The HGF/SF Ligand and MET Receptor Pathway in Cancer

The HGF/SF
HGF/SF Ligand and MET Receptor MET

Pathway in Cancer

Overview: The HGF/SF:MET Pathway Mediates Critical
Functions in Tumorigenesis and Metastasis and Represents
a Potential Therapeutic Target in Cancer

Hepatocyte growth factor/scatter factor (HGF/SF) is the only known ligand
for MET, a receptor tyrosine kinase (RTK).1,2 HGF/SF and MET are widely
expressed in embryonic and adult tissues where the pathway regulates a
variety of cellular functions.3 These functions include proliferation and sur-
vival, as well as motility and epithelial cell polarity.1,3 The HGF/SF:MET
pathway is also necessary for tissue repair and regeneration.3

Dysregulation of HGF/SF:MET signaling is involved in tumor development
and invasiveness.1,4 Clinical evidence has demonstrated that elevated levels
of HGF/SF or MET can correlate with poor prognosis or factors that may
lead to poor outcomes such as increased tumor size and stage, depth of
tumor invasion, and the presence of metastases.5,6 This association exists
in a variety of human cancer types including breast, colon, gastric, liver,
lung, ovary, prostate, and renal cancers, as well as in melanomas and
glioblastomas.6,7 Furthermore, activating mutations of MET play a causal
role in hereditary papillary renal cancer and possibly other cancers as
well. Thus, the HGF/SF:MET signaling pathway represents a potential
target for anticancer therapeutics.3,4

HGF/SF

MET

MET RTK Is Activated by Binding of HGF/SF

MET is a transmembrane RTK.1 The MET protein is a disulfide-
linked heterodimer of a 50-kDa extracellular α-chain and a 140-
kDa β-chain.1,4 The α-chain and part of the β-chain are essential
for ligand binding, while the cytoplasmic portion of the β-chain
contains the kinase domain and a C-terminal tail to facilitate
downstream signaling.1,4

HGF/SF is a large, multidomain protein that is the only known ligand
for MET.2 It is synthesized as a single-chain, inactive precursor that is
cleaved into the active, 2-chain heterodimer by proteolysis.1,2

Ligand binding of the secreted growth factor HGF/SF to MET induces
receptor dimerization and subsequent activation of the intrinsic
kinase domain by autophosphorylation, which subsequently
phosphorylates the tyrosines of the C-terminal substrate binding
site.1,4 Activation of the HGF/SF:MET pathway induces multiple
physiologic processes.3,5

HGF/SF
MET

HGF/SF:MET Activation Triggers Intracellular Signaling
Cascades, Resulting in Cell Proliferation, Survival,
and/or Motility

Binding of the high-affinity extracellular ligand HGF/SF activates
MET. Ligand binding triggers dimerization of 2 MET receptors,
which brings the intracellular kinase domains into close contact,
allowing for auto cross-phosphorylation.2,6 The phosphorylation
events alter the MET protein structure conformation to create a
binding site for the scaffolding adaptor protein Gab1, Grb2, PLC,
or other mediator proteins.1,4,8

Depending on the cell environment and situation, Gab1 recruitment
leads to activation of downstream signaling molecules and diverse
effects on the cell.1,2,4 These events include signaling through: (1)
Shp2 to activate ERK/MAPK, resulting in increased activation and
production of proteins needed for cell cycle progression and cell
proliferation1,6; (2) PI3K, leading to activation of Akt, which promotes
cell survival by inhibiting apoptosis and increasing protein synthesis
needed for cell survival1,6,8,9; (3) Rac1 and cdc42 small GTPases, leading
to alterations in the cytoskeleton that affect cell adhesion, motility,
and polarity.4 Activation of these signaling pathways is commonly
associated with cancer cell growth, invasion, and metastasis.1

HGF/SF
MET

PIP3 PIP2 Gab1 Shp2 Ras
Akt cdc42 Raf
PI3K Gab1 MEK
Rac1
ERK/MAPK

SURVIVAL PAK PROLIFERATION
POLARITY
MOTILITY

HGF/SF:MET Signaling Promotes Oncogenesis

The HGF/SF:MET pathway contributes to the oncogenesis of multiple
tumor types through several mechanisms, including high MET
expression, MET amplification, MET mutations, and HGF/SF-dependent
autocrine and paracrine signaling loops.1,2,4,6 In order for tumors to
grow and rapidly increase in size, tumor cell division must outpace
cell death. HGF/SF:MET signaling promotes both cell division (by
stimulating cell cycle progression) and evasion of apoptosis (by
stimulating cell survival).6,10 Tumor progression and metastatic spread
require loss of normal cell adhesion and polarity and the acquisition
of motile properties.1 HGF/SF:MET signaling stimulates cancer cells to
lose their normal attachments and disrupt tissue organization in order
to escape the primary tumor mass and invade blood and lymphatic
vessels, adjacent tissues, and distant organ sites.1,2,6

Thus, the HGF/SF:MET pathway may be a rational target for anti-
cancer therapies.

HGF/SF
MET

Increase
Proliferation

Disorganized Motile Decrease
Tumor Cells Apoptosis

Multiple Levels of HGF/SF:MET Mutation or Dysregulation
Can Occur in Cancer

In a variety of tumor types, MET expression is commonly elevated and
expression of HGF/SF and/or MET can correlate with poor prognosis or
factors that may lead to poor outcomes such as increased tumor size and
stage, depth of tumor invasion, and the presence of lymph node metastases.
This association had been found in breast, colon, gastric, liver, lung, ovary,
prostate, and renal cancers, as well as in melanomas and glioblastomas.6,7

Genetic mutations or nongenetic events can contribute to increased or
aberrant expression of HGF/SF and MET, which can alter the biological
response of pathway signaling depending on the levels of HGF/SF and
MET.4,6,7 Tumor cells frequently evade the stringent regulatory controls
that keep HGF/SF and MET proteins at physiologic levels in normal cells.3-5

Preclinical studies indicate that there is a complex interdependence
between the HGF/SF:MET and epidermal growth factor receptor (EGFR)
pathways and between the HGF/SF:MET and vascular endothelial growth
factor (VEGF) pathways.11-13 EGFR pathway inhibitor–resistant tumors have
more frequent MET gene amplification, suggesting that HGF/SF:MET signal-
ing may be involved in resistance to this class of targeted therapies.6,7

HGF/SF:MET Pathway Deregulation3-6,14

Site of Pathway GENETIC Result
Deregulation Event Elevated MET

MET gene Amplification3 levels

Activating Constitutively
mutation3,4,6 active MET

HGF/SF gene HGF/SF promoter Elevated HGF/SF
mutation14 levels
Site of Pathway
Deregulation ALTERED REGULATION Result
Event Elevated MET
MET protein
High expression levels
of MET4-6

HGF/SF protein High expression Elevated HGF/SF
of HGF/SF5,6 levels

Aberrant paracrine Elevated pathway
or autocrine activity

HGF production3

Summary: Targeting the HGF/SF:MET Pathway in Cancer

The HGF/SF:MET pathway mediates critical functions in tumorigenesis
and metastasis.3-6 Ligand binding of HGF/SF to MET induces receptor
dimerization and activation that triggers intracellular signaling
cascades, resulting in cell proliferation, survival, and/or motility.1,3-5
HGF/SF:MET signaling promotes oncogenesis through several mechanisms,
and thus may represent a rational target for anticancer therapies.3,4

HGF/SF
MET

References

1. Birchmeier C, et al. Nat Rev Mol Cell Biol.
2003;4:915-925.

2. Sattler M, et al. Curr Oncol Rep. 2007;9:102-108.
3. Cecchi F, et al. Eur J Cancer. 2010;46:1260-1270.
4. Ma PC, et al. Cancer Metastasis Rev. 2003;22:309-325.
5. Dussault I, et al. Drugs Future. 2006;31:819-825.
6. Eder JP, et al. Clin Cancer Res. 2009;15:2207-2214.
7. Hanna JA, et al. Adv Cancer Res. 2009;103:1-23.
8. Gu H, et al. Trends Cell Biol. 2003;13:122-130.
9. Mitsiades CS, et al. Curr Cancer Drug Targets.

2004;4:235-256.
10. Hanahan D, et al. Cell. 2000;100:57-70.
11. Jo M, et al. J Biol Chem. 2000;275:8806-8811.
12. Gherardi E, et al. Nat Rev Cancer. 2012;12:89-103.
13. Sulpice E, et al. Biol Cell. 2009;101:525-539.
14. Ma J, et al. J Clin Invest. 2009;119:478-491.

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