Physiology, Growth Factor

Cellular Level

Wound Healing and Growth Factors

Wound healing is a normal, multiphase, physiological process and is of obvious importance after surgery. Growth factors play critical roles in all three phases of wound healing: (1) the inflammatory phase, (2) the proliferative phase, and (3) the remodeling phase. Platelets are the principal cell type for the inflammatory phase because they release platelet-derived growth factor (PDGF) and TGF-beta, both of which are growth factors that attract macrophages and neutrophils. Neutrophils are white blood cells that can kill bacteria and thereby prevent sepsis at the wound site. Macrophages secrete growth factors that both attract fibroblasts and also play a key role in the second phase of wound healing, the proliferative phase. TGF-beta is also secreted by macrophages and plays a role in wound fibrosis. Both macrophages and endothelial cells can secrete VEGF, and this growth factor promotes angiogenesis (growth of new blood vessels). Macrophages also secrete epidermal growth factor (EGF), and it stimulates fibroblasts to secrete collagenase, which is essential during the remodeling phase. There is evidence suggesting that the complex and changing mixture of growth factors occurring during wound healing modulates macrophage functions.[6][7]

Development

Growth Factors and Cancer

Genetic alterations in signal transduction pathways contribute to many cancer phenotypes such as increased cellular growth, cellular motility, and angiogenesis. One of the key pathways activated by growth factor binding (for example, EGF or insulin-like growth factor 1 [IGF-1]) to a surface receptor is the PI3K/AKT pathway. When activated by a surface receptor, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) can phosphorylate and activate AKT, which is a serine/threonine-specific protein kinase. Once activated by ATK, in turn, it promotes cell survival, cell motility, angiogenesis and also inhibits apoptosis.  Apoptosis is programmed cell death. Many cancer cells show resistance to apoptosis, giving these cells a survival advantage. Many of the processes activated by AKT are known to contribute to cancer. There has, therefore, been considerable effort to develop chemotherapeutic agents that block the activation of the AKT pathway.

Angiogenic growth factors important in cancer include vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), which are both proteins. Tumor growth is very dependent upon the growth of new blood vessels, and blocking this process can kill tumor cells.[8][9][10]

Organ Systems Involved

VEGF, Angiogenesis, and Eye Diseases

VEGF is a crucial factor for initiating and promoting the abnormal growth of new retinal blood vessels (neovascularization) as occurs in diabetic retinopathy and age-related macular degeneration. Age-related macular degeneration is the most common cause of vision loss in people 65 and older. The macula is a small region near the center of the retina and is responsible for detailed vision. A lack of oxygen supply to the retina can cause the secretion of VEGF, which then promotes the growth of new retinal blood capillaries (angiogenesis). Drugs that block VEGF can be effective at stopping some forms of macular degeneration and diabetic retinopathy. One such drug, ranibizumab, can be injected directly into the retina. The “mab” in “ranibizumab” indicates that the drug is from a monoclonal antibody.[11][7]

Clinical Significance

Growth factors are important in both normal physiological processes such as wound healing and abnormal processes such as cancer and diabetic retinopathy. Diabetic retinopathy can result from the abnormal growth of retinal blood vessels and is a major cause of blindness. Mutations in kinases and phosphatases are common in cancer cells. Some cancer drugs block the action of growth factors.