Key takeaways

• Growth factors are secreted proteins that bind cell surface receptors and control proliferation, differentiation, migration and survival.
• Most families — FGF, EGF, insulin/IGF, VEGF, PDGF — signal through receptor tyrosine kinases, converging on the Ras/MAPK and PI3K/Akt pathways.
• The TGF-beta family is the important exception: its receptors are serine/threonine kinases signalling through SMAD proteins, which is why its biology differs so markedly.
• Because so many ligands share so few pathways, specificity comes from receptor expression, ligand availability and cellular context rather than from the pathways themselves.
• The insulin-like growth factors are abbreviated IGF-1 and IGF-2, not ILGF.
• Most growth factors act locally by autocrine or paracrine signalling; insulin, IGF-1 and erythropoietin are the notable endocrine exceptions.
• Several families are established drug targets — anti-VEGF agents in oncology and retinal disease, anti-EGFR antibodies in colorectal and lung cancer.

Contents

• What growth factors are
• Receptor classes and shared pathways
• Classification of the families
• Fibroblast growth factors
• TGF-beta family
• EGF and EGF-like factors
• Insulin and IGFs
• VEGF
• PDGF
• Neurotrophic factors
• Haematopoietic growth factors
• Other key growth factors
• Therapeutic targeting
• Choosing ELISA kits
• Frequently asked questions

Growth factor ELISA kits

One kit for each of the major families described below, for quantifying secreted growth factors in serum, plasma, culture supernatant and tissue lysate.

FGF-2

Human FGF2 / bFGF ELISA Kit

Sandwich ELISAHuman

Basic FGF — the most studied family member, central to angiogenesis, wound healing and stem cell culture.

View product →

TGF-β1

Human TGF-beta 1 ELISA Kit

Sandwich ELISAHuman

The prototypical SMAD-signalling family member; requires acid activation of the latent complex before assay.

View product →

EGF

Human EGF ELISA Kit

Sandwich ELISAHuman

Ligand for EGFR, the receptor tyrosine kinase targeted by cetuximab and the EGFR inhibitor class.

View product →

IGF-1

Human IGF-1 ELISA Kit

Sandwich ELISAHuman

The principal mediator of growth hormone action; measured clinically in acromegaly and growth disorders.

View product →

VEGF-A

Human VEGF-165 ELISA Kit

Sandwich ELISAHuman

The dominant VEGF-A isoform driving angiogenesis and the target of bevacizumab and related agents.

View product →

PDGF-BB

Human PDGF-BB ELISA Kit

Sandwich ELISAHuman

Released on platelet degranulation; central to wound healing, fibrosis and vascular remodelling.

View product →

What growth factors are

A growth factor was originally defined as a secreted, biologically active molecule that affects cell growth. The definition has broadened to cover secreted proteins and peptides that also modulate differentiation, migration and survival — so the name is now narrower than the function.

They act as molecular messengers. Binding a cell surface receptor triggers an intracellular cascade that alters gene expression and cell behaviour, coordinating embryonic development, tissue repair, wound healing and adult homeostasis.

Range of action

A distinction worth making early, since it determines where a factor can be measured:

• Autocrine — the factor acts on the cell that produced it, common in tumour cells that acquire self-sufficiency in growth signalling.
• Paracrine — it acts on neighbouring cells. This is the default mode for FGF, PDGF, EGF and VEGF, and it means serum concentrations may not reflect local tissue activity.
• Endocrine — it travels through the circulation to distant targets. Insulin, IGF-1 and erythropoietin work this way, which is why they are meaningfully measured in blood.

Receptor classes and shared pathways

The families below differ greatly in structure and biology, but they use only a few receptor types — and that classification predicts their behaviour better than the ligand does.

Downstream, the RTK families converge almost entirely on two routes: the Ras/MAPK pathway, driving proliferation and differentiation, and the PI3K/Akt pathway, driving survival, growth and metabolic change.

This convergence raises an obvious question: if EGF, FGF, PDGF and VEGF all activate the same two pathways, why do they produce different outcomes? Specificity comes from elsewhere — which receptors a cell expresses, where and for how long the ligand is available, signal duration and strength, and the transcriptional state the cell is already in. The pathway is shared; the context is not.

Classification of the families

Two points of nomenclature. TGF-alpha is not a member of the TGF-beta family despite the shared name — it is an EGF-family ligand that binds EGFR, and the two are unrelated in structure, receptor and mechanism. And the insulin-like growth factors are correctly abbreviated IGF-1 and IGF-2; the form “ILGF” appears occasionally but is not standard.

Fibroblast growth factors

The FGF family comprises 23 members in humans, binding four receptor tyrosine kinases, FGFR1 to FGFR4. Most require heparan sulphate proteoglycan as a co-receptor, which tethers them to the extracellular matrix and largely confines their action to the local tissue.

They are produced by a broad range of cells — fibroblasts, endothelial and epithelial cells, and macrophages among them — rather than by any single dominant source. Their functions are correspondingly diverse, spanning embryonic development, angiogenesis, wound repair and metabolic regulation, and they act principally through paracrine and autocrine routes.

Signalling proceeds through Ras/MAPK and PI3K/Akt, with substantial crosstalk into Wnt and BMP pathways. Representative members:

• FGF-2 (basic FGF) — angiogenesis, wound healing and tissue regeneration; widely used as a supplement in stem cell culture.
• FGF-7 (keratinocyte growth factor) — acts on epithelial cells; important in skin and lung development and repair.
• FGF-23 — an endocrine member regulating phosphate homeostasis and bone mineralisation, and a clinical marker in chronic kidney disease.

TGF-beta family

The TGF-beta superfamily is the structural outlier here, and the difference is mechanistic rather than cosmetic. It comprises the three TGF-beta isoforms together with activins, inhibins, BMPs and growth and differentiation factors.

Its receptors are serine/threonine kinases, not tyrosine kinases. Ligand binding brings type I and type II receptors together; the type II receptor phosphorylates the type I receptor, which then phosphorylates receptor-regulated SMAD proteins. Phosphorylated SMADs complex with SMAD4, enter the nucleus and act directly as transcription factors. Non-canonical signalling through MAPK and PI3K/Akt also occurs.

A practical point for anyone measuring TGF-beta: it is secreted as a latent complex and is not biologically active until released. Immunoassays therefore require acid activation of samples, and a result without that step reflects only the small free fraction.

• TGF-beta 1 — immune regulation, tissue remodelling and wound healing; central to fibrosis and to the immunosuppressive tumour microenvironment.
• TGF-beta 2 — embryonic development, notably of heart and lung.
• TGF-beta 3 — palate and skin morphogenesis; associated with reduced scarring in wound repair.
• GDF-9 — produced in the ovary; required for follicle development and oocyte maturation.

TGF-beta is also the clearest example of context dependence in this field: it suppresses proliferation in normal epithelium and acts as a tumour suppressor early in carcinogenesis, yet promotes invasion, metastasis and immune evasion in established tumours.

EGF and EGF-like factors

EGF is a small polypeptide produced by fibroblasts, macrophages and salivary glands. It binds EGFR, a receptor tyrosine kinase of the ErbB family, driving dimerisation and autophosphorylation and activating Ras-Raf-MAPK and PI3K-Akt signalling.

Its effects are strongest on epithelial tissue: it promotes proliferation and migration in skin, supports collagen and elastin production during wound healing, and maintains the gastrointestinal epithelium.

Several related ligands bind the same receptor family and are collectively described as EGF-like:

• Amphiregulin (AREG) — skin, lung and intestine; implicated in tissue repair, inflammation and cancer progression, and in placental development.
• Betacellulin (BTC) — pancreas and mammary gland; binds EGFR and other ErbB receptors, and influences insulin secretion.
• Epiregulin (EREG) — skin and gastrointestinal tract; wound healing and tissue regeneration.
• TGF-alpha — despite the name, an EGFR ligand unrelated to the TGF-beta family.

EGFR is among the most heavily targeted receptors in oncology, through antibodies such as cetuximab and small-molecule inhibitors including gefitinib and osimertinib.

Insulin and IGFs

Insulin and the insulin-like growth factors IGF-1 and IGF-2 are structurally related peptide hormones acting through closely related receptor tyrosine kinases — the insulin receptor and IGF-1R.

Insulin is produced by pancreatic beta cells in response to rising blood glucose, and regulates carbohydrate, lipid and protein metabolism: glucose uptake, glycogen storage, and protein and lipid synthesis.

IGF-1 is produced mainly in the liver and mediates most of the effects of growth hormone, promoting growth, proliferation and differentiation. IGF-2 is chiefly a fetal growth factor and is imprinted. Both circulate bound to IGF-binding proteins, which extend half-life and control bioavailability — the reason total and free IGF-1 measurements can diverge.

Signalling runs through insulin receptor substrate proteins to PI3K/Akt, dominant for metabolic effects, and Ras/MAPK, dominant for growth. Dysregulation underlies diabetes, and at the other extreme acromegaly and growth disorders — which is why IGF-1 is used clinically as an integrated measure of growth hormone status.

VEGF

VEGF is the principal regulator of angiogenesis — the growth of new vessels from existing ones — and also drives vascular permeability and lymphangiogenesis. It is produced by endothelial cells, macrophages and many tumours, and signals through VEGFR1, VEGFR2 and VEGFR3, with VEGFR2 carrying most of the angiogenic signal.

The family divides by function: VEGF-A is the main angiogenic isoform, while VEGF-C and VEGF-D act chiefly on lymphatic endothelium through VEGFR3. Downstream signalling is again PI3K/Akt and MAPK/ERK, with crosstalk into Notch, which patterns tip and stalk cells during vessel sprouting.

Hypoxia is the dominant physiological trigger: HIF-1-alpha stabilised under low oxygen induces VEGF transcription, coupling vessel growth directly to tissue oxygen demand. That mechanism explains both wound revascularisation and the pathological angiogenesis of solid tumours, diabetic retinopathy and age-related macular degeneration — the diseases anti-VEGF therapy treats.

PDGF

PDGF exists as five dimers — PDGF-AA, -AB, -BB, -CC and -DD — signalling through PDGFR-alpha and PDGFR-beta. It is released on platelet degranulation at sites of injury, and also produced by smooth muscle cells, fibroblasts and macrophages.

Its central role is in wound healing and mesenchymal tissue: it recruits and stimulates fibroblasts to deposit extracellular matrix, and drives smooth muscle cell migration and proliferation during vessel repair. Pericyte recruitment to nascent vessels is PDGF-BB dependent, which is why it works alongside VEGF rather than in parallel to it.

Dysregulation contributes to pulmonary and hepatic fibrosis through excessive matrix deposition, and to several cancers. Imatinib, developed for BCR-ABL, also inhibits PDGFR and is used in tumours driven by PDGFR fusions.

Neurotrophic factors

The neurotrophins support neuronal development, survival and synaptic plasticity. The family comprises nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophins 3 and 4.

They signal through two receptor systems with opposing consequences: the Trk receptor tyrosine kinases — TrkA for NGF, TrkB for BDNF and NT-4, TrkC for NT-3 — promote survival, while p75NTR can promote apoptosis when Trk signalling is absent. The balance between them determines whether a neuron lives or dies, and it is the mechanism behind developmental neuronal pruning.

NGF supports sympathetic and sensory neurons and is also central to pain signalling, which is the basis of anti-NGF analgesics. BDNF is the most abundant neurotrophin in the adult brain and is required for long-term potentiation and memory formation.

Haematopoietic growth factors

These regulate blood cell production and mostly act through cytokine receptors and JAK-STAT rather than receptor tyrosine kinases — a mechanistic distinction from the families above.

Erythropoietin is produced by the kidney in response to hypoxia — the same oxygen-sensing mechanism that drives VEGF — and beyond erythropoiesis has tissue-protective effects under investigation in kidney and neurological disease.

Other key growth factors

• Hepatocyte growth factor (HGF). Produced by mesenchymal cells and signalling through the MET receptor tyrosine kinase. Drives liver regeneration, and promotes proliferation, survival and migration more broadly. MET is a significant oncology target, and HGF-MET signalling is a recognised mechanism of resistance to EGFR inhibitors.
• Hepatoma-derived growth factor (HDGF). First identified in hepatoma cells; contributes to proliferation, survival and angiogenesis, and is implicated in cancer progression.
• Migration stimulating factor (MSF). A truncated fibronectin isoform that stimulates cell motility. It is related to fibronectin rather than to HGF, despite occasional confusion between the two.
• Placental growth factor (PlGF). A VEGF-family member binding VEGFR1; studied in pre-eclampsia, where the ratio of soluble FLT1 to PlGF has diagnostic value.

Therapeutic targeting

Because growth factor signalling drives proliferation, it is heavily targeted in oncology — and supplemented where regeneration is wanted.

The pattern mirrors that of kinase inhibitors generally: agents succeed where a tumour is selectively dependent on one axis, and disappoint where the pathway is broadly required. Resistance frequently arises by switching to a parallel growth factor route — HGF-MET activation bypassing EGFR blockade being the standard example.

Frequently asked questions