EPIDEMIOLOGY OF HCC

Generally, HCC results from a series of liver insults either acute or sub-acute which progress slowly into fibrosis and subsequent cirrhosis. Less commonly, HCC develops without previous liver cirrhosis. In the cirrhotic liver, HCC is the end result of a progressive hepatic carcinogenesis sequence, beginning with regenerative nodules, dysplastic nodules and final evolution into HCC.⁴ Most of the patients with HCC have an associated history of viral hepatitis infection. HBV and Hepatitis C virus (HCV) account for 50% and 25% of all cases of HCC, respectively.⁵ Obesity and diabetes mellitus have also been associated with an increased risk of HCC due to the development of non-alcoholic steatohepatitis (NASH).⁶ Chronic alcohol consumption can be synergistic with hepatitis in the development of HCC.⁷ Chronic aflatoxin exposure is another risk factor for HCC but this is less common in the USA, mostly occurring in Asia and Africa.⁸

PATHOPHYSIOLOGY OF ANGIOGENESIS IN HCC

Angiogenesis refers to the expansion and remodeling of the primary embryonic vascular network. This occurs physiologically in adults during the menstrual cycle and during processes such as wound healing. Understanding the pathophysiology of angiogenesis is critical in the management of patients with HCC. Under non-pathological conditions, angiogenesis is a highly ordered and tightly regulated process with complex but balanced interactions between pro-angiogenic and anti-angiogenic factors. These factors can be divided into secreted factors and membrane bound factors.⁹ Secreted factors include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietins (Ang), and platelet-derived growth factors (PDGF). Membrane bound factors include neuropilin receptors (NRP). Uncontrolled angiogenesis can be seen in the setting of solid tumors and diabetic retinopathy.¹⁰

Tumor-induced angiogenesis is mediated by two essential factors, over-expression of angiogenic factors, as well as inhibition of anti-angiogenic factors, resulting in increased tumor vascular burden with abnormal blood vessels which lack normal vascular structure with deficient pericytes, smooth muscle cells, and intact basement membrane.¹¹

Knowledge of the particular effect of angiogenic factors has been important in the development of the pharmaceutical/therapeutic options in managing uncontrolled angiogenesis such as that found in tumors. These factors may be used either via stimulation or inhibition of angiogenesis to have a direct effect on cancer treatment.¹²

Vascular Endothelial Growth Factor (VEGF)

VEGF, the most well-known angiogenic factor, is a secreted factor and a key regulator.¹³ VEGF is normally expressed in the human body at low levels but has high expression in tumors. It was found that about 91% of advanced HCCs show elevated VEGF expression, relative to normal conditions.^14,15 VEGF-A is the isoform responsible for angiogenesis and vascular remodeling, it binds to tyrosine kinase-related receptors (VEGFR).¹⁶ There are at least 3 known members of these receptors: VEGFR-1, VEGFR-2, and VEGFR-3. VEFGR 1 and 2 are considered the most important receptors in angiogenesis. The levels of VEGFR-2 have been correlated with a worse outcome in HCC.^17,18 Binding of VEGF with its receptor stimulates a transduction signal that leads to proliferation and migration of endothelial cells (EC), as well as induction of angiogenesis.^19,20 Bevacizumab is an example of a VEGF-A antibody which has been widely used in brain and colorectal cancers, among others.²¹

Fibroblast Growth Factor (FGF)

FGFs are a family of growth factors containing several members which interact with tyrosine kinase receptors (FGF receptors (FGFR) 1 through 4).²² FGFs and its receptors have numerous functions including differentiation as well as maintenance of neovascularization initiated by VEGF.²³ This is mediated by the enzyme Heparanase which induces angiogenesis, new vessel formation and stimulation of endothelial cell invasion to induce distant metastasis.^23,24

FGFRs are normally expressed in adult cells with FGFRs 3 and 4 being the most commonly expressed by normal hepatocytes.²⁵ Clinical studies demonstrate the importance of FGF subtype-19 (FGF19) in tumor-induced angiogenesis, where it was shown that FGF19/FGFR4 complex was overexpressed in adult HCC.²⁶ In addition, administration of FGF19 neutralizing antibodies prevents HCC development in mice.²⁷

A recent pre-clinical study showed that the FGF signaling pathway maintains survival of murine HCC after angiogenesis inhibition, confirming the integral role of FGR/FGFR in HCC induced angiogenesis. Furthermore, it suggested the need of dual inhibition of VEGF and FGF axes to enhance cancer cell death.²⁸

Angiopoietins and Tie Receptors

Angiopoietins (Ang) are secreted proteins that play an important role in HCC. These proteins interact with Tie receptors, which are membrane bound tyrosine kinase receptors. The Ang/Tie complex enhances vascular stability and induces apoptosis and cellular matrix destabilization in the absence of VEGF.^29,30 Over-expression of Ang-2, relative to Ang-1, is found to be correlated with HCC. It was hypothesized that the role of Ang/Tie complex in the development of HCC is much more important than the VEGF system, which makes HCC a suitable neoplasm for anti-angiogenic therapy.³¹

Platelet-Derived Growth Factor (PDGF)

PDGFs are secreted growth factors closely related to VEGF³² and are important in HCC-induced angiogenesis. PDGF binds to tyrosine kinase receptors; PDGF receptors (PDGFR) α and β.³³ Binding of the growth factors with their corresponding receptors leads to activation of signaling cascade which leads to upregulation of VEGF and recruitment of perivascular cells.³⁴ The role of the PDGF/PDGFR complex in angiogenesis was found to contribute to tumor development, along with its autocrine role in the stimulation of cancer cells.³⁵ Overexpression of PDGF-C and B subtypes was found to correlate with liver fibrosis and progression of dysplastic nodules to HCC in mice models.^36,37

Neuropilin Receptors (NRP)

The two homologs of NRP family (namely NRP-1 and NRP-2) each has a different action and role.³⁸ In the liver, NRP-1 receptors are expressed in veins and capillaries and bind with VEGF to act as co-receptors for VEGF.^39–41 Hepatic NRP-1 was found to bind hepatocytes growth factor (HGF) which has potent angiogenic activity for hepatocytes.⁴² NRP-1 co-localizes with PDGF receptor-β, resulting in tumoral spread.⁴³

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