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Chapter 2
Biology of Hepatocellular Carcinoma
Maria Luisa Balmer and Jean-François Dufour
Keywords Angiogenesis · Apoptosis · HCC · Metastasis · miRNA · Oncogene ·
Stem cells · Telomeres
From Genotype to Phenotype – Or What a Cell Needs
to Become a Cancer Cell
Being a cancer cell is not easy. You have to maintain DNA replication and protein
production under adverse conditions in the abnormal architecture of a tumour which
often deprives you of oxygen and nutrients. Thus, survival requires a complete kit
of stress response tools that you have to acquire before becoming a cancer cell.
From a more scientific point of view, we can see tumorigenesis as fast-track
evolution in miniature edition where genetic alterations drive the progressive trans-
formation of normal human cells into highly malignant derivates that seem to be
advantageous to their normal counterparts. Investigations have been conducted at

different molecular levels including DNA level, RNA level and protein level, with
regard to chromosomal imbalance and genetic instability, epigenetic alteration,
gene expression and gene regulation and translation [1]. Whatever the level, can-
cer cells need to acquire a combination of properties which typify their malignant
phenotype in the end (Fig. 2.1). Six essential alterations in cell physiology that col-
lectively dictate malignant growth have been proposed: self-sufficiency in growth
signals, insensitivity to growth inhibition (antigrowth), evasion of programmed cell
death (apoptosis), limitless replicative potential, sustained angiogenesis and tissue
invasion and metastasis [2].
In this chapter we briefly discuss these six properties as they are common in most
cancers, including HCC.
J F. Dufour (B)
Department of Clinical Pharmacology and Visceral Research, University of Bern, Bern,
Switzerland
21
K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma,
DOI 10.1007/978-1-60327-522-4_2,
C

Springer Science+Business Media, LLC 2011
22 M.L. Balmer and J F. Dufour
Fig. 2.1 The long and winding road to cancer
Growth signals are essential to move a cell from its quiescent state into an active
proliferative state. Cancer cells generate many of their own growth signals, thereby
reducing their dependence on stimulation from their normal tissue environment.
This can happen by synthesis of their own growth signals (autocrine stimula-
tion), growth factor receptor overexpression, ligand-independent signalling through
structural alteration of receptors and alterations in components of the downstream
cytoplasmic circuitry that receives and processes the signals emitted by ligand-
activated growth factor receptors and integrins. Tumour development is not only

the result of selection of a genetically mutated population of cells with advanta-
geous capabilities but rather the result of a tiny communication between the altered
cancer cell and its unaltered neighbours such as fibroblasts, endothelial cells and
inflammatory cells which maintain tumour growth.
Within a normal tissue, multiple antiproliferative signals operate to maintain cel-
lular quiescence and tissue homeostasis. These growth-inhibitory signals, like their
positive counterparts, are received by transmembrane surface receptors coupled to
intracellular signalling circuits. At the molecular level, many antiproliferative sig-
nals are funnelled through the retinoblastoma protein (pRb) and its two relatives,
p107 and p130, which block proliferation by inhibiting progression from G1- into
S-phase of the cell cycle [3]. The pRb signalling circuit, as governed by TGFβ
and other extrinsic factors, can be disrupted in a variety of ways: some cancer
cells display mutant, dysfunctional receptors while others lose TGFβ responsiveness
through downregulation of their TGFβ receptor.
Apoptosis represents a physiological way to eliminate excess cells during both
development and regeneration. Apoptosis can be triggered by an extrinsic pathway
(death receptor associated) as well as an intrinsic pathway (mitochondria pathway),
both of which might be inactivated during tumour development. Resistance to apop-
tosis can be acquired by cancer cells through a variety of strategies. Surely, the most
commonly occurring loss of a pro-apoptotic regulator through mutation involves the
2 Biology of Hepatocellular Carcinoma 23
p53 tumour suppressor gene. The resulting functional inactivation of its product, the
p53 protein, is seen in greater than 50% of human cancers and results in the removal
of a key component of the DNA damage sensor that can induce the apoptotic effector
cascade [4].
Many and perhaps all types of mammalian cells carry an intrinsic, cell-
autonomous program that limits their multiplication and stops their growth. Tumour
cells have to exhaust their endowment of allowed doublings and breach the mortality
barrier to acquire unlimited replicative potential. Telomeres, which are composed
of several thousand repeats of a short six base-pair sequence element, and which

are shortened in each cell doubling, limit one cell’s lifetime. Therefore, telomere
maintenance either by upregulating expression of the telomerase enzyme [5]orby
recombination-based interchromosomal exchanges of sequence information [6]is
evident in virtually all types of malignant cells. By one or the other mechanism,
telomeres are maintained at a length above a critical threshold, and this in turn
permits unlimited multiplication of descendant cells.
The oxygen and nutrients supplied by the vasculature are critical for cell func-
tion and survival. Thus tumours need to induce blood vessel formation to maintain
growth and viability. One common strategy is increased expression of angiogen-
esis inducers as vascular endothelial growth factor (VEGF) and fibroblast growth
factor (FGF) or downregulation of angiogenesis inhibitors as thrombospondin-1 or
β-interferon.
The development of cancer metastasis is a highly complex event, involving the
generation of new blood and lymph vessels, growth, invasion with breakdown and
cross talk of the host matrix, escape from immune surveillance, transport to other
sites with adhesion, and subsequent invasion of the organ that hosts the metasta-
sis. Several participants in this tightly orchestrated procedure are important, for
instance cell-adhesion molecules, signalling pathways, immune cells, enzymes and
receptors, acting all in concert to guide the tumour cell to its new home.
To reach the six capabilities necessary for survival, you have to be highly
selected as a cancer cell. Genomic instability, altered transcription and translation,
deregulated protein synthesis all act in concert to equip you with the necessary
armamentarium to reach the cancer phenotype.
Biological Features of Liver Cancer – The Hallmark
of Hepatocellular Carcinoma
Usually, HCC arises as a consequence of underlying liver diseases such as viral
hepatitis and liver cirrhosis. Highly variable clinical phenotypes in HCC patients
indicate that HCC comprises several biologically distinctive patterns. Patients can
be categorized in subgroups by different grades of differentiation, proliferation rates,
ability to invade vessels, potential for metastasis, sensitivity to chemotherapeutic

agents, etc. [7]. When the liver gets injured by factors like HBV/HCV, alcohol
or aflatoxin B1, necrosis will appear in the liver accompanied by the subsequent
24 M.L. Balmer and J F. Dufour
hepatocyte proliferation. After continuous cycles of destructive–regenerative
process accumulate to some extent, the liver will suffer from cirrhosis. The main
characteristic of cirrhosis is that abnormal nodules appear in the liver surrounded by
collagens and scarring. Subsequently, the hyperplastic nodules will turn into dys-
plastic nodules (DNs) inducing a high risk of developing HCC for those patients
[8]. DNs are classified into low grade and high grade according to cytological and
architectural atypia on microscopic examination [9]. One-third of high-grade DNs
will progress to HCC in 2 years, and the rate increases to 81% in 5 years [10].
Coming back to the introduced route of cancer development, HCC phenotype
can result as a consequence of different alterations on different molecular levels.
The observed genetic aberrations associated with HCC include the amplification or
deletion of chromosomal regions, copy number changes of genes and abnormal epi-
genetic alterations. Chromosomal amplification regions often harbour oncogenes,
whereas the chromosomal deletion regions often include tumour suppressor genes,
both conferring a growth advantage for tumorigenesis in HCC [11]. These aber-
rations can be caused by different environmental factors like virus infection and
alcohol and/or aflatoxin consumption [12, 13]. Epigenetic modifications refer to
changes in DNA/chromatin that do not involve changes in the DNA sequence, for
instance DNA methylation or histone modifications. A number of studies have indi-
cated that promoter hypermethylation may be a key mechanism involved in the
inactivation of some tumour suppressor genes in HCC [1]. Changes in the expres-
sion of many genes are also evident at both mRNA and protein levels. Such changes
can be the consequences of the genetic aberrations and environmental interactions.
As a complex disease, the genesis and development of HCC could not be decided by
a single factor or a simple collection of single factors, but rather by interactions of
multiple proteins, genes and miRNAs in biological pathways. Furthermore, signif-
icant and complex cross talks among the different pathways exist and are involved

in different aspects of HCC development and progression. These cross talks, largely
not understood at the molecular level, could potentially account for the resistance
to molecularly targeted drugs, which are able to hit pathways only at one or few
sites [14].
In this section, we discuss the hallmarks of liver cancer which are important for
diagnosis and treatment of the disease.
Liver Stem Cells
Stem cells are generally characterized by their capacity for self-renewal through
asymmetrical cell division, multipotency for producing progeny in at least two
lineages, long-term tissue reconstitution, and serial transplantability [15]. When
mature hepatocytes and cholangiocytes are damaged or inhibited in their replication
a reserve compartment of hepatic progenitor cells located within the intrahepatic bil-
iary tree is activated [16]. The activation of this stem cell compartment is observed
in circumstances of prolonged necrosis, cirrhosis and chronic inflammatory liver