasis, inflammation (growth factors involved), proliferation, and remodeling and maturation

Post-Wound Activation

• Vascular constriction and fibrin clot formation occur
• Pro-inflammatory cytokines and growth factors such as TGF-β, PDGF, FGF, and EGF are released from the clot and surrounding wound tissue
• Fibroblasts produce collagen and elastin
• Epidermal cells grow over connective tissue to close the wound
• PMNs (polymorphonuclear leukocytes) are a type of immune cell with granules containing enzymes released during infections, allergic reactions, and asthma; neutrophils, eosinophils, and basophils include PMNs.

Insulin-Like Growth Factors (IGFs)

• There are two peptides: IGF-1 and IGF-2, with a chemical structure similar to proinsulin
• Insulin-like growth factor-I (IGF-I) functions as the major mediator of growth hormone (GH)-stimulated somatic growth
• It is also a mediator of GH-independent anabolic responses in many cells and tissues
• IGFs are synthesized in the liver and secreted into the bloodstream

IGF Biological Effects

• They include promoting cell cycle progression, organogenesis in fetal development (IGF-2), longitudinal body growth, and increased body weight
• It supports male and female reproductive tissue function and neuronal tissue growth and differentiation
• IGFs are found in maternal milk

IGF and Cancer

• IGFs can sustain uncontrolled cell growth in cancer
• Transformed cells have high levels of IGF receptors
• Growth of these cells slows down by blocking the IGF-receptor, making it a therapeutic target

Other Uses for IGF

• Cachexia (wasting disease)
• Type II diabetes (helps cells uptake more glucose)
• Dwarfism (as part of GH-IGF pathway)
• Tissue repair in adults
• Reproductive disorders
• Peripheral nerve damage

Epidermal Growth Factor (EGF)

• EGF was one of the first growth factors identified
• Skin is its major target and is important in the wound-healing process
• Synthesized by monocytes, kidney, and duodenal cells
• It is found in maternal milk and plays an important role in the continuing process of cell proliferation, differentiation, and maturation of the newborn's intestinal epithelium, contributing to epithelial protection from injury

Platelet-Derived Growth Factor (PDGF)

• It is synthesized by platelets, endothelial cells, and the placenta
• PDGF affects fibroblasts and smooth muscle cells
• It is released during the wound-healing process by activated platelets at the damage site, acting 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)

• It is a family of 20 proteins (FGF 1-20)
• FGFs have a range of responses, including mitogenic, chemotactic, and angiogenic
• They promotes proliferation of many cells, inhibits some stem cells, and induces mesoderm to form in early embryos
• Earlier FGFs work directly on fibroblasts, while newer members do not
• FGFs tightly bind heparin molecules in the extracellular matrix (ECM), an external lattice of proteins and polysaccharides secreted by surrounding cells in most tissues, in wound repair

Transforming Growth Factors (TGFs)

• Exist in α and β forms and bind transmembrane glycoproteins receptors
• TGF-α is a membrane protein homologous to EGF, can bind the EGF receptor, and is produced by many tissues

TGF-β

• Identified by its ability to transform some fibroblast cell lines
• It inhibits the cell cycle (particularly in hemopoietic and epithelial cells)
• TGF-β stimulates the growth of other cells, such as connective tissue, bone, and cartilage
• TGF-β is involved in tissue remodeling, wound repair, and hemopoiesis
• Drug targets for various cancer types including leukemia

Neurotrophic Factors (NTs)

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

NTs and Disease

• Death of neurons; in vitro studies show the response of neurons to NTs
• Amyotrophic Lateral Sclerosis (ALS) Lou Gehrig's disease involves progressive degeneration of motor neurons, brainstem, and spinal neurons, resulting in muscle wasting, paralysis, and death
• IGF-1 and NTs can improve motor neuron function in vitro and in vivo (animal studies)
• NTs show promise in the treatment of Alzheimer's, Parkinson's, and Huntington's diseases

Growth Factors and Receptors in Clinical Use

• Growth factors play an important role in various cellular processes
• Growth factors themselves and their inhibitors or antibodies can be widely used in disease therapy
• Nowadays, researchers have made great progress in the treatment of oncologic diseases, cardiovascular diseases, and diabetes mellitus
• Herceptin is a Her2 antibody designed to cure breast cancer
• Iresa, a tyrosine kinase inhibitor aimed at EGFR, shows the potential to prevent colon cancer and non-small cell lung carcinoma
• Hepatocyte growth factor can enhance the ability of cardiac stem cells to promote myocardial regeneration
• Insulin-like growth factor-1 (increases cellular glucose uptake) can be used for the treatment of diabetes mellitus
• Epidermal growth factor has the potential to alleviate diabetic foot ulcers