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
controls (p < 0.001). In addition, there was no significant difference in serum levels of VEGF-C and its receptor VEGFR-2 17 . These findings support that different VEGF members have different biological roles and may help in targeting therapies to specific ligands and their receptors mediating their effects. This targeting of VEGF-A and VEGFR-1 may prove to be beneficial. PDGF and HCC: In a study of whole-cell lysates from HCC tissues, the majority of HCC tissues had a 7-fold increase in total PDGFR? levels compared to controls. Higher levels in PDGFR? were only characterized in 6 of 22 tumors, but were higher in samples associated with cirrhosis 18. PDGFR? is essential in the development in several tissues, proliferation, morphogenesis, angiogenesis, and epithelial-mesenchymal interactions 19. It has been previously established that PDGFR? is associated with tumor cell proliferation, progression, and angiogenesis. Using an in vivo assay using hepatoma cells, overexpression of PDGFR? led to high tumorigenic potential; these samples also included increased microvessel density compared to the controls 20. When injury occurs or vascular damage presents, thrombosis occurs. Platelets become activated, adhered to the injured area, aggregate together and secrete platelet granules. These granules can contain several factors including both VEGF and PDGF (and others). Since both these molecules are elevated in HCC patients, it suggests that platelets may play a significant role in tumor development and metastasis 21. The role of platelets and their granules have been investigated and characterized in many types of cancer. Furthermore, targeting VEGF and PDFG and their respective receptors may be useful in treating patients with HCC and better patient prognosis. Current Treatments for HCC: The process of angiogenesis is essential for cancer development and its metastasis. Since VEGF is critical for angiogenesis to occur, VEGF-targeted agents have already been developed as potential treatments for patients with HCC. One agent developed for cancer treatment use was Sorafenib. Sorafenib is an orally active multikinase inhibitor. The function of the drug is to block many important cellular factors involved in tumor-cell proliferation, angiogenesis, and has been found to increase the rate of apoptosis 22. Sorafenib inhibits the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activities of VEGFR-1,2,3 and PDGFR- ? 22, 23. Utilizing mouse xenografts, it has been shown that administering sorafenib reduces angiogenesis and increases cancerous cell apoptosis 24. Furthermore, in a phase III trial called Sorafenib Hepatocarcinoma Assessment Randomized Protocol (SHARP; ClinicalTrials.gov number, NCT00105443) ,the use of sorafenib increased median survival and the time to progression by 3 months in patients with HCC 25. In fact, as of 2017 Sorafenib is currently the sole systemic agent approved in the United States for the treatment of HCC. As with all treatments, there are downsides. Not only is the drug costly, it has been shown to have considerable drug-related symptoms for little benefit 26. Also some patients exhibit resistance or intolerance to sorafenib. Another drug, Lenvatinib, is a different, buy similar multikinase inhibitor.
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.