Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

504 Liver Cancer, molecular biology
B virus (HBV) or ! hepatitis C virus (HCV). Other
major risk factors include alcoholic cirrhosis,
dietary intake of aflatoxin B1, a fungal metabolite
that contaminates crops in some tropical
areas, and inherited metabolic disorders such
as tyrosinemia, hemochromatosis, and a1-antitrypsine
deficiency. Increased risk of HCC development
is associated with combined infections
with HBV and HCV, with aflatoxin intake
in chronic HBV carriers, and with alcohol abuse
in HCV infected patients.
Role of viral factors
Chronic HBV infection plays a complex role in
liver carcinogenesis, involving both direct and
indirect mechanisms.
Direct mutagenic role
HBV DNA frequently integrates into host
cell chromosomes. HBV integrations seem to
occur randomly over the entire human genome,
with no preferential site. Viral DNA integration
is frequently associated to gross genetic alterations
such as chromosomal translocations, deletions
or amplifications of large chromosomal
regions. Therefore, integration of HBV DNA
may promote genomic destabilization, in
turn favoring the accumulation of genetic mutations
at early steps of HCC development. In
occasional cases, viral integration has been
shown to induce insertional mutagenesis of cellular
genes. In four independent HCC cases,
viral DNA integration sites have been identified
within cellular genes that play important roles
in the control of cellular growth, differentiation
or viability: retinoic receptor-beta, cyclin A2,
mevalonate kinase and SercA1 genes. These tumors
produce viro-cellular chimeric proteins
endowed with transforming capacities. The recent
development of PCR-based technologies
for rapid isolation of viral integration sites
will probably allow a better evaluation of the
exact prevalence of such oncogenic insertional
events in a near future. Another argument favoring
a direct tumorigenic role of HBV comes
from studies of animal models for virally-induced
liver cancer. Woodchucks chronically infected
with the woodchuck hepatitis virus
(WHV), an hepadnavirus closely related to
HBV, develop frequent and early onset HCC,
while uninfected animals rarely show any neoplasm.
WHV DNA is found integrated in the
vicinity of an oncogene of the MYC family
(either ! MYC or ! MYCN) in more than 80%
of woodchuck liver tumors. ! MYC genes act
as important regulators of cell growth, death
and differentiation, and their abnormal expression
has been implicated in the genesis of multiple
human neoplasms. Integration of WHV
DNA induces aberrant overexpression of the
targeted MYC oncogene, which in turn initiates
the malignant process. The strong oncogenic
impact of these mutagenic insertions has
been demonstrated in transgenic mice recapitulating
the multistep process of liver carcinogenesis.
Oncogenic potential of the HBX transactivator
The HBV regulatory protein X (HBX) has
pleiotropic functions and it can interfere with
multiple cellular pathways controlling cell cycle,
proliferation, DNA repair and apoptosis.
In transgenic mouse strains, liver expression
of HBX can either induce liver cancer or act
as a co-factor and a tumor promoter in liver
carcinogenesis.
Immunopathogenesis
There is a general consensus that hepatocellular
damage in human hepatitis B is caused by
the host immune response and not by the virus
itself. Evidence for an indirect role of HBV in
cancer formation has been provided by transgenic
mouse models. Sustained viral replication
and expression of most viral genes in the liver
can be achieved in HBV transgenic mice with
no pathological consequence. However, sustained
expression of the large envelope protein
of HBV in the mouse liver induces a process of
necrosis and regeneration that ultimately leads
to malignant transformation. Moreover,
chronic hepatitis induced by the cellular immune
responses against the HBV surface antigen
(HBsAg) has been associated with frequent
emergence of liver tumors. Thus, a potentially
important factor in tumorigenesis is the accelerated
turnover of infected hepatocytes, which
results from continuous cell death triggered by
the host immune response ad subsequent cell