Growth Factors and Receptors

Slide 1 · Growth factors and receptors

From controlled regeneration to angiogenesis, fibrosis, and cancer

A mechanism-based pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Orientation

Explain

Connect ligand binding to receptor activation and altered gene expression.

Compare

Identify major growth-factor families, receptors and key actions.

Apply

Relate VEGF, TGF-β and other factors to tissue injury and repair.

Interpret

Distinguish controlled regeneration from pathologic pathway activation.

Slide 3 · Growth factors: More than mitogens

Conceptual foundations

Extracellular signals that alter cellular behavior

Cell survival, proliferation, migration, differentiation and biosynthesis are regulated in a context-dependent manner.

Slide 4 · From ligand to cellular response

Conceptual foundations

Growth factor

Extracellular ligand

Specific receptor

Membrane engagement

Signal transduction

Kinase-linked events

Gene program

Transcriptional response

Cell behavior

Growth or repair

The signal is converted into a change in protein activity and gene expression.

Slide 5 · How growth factors support cell division

Conceptual foundations

Receptor-dependent growth signal

Cell-cycle entry

Promotes entry into a new cycle

Checkpoint progression

Relieves inhibitory blocks

Cell survival

Limits apoptosis

Biosynthesis

Increases macromolecule production

Slide 6 · Growth factors regulate nongrowth functions

Conceptual foundations

Migration

Cell movement during tissue repair

Differentiation

Changes in tissue pattern or cell fate

Synthetic capacity

Production of proteins and matrix

Survival

Maintenance of viable cells

Chemotaxis

Recruitment toward injury-associated cues

Morphogenesis

Organized tissue development

Slide 7 · Homeostasis versus injury response

Conceptual foundations

Setting

Biologic problem

Growth-factor role

Steady state

Routine cell turnover

Regulate normal cellular proliferation

Acute injury

Damaged cells need replacement

Coordinate replacement and repair

Healing tissue

Cells must move and synthesize matrix

Support migration and matrix production

Slide 8 · When growth signals escape control

Conceptual foundations

Normal signal

Ligand-dependent

Pathway dysregulation

Excess input or altered receptor

Persistent signaling

Constitutively active output

Cell proliferation

Inappropriately sustained

Growth-factor pathway genes may behave as oncogenes after activating alterations.

Slide 9 · Receptor kinase classes

Conceptual foundations

Receptor class

Representative factors

Catalytic output

Receptor tyrosine kinase

EGF, HGF, PDGF, VEGF, FGF

Tyrosine phosphorylation

Serine/threonine kinase receptor

TGF-β

Smad pathway activation

Slide 10 · The growth-factor landscape

Conceptual foundations

EGF / TGF-α

Epithelial proliferation and migration

HGF / MET

Hepatocyte response and cell motility

PDGF

Cell recruitment and mesenchymal proliferation

VEGF

Blood vessels and permeability

FGF

Development, repair and angiogenesis

TGF-β

Matrix accumulation and inflammation control

Slide 11 · EGF and TGF-α share an overlapping receptor system

EGF and ERBB family

Ligands

Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) belong to the EGF family.

Biologic relationship

They bind overlapping receptor sets and share many activities.

Do not confuse TGF-α (EGF-family ligand) with TGF-β (a distinct kinase-receptor family).

Slide 12 · Sources and target cells of EGF-family ligands

EGF and ERBB family

Ligand

Representative sources

Responsive targets

EGF

Macrophages, epithelial/other cells

Hepatocytes, fibroblasts, epithelia

TGF-α

Macrophages, keratinocytes, other cells

Hepatocytes and epithelial cells

Slide 13 · The ERBB receptor family

EGF and ERBB family

Four family members

EGF receptor family includes four related ERBB membrane receptors

EGFR

Also called EGFR1 or ERBB1

ERBB2

Also termed HER2

Receptor dysfunction

Amplification, mutation or overexpression in neoplasia

Slide 14 · Ligand engagement of an EGF-family receptor

EGF and ERBB family

Ligand binds a specific extracellular receptor domain.

Intracellular kinase signaling transmits the response.

The resulting program varies by target cell.

EGF / TGF-α

Extracellular

Cytoplasm

ERBB receptor tyrosine kinase

Slide 15 · EGF-family activities in repair

EGF and ERBB family

EGF-family ligand

Released locally

Responsive cell

Epithelial or stromal

Proliferation

Cell population expands

Migration

Surface restitution

Table 1.1 also describes EGF-associated granulation-tissue formation.

Slide 16 · EGFR alterations in human cancers

EGF and ERBB family

Type of dysregulation

Mutation and/or receptor amplification

Cancer contexts

Lung, head and neck, breast and brain tumors are examples.

Effect

Growth-regulatory signaling can become excessive.

Interpretation

Alteration type and tumor context determine whether targeting is relevant.

Slide 17 · ERBB2 (HER2) and breast carcinoma

EGF and ERBB family

HER2 overexpression is present in a subset of breast cancers

The receptor itself is a potential molecular target. This is a receptor-level example of oncogenic growth-factor signaling.

Slide 18 · Targeting abnormal ERBB signaling

EGF and ERBB family

Abnormal ERBB activity

Receptor-directed therapy

Antibody or small molecule

Reduced kinase-pathway signaling

Clinical effect

Context dependent

Clinical effectiveness of receptor-directed agents in selected cancers; No universal response is implied.

Slide 19 · HGF: Growth factor and scatter factor

HGF and MET

Hepatocyte growth factor promotes growth and cell movement

The name “scatter factor” reflects its ability to promote migration; It also participates in embryonic morphogenesis.

Slide 20 · Where HGF is produced

HGF and MET

Fibroblasts

Stromal source in many tissues

Other mesenchymal cells

Additional local HGF producers

Endothelial cells

Contribute to paracrine signaling

Nonhepatocyte liver cells

Support hepatocyte responses within the liver

Slide 21 · HGF activation is injury-linked

HGF and MET

Pro-HGF

Inactive precursor

Local serine proteases

Released at injury sites

Proteolytic cleavage

Ligand becomes active

HGF

Available for MET signaling

Proteolytic processing couples growth-factor availability to the injury milieu.

Slide 22 · MET is the HGF receptor

HGF and MET

MET is a cell-surface receptor with intrinsic tyrosine kinase activity.

Ligand-dependent signaling alters growth and movement programs.

Altered MET expression or sequence can contribute to malignancy.

HGF

Extracellular

Cytoplasm

MET tyrosine kinase

Slide 23 · HGF-responsive epithelial tissues

HGF and MET

Liver

Hepatocytes and biliary epithelium

Lung

Respiratory epithelium

Kidney

Renal epithelial compartments

Breast

Mammary epithelium

Skin

Cutaneous epithelium

Other epithelia

Broader epithelial response

Slide 24 · HGF is simultaneously mitogenic and motogenic

HGF and MET

HGF–MET signaling

Proliferation

Expansion of responsive cells

Migration

Cell motility / scatter response

Survival

Protection of hepatocytes

Morphogenesis

Developmental tissue patterning

Slide 25 · MET dysregulation in cancer

HGF and MET

Alterations

Overexpression or mutation of MET

Tumor examples

Renal and papillary thyroid carcinomas; Some lung carcinomas

Biologic significance

Receptor signaling can support inappropriate growth

Therapeutic relevance

Selected lung tumors with MET alterations may be treated using MET-directed drugs

Slide 26 · PDGF is a family of two-chain ligands

PDGF and recruitment

Platelet-derived growth factors consist of paired polypeptide chains

Different PDGF isoforms have distinct activation requirements, but their signaling is mediated through PDGF receptors.

Slide 27 · PDGF isoforms differ in activation

PDGF and recruitment

PDGF isoforms

Activation requirement

Concept

PDGF-AA, -AB, -BB

Directly biologically active

Available without the specified proteolytic maturation

PDGF-CC and -DD

Proteolytic cleavage required

Extracellular processing permits activation

Slide 28 · PDGF is not produced by platelets alone

PDGF and recruitment

Activated platelets

Granule storage and release

Activated macrophages

Inflammation-associated synthesis

Endothelial cells

Vascular source

Smooth muscle cells

Vascular wall source

Tumor cells

May produce PDGF

Other tissues

PDGF production is widely distributed

Slide 29 · Two related PDGF receptor types

PDGF and recruitment

PDGFR-α and PDGFR-β are intrinsic receptor tyrosine kinases.

PDGF ligand isoforms bind members of the receptor system.

These signals are central to local cell recruitment and proliferation.

PDGF dimers

Extracellular

Cytoplasm

PDGFR-α / PDGFR-β

Slide 30 · PDGF recruits and expands repair cells

PDGF and recruitment

PDGF receptor activation

Chemotaxis

Moves cells toward injury

Fibroblast growth

Expands stromal cells

Smooth muscle growth

Expands vascular wall cells

Endothelial effects

Supports vascular repair

Slide 31 · PDGF in an injury-response sequence

PDGF and recruitment

Tissue injury

Platelet activation

Granule release

PDGF gradient

Cell recruitment

Stromal response

Proliferation / matrix

PDGF couples early local injury signals to fibroblast and vascular-cell responses.

Slide 32 · VEGF is a family, not a single molecule

VEGF and angiogenesis

VEGF-A

Major angiogenic VEGF after injury and in tumors

VEGF-B

Embryonic vessel-development role

PlGF

Placental growth factor; Vessel development

VEGF-C

Angiogenesis and lymphangiogenesis

VEGF-D

Angiogenesis and lymphangiogenesis

Structure

VEGF family members are dimeric proteins

Slide 33 · Functional distinctions across VEGF ligands

VEGF and angiogenesis

Family component

Emphasis

Principal context

VEGF-A

Angiogenesis

Injury and tumors

VEGF-B / PlGF

Vessel development

Embryogenesis

VEGF-C / VEGF-D

Blood and lymphatic vessel formation

Angiogenesis + lymphangiogenesis

Slide 34 · Hypoxia is a major stimulus for VEGF

VEGF and angiogenesis

Reduced O₂ availability

HIF-1 activity

Hypoxia response

VEGF expression

Endothelial response

New vascular supply

The hypoxia–HIF-1–VEGF axis links inadequate oxygenation to angiogenic signaling.

Slide 35 · HIF-1 couples oxygen sensing to transcription

VEGF and angiogenesis

Hypoxic tissue → HIF-1 activation

Transcriptional effect

Higher VEGF expression

Paracrine signaling

VEGF reaches endothelium

Vascular response

Proliferation and migration

Slide 36 · VEGF production also rises with injury mediators

VEGF and angiogenesis

Hypoxia

Dominant regulator

PDGF

Can increase VEGF production at injury sites

TGF-α

Another injury-associated VEGF inducer

Slide 37 · The VEGF receptor family

VEGF and angiogenesis

Receptor

Biochemical type

Importance

VEGFR-1

Tyrosine kinase

Part of VEGF receptor network

VEGFR-2

Tyrosine kinase

Major receptor for endothelial angiogenic responses

VEGFR-3

Tyrosine kinase

Part of VEGF signaling, including lymphatic responses

Slide 38 · VEGFR-2 drives the canonical angiogenic response

VEGF and angiogenesis

VEGFR-2 is highly expressed by endothelial cells.

It is the most important VEGF receptor for angiogenesis.

Downstream effects include migration, proliferation and lumen formation.

VEGF

Extracellular

Cytoplasm

VEGFR-2 (endothelium)

Slide 39 · Angiogenesis involves coordinated cellular behaviors

VEGF and angiogenesis

VEGF signal

Endothelial migration

Endothelial proliferation

Sprout organization

Formation of lumina

A patent capillary requires more than endothelial proliferation alone.

Slide 40 · Capillary sprouting: An original schematic

VEGF and angiogenesis

Endothelial cells leave the existing vessel wall to form a sprout.

Migration and proliferation support extension.

Lumen formation is a central later step.

Tip-cell movement

Parent vessel lumen

Schematic

Slide 41 · VEGF changes vascular permeability

VEGF and angiogenesis

VEGF signal at blood vessels

Angiogenesis

New vessel formation

Permeability

Increased vascular leakage

Vasodilation

Change in vessel caliber

Slide 42 · VEGF also maintains resting endothelium

VEGF and angiogenesis

Kidney

Podocyte-associated local VEGF signaling

Eye

Retinal pigment epithelium as local source

CNS

Choroid plexus-associated expression

Slide 43 · Tumor angiogenesis uses a normal repair program

VEGF and angiogenesis

Tumor expansion

Relative tissue hypoxia

VEGF induction

Vascular recruitment

Support for further growth

An otherwise adaptive angiogenic response can be co-opted by neoplasia.

Slide 44 · VEGF-directed therapy in oncology

VEGF and angiogenesis

Rationale

Some tumors rely on angiogenesis for continued growth and spread.

Therapeutic approach

Blocking VEGF can suppress vascular support; Selected renal and colorectal cancers.

Biologic rationale is not equivalent to clinical effectiveness in every tumor.

Slide 45 · VEGF-driven ocular vascular disease

VEGF and angiogenesis

Wet age-related macular degeneration

Pathologic neovascularization and leakage

Diabetic macular edema

Leakage-associated retinal edema

Retinopathy of prematurity

Abnormal angiogenesis in the developing retina

Slide 46 · Excess soluble VEGFR-1 and preeclampsia

VEGF and angiogenesis

Increased soluble VEGFR-1

S-FLT-1

VEGF sequestration

Less free ligand

Impaired endothelial support

Preeclampsia phenotype

Hypertension and proteinuria

The text describes elevated maternal s-FLT-1 as a possible pathogenic mechanism.

Slide 47 · FGF is a broad ligand family

FGF and matrix storage

More than 20 fibroblast growth factors are described

FGFs regulate development and tissue repair; Individual family members have different target-cell profiles.

Slide 48 · FGF-1, FGF-2 and FGF-7

FGF and matrix storage

Factor

Alternative name

Instructional role

FGF-1

Acidic FGF

Well-characterized family member

FGF-2

Basic FGF

Angiogenic and repair-associated activities

FGF-7

Keratinocyte growth factor (KGF)

Keratinocyte migration, proliferation and differentiation

Slide 49 · Heparan sulfate stores released FGFs in the ECM

FGF and matrix storage

FGF released

Into extracellular space

Heparan sulfate binding

Matrix sequestration

ECM reservoir

Inactive pool

Proteolysis

Locally releases factor

ECM binding creates spatial and temporal control of FGF availability.

Slide 50 · Injury can mobilize matrix-bound FGF

FGF and matrix storage

Before injury

FGF is retained through association with heparan sulfate in the extracellular matrix.

At a wound site

Proteolytic activity can release stored factor to participate in healing.

The matrix functions as a growth-factor reservoir, not only as structural support.

Slide 51 · FGF signals through four receptor kinases

FGF and matrix storage

FGFR1 through FGFR4 have intrinsic tyrosine kinase activity.

Receptor activation contributes to tissue development and healing.

The precise cellular effect depends on ligand and tissue context.

FGF

Extracellular

Cytoplasm

FGFR1–FGFR4

Slide 52 · FGF-2 and angiogenesis

FGF and matrix storage

Available FGF-2

Endothelial response

Migration / proliferation

Angiogenic growth

FGF-2 has the cellular activities needed to support angiogenesis.

Slide 53 · FGF-7 targets keratinocyte repair

FGF and matrix storage

FGF-7 / KGF from fibroblasts

Migration

Keratinocyte movement

Proliferation

Epithelial expansion

Differentiation

Maturation of epithelial cells

Slide 54 · TGF-β belongs to a distinct superfamily

TGF-β and fibrosis

TGF-β1, β2, β3

Three TGF-β isoforms; β1 is most widespread

Related families

BMPs, activins and inhibins are included in the broader group.

Principal signals

Extracellular matrix synthesis and immune regulation

Critical distinction

TGF-β uses serine/threonine kinase receptors, unlike the RTK examples.

Slide 55 · TGF-β is widely produced and locally activated

TGF-β and fibrosis

Multiple source cells

Platelets, leukocytes, stromal cells

Inactive precursor

Secreted form

Proteolytic processing

Active TGF-β

Receptor engagement

Many cells can supply TGF-β, including endothelial and epithelial cells.

Slide 56 · Type I and type II TGF-β receptors

TGF-β and fibrosis

Feature

TGF-β receptor system

Most other families here

Kinase activity

Serine / threonine

Tyrosine

Canonical effectors

Smad transcription regulators

RTK-associated signaling pathways

Functional emphasis

Matrix accumulation, immune regulation

Growth, motility or angiogenesis

Slide 57 · Smad signaling connects receptor to nucleus

TGF-β and fibrosis

TGF-β binds receptor

Kinase-mediated Smad phosphorylation

Smad complex formation

Nuclear translocation

Gene transcription altered

Activated Smad complexes cooperate with DNA-binding partners to regulate target genes.

Slide 58 · TGF-β effects depend on cellular context

TGF-β and fibrosis

Same ligand: TGF-β

Fibroblast context

Matrix synthesis and scar formation

Immune context

Suppressed inflammatory activity

Tissue context

Effects modified by concurrent signaling

Slide 59 · TGF-β favors extracellular matrix accumulation

TGF-β and fibrosis

TGF-β signaling

Collagen

Increased synthesis

Fibronectin

Increased synthesis

Proteoglycans

Increased synthesis

Slide 60 · MMP and TIMP regulation favors retention

TGF-β and fibrosis

Component

TGF-β effect

Net matrix consequence

Matrix metalloproteinases (MMPs)

Reduced matrix-degrading activity

Less extracellular-matrix breakdown

Tissue inhibitors of MMPs (TIMPs)

Increased inhibitory activity

Further protection from degradation

Collagen production

Increased synthesis

Greater matrix accumulation

Slide 61 · Scar formation is a controlled use of TGF-β

TGF-β and fibrosis

Tissue injury

TGF-β signaling

Matrix synthesis rises

Matrix degradation falls

Scar formation

Matrix deposition is physiologic in repair but harmful when persistent or excessive.

Slide 62 · Persistent TGF-β activity can drive fibrosis

TGF-β and fibrosis

Lung

Fibrotic remodeling reduces functional parenchyma

Liver

Persistent matrix deposition disrupts organ architecture

Kidney

Progressive fibrosis impairs renal function

Intestine

Chronic inflammation can cause fibrotic tissue remodeling

Slide 63 · TGF-β limits inflammatory responses

TGF-β and fibrosis

TGF-β anti-inflammatory signal

Lymphocytes

Reduced proliferation

Other leukocytes

Reduced activation / activity

Inflammation

Limitation and termination of response

Slide 64 · Loss of TGF-β restraint permits inflammation

TGF-β and fibrosis

Physiologic regulation

TGF-β helps dampen leukocyte-driven inflammation after injury.

Deficient signaling

Widespread persistent inflammation in animals lacking TGF-β.

Anti-inflammatory and profibrotic effects can coexist within the same tissue.

Slide 65 · Growth-factor receptors: Comparative map

Integration

Growth factor

Principal receptor

Signature response

EGF / TGF-α

EGFR family (ERBB)

Epithelial cell growth

HGF

MET

Epithelial growth and motility

PDGF

PDGFR-α / β

Chemotaxis; Stromal proliferation

VEGF

VEGFR-1 / 2 / 3

Angiogenesis; Permeability

FGF

FGFR1–4

Repair; Angiogenesis

TGF-β

TGF-βRI / RII

Fibrosis; Immunoregulation

Slide 66 · Repair requires distinct, overlapping signals

Integration

Cell replacement

EGF, TGF-α and HGF support proliferation

Stromal recruitment

PDGF directs and expands repair cells

New vessels

VEGF and FGF-2 support angiogenesis

Epithelial restitution

EGF-family signals and FGF-7 aid surface repair

Matrix deposition

TGF-β drives ECM synthesis and retention

Inflammation resolution

TGF-β restrains inflammatory activity

Slide 67 · Angiogenesis and fibrosis are not synonyms

Integration

Repair component

Predominant signal

Pathologic excess

Vessel sprouting

VEGF; Also FGF-2

Tumor vascularization or pathologic ocular vessels

Fibroblast recruitment

PDGF

Excess stromal-cell activity

Matrix accumulation

TGF-β

Organ fibrosis and impaired function

Slide 68 · The oncogenic problem can be receptor-level

Integration

Altered pathway gene

Mutation / amplification

Persistent signal

Growth program stays active

Unrestricted proliferation

Therapeutic target

When alteration is actionable

EGFR, HER2 and MET illustrate clinically relevant pathway dysregulation.

Slide 69 · Clinical application: Altered MET signaling

Application

A lung carcinoma is found to harbor an activating alteration in the MET signaling system.

Question

What is the receptor-level therapeutic rationale?

Teaching answer

MET is an HGF-responsive receptor tyrosine kinase. Selected MET-altered cancers may be susceptible to MET-directed inhibition; Eligibility depends on the actual alteration.

Slide 70 · Clinical application: Vascular-endothelial dysfunction

Application

A pregnant patient develops hypertension and proteinuria. Increased circulating soluble VEGFR-1 is proposed as a contributing factor.

Question

How can soluble VEGFR-1 contribute?

Teaching answer

Soluble VEGFR-1 can sequester free VEGF, reducing signaling that helps maintain normal endothelial function; This is one proposed mechanism of preeclampsia.

Slide 71 · Four high-yield pathway associations

Synthesis

1

EGFR / HER2

Proliferative signaling and cancer-associated receptor abnormalities

2

HGF / MET

Epithelial motility and oncogenic kinase signaling

3

VEGF / VEGFR-2

Endothelial sprouting, permeability and angiogenesis

4

TGF-β / Smads

Matrix production, fibrosis and immunoregulation

Slide 72 · Knowledge check: Identify the signal

Synthesis

Clinical or experimental observation

Likely pathway

Abnormal endothelial sprouting after hypoxia

HIF-1 → VEGF → VEGFR-2

Fibroblast chemotaxis at wound margin

PDGF → PDGFR

Matrix deposition with decreased degradation

TGF-β → Smads / MMP–TIMP effects

Motogenic response in epithelial cells

HGF → MET

Slide 73 · Principal reference and content boundaries

Reference

1

Primary textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026). Chapter 1, “Growth Factors and Receptors,” pp. 18–20.

2

Context

The preceding “Signal Transduction Pathways” section (pp. 16–17) supplies receptor-kinase background.

3

Visual source

Diagrams are originally authored schematic PowerPoint objects, not reproduced textbook figures.

4

Clinical scope

Therapeutic examples are mechanistic teaching context from the supplied source, not treatment protocols.