Primary liver cancer, cancer emanating
in the liver, is the sixth most diagnosed cancer 1. Furthermore hepatocellular carcinoma (HCC), a primary liver
malignancy, was reported to be the third cause of cancer-related deaths in 2012.
However, HCC incidence and
mortality rates vary vastly 2. The
dominant risk factors for HCC is cirrhosis due to chronic hepatitis B or
hepatitis C. Other risk factors include, but are not limited to age, having
a body mass index higher than thirty, diabetes mellitus and related
non-alcoholic fatty liver disease 3. Like many cancers, the best approach to treating
HCC is its prevention.
However, if cancer does develop, HCC is known to
be a highly vascularized cancer. The process of developing new blood vessels
from pre-existing vessels known as angiogenesis is thought to contribute to
HCC’s development and progression. It
is now thought that VEGF ( vascular endothelial growth factor) can be used in diagnosing
and monitoring patients with HCC ( 4.
There are a total of nine proteins in the
immediate VEGF family 5. VEGFs are highly conserved in all vertebrate
species; for example, VEGF-A has been identified in zebrafish, frogs, birds,
and mammals 6. The highly conserved protein among a variety of
species suggests an important role in biological processes.
Furthermore, VEGF and its receptors are known for
their vital role as regulators of angiogenesis and their involvement in vascular
permeability. Currently, nine family proteins have been identified, but
due to alternative splicing many isoforms exist; for example VEGF-A undergoes
alternative splicing leading to nine different subtypes. Interestingly, it is
thought that each different VEGF isoform plays a distinct role in vascular and
arterial development. For example, VEGF-A has been shown to interact with VEGFR-1
and VEGFR-2; VEGF-1 is characterized more so in pathological conditions such as
cancer, ischaemia and inflammation while VEGFR-2 is involved in endothelial
growth and survival signals, but both acting as tyrosine kinase receptors 7.
VEGF family members transduce their signal
intracellularly via a membrane-bound tyrosine kinase receptor. VEGF-A and B preferably bind to VEGFR-1;
VEGF-A, VEGF-C, D and E have an ability to bind VEGFR-2; VEGF-C and D binds to
VEGFR-3 8. The activation of VEGF receptors is essential
Many of the VEGF family members are regulated by
hypoxia inducible factor ( HIF) 9; hypoxia triggers expression of many growth
factors including VEGF and other angiogenetic factors. In liver cancer,
HIF-1? is highly expressed and this high
expression is significantly higher than normal liver tissues 6. Other metabolic regulators and transcription
factors include E-twenty-six growth factor and reactive oxygen species which
regulate the expression of VEGF family of ligands and its receptors (10,11).
growth factor ( PDGF) is a key area of research in cancer development and
progression. The over activity of PDGF receptor
signaling may increase tumor growth. In the progression of HCC in combination
with epithelial-mesenchymal transition, levels of PDGF-A, PDGFR? and ? are increased (12.
First, it is important to understand
PDGF normal structure and function. PDGF is a dimeric molecule that has disulfide
bonded A and B polypeptide chains. The
chains can homo and heterodimerize. Their cellular effects are mediated by
binding to tyrosine kinase receptors known as the alpha-receptor (PDGFR?) and
the beta-receptor (PDGFR ?) 13. The
family isoforms are known to stimulate growth, survival and motility in many
cell types and play a role in adult tissue homeostasis 13.
PDGF signaling is evident in
epithelial cancers; this causes stromal recruitment which may be involved in
epithelial- mesenchymal transition. As a result, increasing tumor growth, angiogenesis, invasion, and
VEGF and HCC
Meta-analysis, conducted by Zhan et al., studied
the relationship between VEGF levels and the prognostic significance in
patients with HCC. It was concluded that high levels of VEGF correlated with
poor overall survival in HCC patients 15. Using an enzyme immunoassay, Plasma VEGF levels
in stage I, II, III, IVA, and IVB HCC patients were measured as 27.6 +/- 16.1,
26.5 +/- 13.7, 35.8 +/- 15.3, 45.4 +/- 39.4, and 103.1 +/- 123.2 pg/ml 16. Interestingly, Jinno et. al findings suggest advanced
metastasis in patients with HCC showed significantly higher levels of VEGF
compared to patients at earlier stages.
In another study, VEGF-A and its receptor
VEGFR-1, had significant higher levels in patients with HCC compared to
Lenvantinib targets VEGFR, FGFR, PDGFR- ?, RET, and KIT 27. A recent 2017 study investigated
sorafenib versus lenvatinib as the first recommended therapy for unresectable
HCC. The study concluded that levatinib showed noninferiority
in overall patient survival and had improvements in secondary endpoints:
progression-free survival, time to progression, and objective response rates 27. Sorafenib being the only
approved drug treatment for HCC patients needs to change. As trials continue
with Levantinib and other potential treatments, hopefully the prognosis
improves for patients with HCC.
Relatively new imaging equipment and
ablation (RFA) instruments has changed treatments available. RFA is now a
potential alternative to surgical resection for patients with HCC. RFA has many
benefits including: minimally invasive, ease of operating, and the procedure is
repeatable. It also has been seen to increase immunity and reduce the levels of
VEGF in serum 28.
cancer to thrive, it needs to create its own blood supply. This process of
angiogenesis and the expression of VEGF is critical for tumor development.
There has been a plethora of evidence showing that high serum levels of VEGF
and PDGF, especially the ligands and receptors overexpressed in HCC, are highly
characterized and present. We conclude that these still remain important
targets for future treatments in patients with HCC. As lenvantinib
trials continue, drugs continue to be developed, and other treatment utilized,
hopefully HCC will no longer be one of the leading causes of cancer-related deaths.