An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a worldwide malignancy and the third leading causes
of cancer-related deaths 1],2]. The incidence of primary liver cancer is increasing in several developed countries
and the increase will likely continue for some decades as a result of viral infection
of hepatitis C 3],4]. Liver transplant and surgery are considered the potential effective curative treatment
for HCC, although most patients have a poor prognosis due to unresectable disease
at presentation, multidrug resistance (MDR) 5] and tumor recurrence. In most cases, this pathology develops in patients with chronic
liver disease (70-90% of all patients) 6]. In order to bypass these problems, several regional cancer therapy and multimodality
treatments, have been developed 7],8]. Additionally, to improve the treatment outcome of patients diagnosed with HCC, several
in vivo studies by using different techniques on HCC mouse models have been performed. This
review will focus on the latest papers on the efficacy of loco-regional therapy and
combined treatments in patients and mouse models of hepatocellular carcinoma.
Loco-regional treatments in patients with hepatocellular carcinoma
Loco-regional therapies, including image-guided tumor ablation, percutaneous ethanol
injection (PEI), transcatheterial chemoembolization (TACE) and transarterial radioembolization
(TARE) are commonly used as a nonsurgical approach for HCC patients 9]-11]. For patients with early-stage unresectable HCC, image-guided tumor ablation (chemical
or thermal) is recommended. Chemical ablation is used for treatment of nodular-type
HCC and it is based on PEI which leads to tumor necrosis. One limit of PEI is represented
by tumor recurrence in HCC patients as well as needs of multiple sessions 12],13]. Acetic acid injection is considered an alternative to PEI for chemical ablation
of HCC, although it is not commonly used due to lower survival outcomes of patients
14]. Among thermal ablative therapies used in clinical practice, radiofrequency ablation
(RFA) which induces thermal injury to the cancer tissue through electromagnetic energy
deposition, is considered as the standard treatment for local ablation of HCC due
to its anticancer effects and survival benefit for patients 6],15]-22]; . On the contrary, several clinical studies have demonstrated that radiofrequency
ablation for HCC increased risk of local tumor progression and incomplete ablation
23]-26]. To bypass these problems, novel thermal techniques (microwave ablation; MWA, laser
ablation and cryoablation) 27]-29] and non-thermal techniques (reversible electroporation ECT, irreversible electroporation
IRE and light-activated drug therapy), for HCC tumor ablation have been developed.
Clinical studies show that non-thermal techniques seem to overcome the limitations
of chemical and thermal-based techniques in the treatment of HCC 30],31]. Another approach used to noninvasive multinodular HCC tumors at the intermediate
stage, is TACE, which belongs to image-guided transcatheter tumor therapy. This technique
is based on an intra-arterial infusion of a drug (mainly cisplatin or doxorubicin)
with or without a viscous emulsion, followed by embolization of the blood vessel with
embolic agents that leads to ischemia and cytotoxic effects or liver internal radiation
using yttrium-90 (90Y) spheres. There are two types of TACE; the first one is called conventional TACE
that consists in the administration of an anticancer in lipiodol emulsion followed
by embolic agents 16],24],25],32]; and the second one, is called TACE with drug-eluting beads that uses embolic microspheres
that release the drug in the sustained-released system 33],34]. Several studies have demonstrated that TACE with drug-eluting beads significantly
increases efficacy and safety for patients respect to conventional TACE 35],36]. A new technique that can be considered a potential treatment for patients with HCC
alternative to TACE, is TARE. This approach consists in the infusion of radioactive
substances including microsphere containing yittrium-90 (90Y) or similar agents, into hepatic artery 37]-39]. By using this technique, these microspheres will be delivered to the area which
surrounds the tumor, with low-penetration to the tumor itself. Several clinical studies
have demonstrated that radioembolization treatment with 90Y can be safely used in patients with HCC 40],41], although this technique leads to several possible side-effects (gastric ulceration,
pancreatitis, radiation pneumonitis, etc.). Further investigations will be necessary
in the setting of randomized controlled trials (RCT). It is important to underline
that any loco-regional treatment described above, summarized in Table 1, leads to a high rate of tumor recurrence in patients. For this reason, new combined
treatments for HCC have been developed. These combined strategies are focused on the
synergy between molecular targeted drugs (i.e. sorafenib, etc.) and loco-regional
treatments 42]-46]. Clinical trials on these new techniques are currently ongoing and can be used as
therapy of election for patients with HCC.
Table 1. Effects of Loco-regional treatment on patients with hepatocellular carcinoma
The efficacy of Loco-regional treatment in mouse models of hepatocellular carcinoma
Loco-regional therapies are considered the best treatments in patients with unresectable
HCC. One of the principal obstacles implicated in their unsuccessful therapy is MDR.
In order to improve the treatment outcome of patients diagnosed with HCC, several
in vivo studies by using loco-regional techniques and combined treatments on HCC mouse models
have been performed. The first study that tested an effective strategy for the treatment
of HCC with MDR, demonstrated that chemicals in combination with adriamycin (ADM),
mitomycin, 5-fluoruracil (5-FU), mutant human tumor necrosis factor-? (rmhTNF-?) and
hydroxyapatite nanoparticles (nHAPs), could be beneficial for the local treatment
of advanced HCC in vitro and in vivo experimental conditions. Specifically, it has been showed that the chemicals acted
in synergism with rmhTNF-? and nHAP in suppressing the growth of human hepatoma MDR
liver hepatocellular (HepG2)/ADM cells by inducing apoptosis and by reducing tumor
growth in liver hepatocellular mouse model 52]. Another group demonstrated that Glypican-3 (GPC3), a carcinoembryonic antigen, could
be considered as an ideal target for anticancer immunotherapy against HCC. In this
study, the authors compared the induction of the GPC3-specific T-cell-mediated immune
response after loco regional therapies, such as RFA or TACE in HCC patients and tumor-bearing
mice 53],54]. Recently has been developed a new bioelectrical technology in cancer therapy, the
nanosecond pulsed electric field (nsPEF). NsPEF can generate pulsed high voltage electric
field in ultra-short nanosecond duration, to produce immediate power which could ablate
targeted tumor 54]. It has been reported that nsPEF treatment, is efficient to control hepatocellular
carcinoma growth in HCC mouse model. In this study, was investigated the use of nsPEF
on a human HCC cell lines and a high pulmonary metastatic potential HCC xenograft
mouse model (HCCLM3). The multiple fractionated dose of nsPEFs efficiently inhibited
tumors without increasing the risk of secondary metastasis, indicating that nsPEF
can be used as a loco-regional therapy for hepatocellular carcinoma 55]. Recently it has been demonstrated that targeted gold nanoconjugates in combination
with RF halted the growth of subcutaneous human hepatoma (Hep3B) xenografts. These
xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation
compared to controls 56]. Taken together all these different data, summarized in Table 2, suggest that these combined treatments could represent new methods to deliver effective
and safe therapies to patients with advanced HCC.
Table 2. Effects of Loco-regional treatment on tumor growth in mouse models of hepatocellular
carcinoma