Table 1.

Growth factors in normal physiology and cancer

GF Family	GF Receptors	Origins/ Targets	Physiologcal Roles/Selected Examples of Gene Knockout (KO) Animals, Including Conditional KO
EGF	ErbB-1 (EGFR) ErbB-2 (HER2) ErbB-3 ErbB-4	Origins: Macrophages Monocytes Epithelial cells Neural cells Tumor cells Targets: Epithelial, Endothelial, Neural cells	Cell proliferation, organ development, tissue repair ErbB-1 KO: defects in brain, cell proliferation, migration, differentiation of epithelial cells, e.g. skin, lung, intestine, placenta ErbB-2 KO: defects in muscle spindle, myoblast cell survival, cardiac phenotype (trabeculae formation) ErbB-3 KO: defects in ductal morphogenesis, mammary glands, early cardiac valve formation ErbB-4 KO: defects in neural development, mammary glands TGFα KO: defects in skin, coat, nails (waved phenotype), cardiovascular defects, defects in vision, eye, vibrissae, muscle, adiposis EGF KO: defects in digestive functions, skin, nails, vision, eye, reproductive, immune defects NRG1 KO: prenatal-perinatal lethality, defects in muscle, nervous system, cardiovascular defects NRG2 KO: postnatal lethality, defects in growth, size, reproductive defects
EGF
TGFα
NRG 1-4
Amphiregulin
Betacellulin
Epiregulin
HB-EGF
Epigen
IGF	IGF1R IGF2R Insulin receptor	Origins: Liver Tumor cells Targets: Many cell types/tissues Tumor cells	IGF1: childhood, pubertal growth, produced throughout life time, anabolic effects Growth HormoneR KO and transgenics: defects in neuroendocrine, reproductive functions IGF1 KO: defects in growth, size, liver, biliary ducts, nervous system, homeostasis, inner ear maturation, cardiovascular defects, adipose IGF2 KO: prenatal-perinatal lethality, defects in embryogenesis, growth, size, skeleton, vision, eye, homeostasis, limbs, digits, tail, liver, biliary ducts, muscle, skeleton, cellular, cardiovascular, endocrine, exocrine, renal and urinary defects
IGF1
IGF2
TGF-β	TGF-βR1 TGF-βR2	Origins: Platelets Bone Several cell types Targets: Fibroblasts Endothelial cells Keratinocytes Lymphocytes Monocytes	TGF-β: ECM formation, fibroblast activity, chemotaxis TGF-βR1 KO: embryonic lethal TGF-βR2 KO: embryonic lethal, defects in yolk sac hematopoiesis, vasculogenesis SMAD5 KO: embryonic lethal, defects in vascular, cardiac, craniofacial, heart development, ventral closure SMAD4 KO: embryonic lethal, heterozygous KO: duodenal polyps similar to human polyps TGF-β1 KO: immune, digestive, alimentary, renal, respiratory, endocrine, exocrine, hematopoietic, urinary defects, defects in growth, size, liver, biliary ducts, homeostasis, life span, aging TGF-β2 KO: prenatal-perinatal lethality, cardiovascular, endocrine, exocrine, immune, reproductive, respiratory hearing, vestibular, ear, renal, urinary, digestive, alimentary defects, defects in homeostasis, skeleton, vision, eye, nervous system, muscle, limbs, digits, tail, growth, size, craniofacial, embryogenesis
TGF-β1–3
BMPs
Activins
VEGF	VEGFR1 (Flt-1) VEGFR2 (Flk-1, KDR) VEGFR3 (Flt-4)	Origins: Endothelial cells Tumor cells Targets: Vascular endothelium Macrophages Monocytes	Angiogenesis, blood flow, endothelial cell proliferation, enhanced chemotaxis/ homing of vascular precursor cells, recruitment of bone marrow progenitors VEGFA KO: prenatal-perinatal lethality, defects in life span, aging, growth, size, behavior, muscle, nervous system, skeleton, skin, coat, nails, cardiovascular and reproductive functions VEGFB KO: defects in vision, eye, homeostasis, cardiovascular function VEGFC KO: prenatal-perinatal lethality, defects in immune, cardiovascular functions
VEGFA (=VEGF)
VEGFB
VEGFC
VEGFD
PlGF
HGF	HGFR Met Ron	Origins: Mesenchymal and tumor cells Targets: Endothelial Epithelial cells	Development, homeostasis, regeneration, cellular growth, motility, morphogenesis, organ development, regeneration, wound healing Matrix invasion in angiogenesis HGFR KO: embryonic lethal, defects in development of placenta, liver, skeletal muscle HGF KO: prenatal-perinatal lethality, defects in embryogenesis, growth, size, liver, biliary ducts, hematopoietic, cardiovascular defects
HGF
MSP
FGF	FGFR1–4	Origins: Monocytes, Macrophages Endothelial cells Targets: Endothelium Fibroblasts Keratinocytes	Proliferation of endothelial cells, keratinocytes, fibroblasts, chemotaxis, mesoderm induction, limb formation, brain development, angiogenesis, keratinocyte organization, wound healing FGF KO: embryonic/early postnatal lethality FGF signaling disorders in humans: hereditary diseases, cancer Epidermal FGFR2b KO: increased sensitivity to chemical carcinogenesis, induction of EMT FGF1 KO: nervous system, hematopoietic, homeostasis FGF2 KO: cardiovascular, hematopoietic, muscle, nervous system, behavior FGF3 KO: postnatal lethality, limbs/digits/tail, hearing, behavior FGF10 KO: prenatal-perinatal lethality, defects in embryogenesis, skeleton, digits, tail, vision, eye, respiratory, reproductive, cardiovascular, digestive, alimentary, renal and urinary defects FGF12 or 14 or 17 KO: behavior, nervous system FGF15 or 16 KO: prenatal-perinatal-postnatal lethality, cardiovascular defects
FGF1 (acidic)
FGF2 (basic)
(22 members in human)
PDGF	PDGFRα PDGFRβ	Origins: Platelets Macrophages Neutrophils Smooth muscle Pericytes Fibroblasts Targets: Fibroblasts Smooth muscle	Proliferation of smooth muscle cells, fibroblasts, blood vessel formation, smooth muscle cell recruitment, chemotaxis, role in connective tissues, endothelial cells, regulation of vessel growth, pericyte recruitment PDGFA KO: prenatal-perinatal-postnatal lethality, lung emphysema, defects in development of lung alveoli, alveolar smooth muscle cell progenitors, growth, size, cardiovascular defects PDGFB KO: prenatal-perinatal lethality, cardiovascular defects, defects in kidneys, development of smooth muscle cells of blood vessel, bleedings during birth PDGFC KO: prenatal-perinatal-postnatal lethality, perinatal death due to feeding defects, homeostasis, respiratory difficulties, skeleton, skin, coat, nails, digestive, alimentary defects PDGFRβ KO: pericyte deficient mice, vessel dilation, leakage, rupture
PDGFA/A
PDGFB/B
PDGFC/C
PDGFD/D
PDGFA/B
IL-8	CXCR1, CXCR2 (Receptors are coupled to G-proteins)	Origins: Macrophages Epithelial cells Endothelial cells Melanoma cells Targets: Neutrophils Granulocytes Endothelial cells	Mediator of inflammatory responses, chemoattractant of neutrophils and granulocytes, angiogenic factor CXCR1/2 expression in malignant melanoma
(CXC chemokine)