Molecular Mechanism of

Carcinogenesis
 CANCER IMMUNOSURVEILLANCE OR
IMMUNOCONTROLLING

The recruitment of the immune system after Ag

recognition allows the immune system to survey and to
control the cancer process.

 Proposed originally in 1909 by Paul Ehrlich

 Refined in late 1950s by Burnet and Thomas

“immunosurveillance”

 Uncovered new important insights of immune system

and tumor development 2001 by Shankaran et al.
“immunoediting”
 CANCER IMMUNOCONTROLLING
Cancer immunocontrolling consists of three
distinct phases : Healthy tissue

 Elimination phase
• Carcinogens
• Radiation
 Equilibrium phase • Viral infections
• Chronic inflamation
(cancer persistance/dormancy • Inherited genetic
mutations
Danger signals
 Escape phase NKG2D ligand
(cancer progression) Transformed cells
Tumor
antigen Normal cell

Elimination Equilibrium Escape

ELIMINATION PHASE: protection by extrinsic tumor suppression
NKT
cell
NK
CD8+T CD8+T
cell cell

CD4+
T cell
CD4+
T cell Equilibrium phase
γδ T
Mɸ cells CD8+
DC

• Perforin
Innate and
• IFN-α/β
adaptive immunity • IFN-γ
• TRAIL
• NKG2D
• IL-12

Normal cell

Highly immunogenic
transformed cell
EQUILIBRIUM PHASE: cancer persistence/dormancy

CD8+T
cell CD4+ IL-12
T cell
IFN-δ

Escape phase

Genetic instability and

Immunoselection (i.e., editing)

Normal cell Poorly immunogenic

transformed cell
Highly immunogenic Immunosuppressive
transformed cell transformed cell
ESCAPE PHASE : cancer progression
Mɸ
CD8+T NK
cell
• TGF-β
CTLA-4
• IL-6
PD-L1 • IL-10
• Galectin-1
FasL • VEGF
• IL-10

Bcl-2,FLIP
VEGF CD8+T MHC
M2 cell
Mɸ
CTLA-4

Treg

Chronic Poorly immunogenic

inflammation transformed cell
Immunosuppressive
Transformed cell
Dual role of TGF-β signaling in cancer progression
Role of IL-6 in cancer progression
Role of IL-10 in cancer progression
Role of Glactin-1 in cancer progression
Tumor cell killing pathways mediating through autoantibodies

(CDC)
(CDC)

CDC
Suppression
phénotypique des
antigènes
Different ways for self antigens to become tumoral antigens

Tumoral cell

Mutated
peptide

Normal cell

Peptides of overexpressed
self protein
Tumoral cell
Self protein MHC class I
Self
peptide

Post translational modifications, Modified,

inappropriated
truncated peptides expression
Tumoral cell
 MOLECULAR MECHANISMS IN CARCINOGENESIS

Risk factors Organ & Tissues involved

Chronic inflammation e.g.

Cellular damage

Reactive cell proliferation

Genetic/epigenetic alterations in regulatory genes

Enhanced Enhanced Stromal

proliferation angiogenesis proliferation
signaling (VEGF)
(IL-6, TGF-ß) Dysregulation Capacity of
of apoptosis invasion and
(K-ras,p-53) diffusion
(Giammarco F. World J Gastrointest Pathophysiol.2010)
(MMP, Aspartyl ß-hydroxylase)
Malignant tumors development is a multistep process of cellular
transformation. Cells undergo genetic and epigenetic alterations in
regulatory genes, which accumulate and lead to the activation of
oncogenes and the dysregulation of tumor suppressor genes
(TSGs). A multitude of mutated genes and pathways have been
described in malignant cells. Even if a small number of
transformed cells arise in normal organ, malignancy generally
develops in a background of chronic inflammation and the
consequent cells injury associated with different risk factors.
Some risk factors related to the development of transformed cells
are well known. Among them, in case of primary liver cancer, age
greater than 65 years, liver fluke infestation by Opistorchis viverrini
and Clonorchis sinensis, primary sclerosing cholangitis (PSC),
hepatolithiasis, Caroli’s disease, congenital choledochal cysts, bile
duct adenoma, anomalous pancreaticobiliaryjunction
malformations, thorotrast.
A number of other factors predisposing to CC development have
also been described: smoking, papillomatosis, liver cirrhosis,
diabetes mellitus, dioxin and vinyl chloride intoxication, HIV, HBV
and HCV infections. However, none of these specific conditions is
often detectable in patients affected by this cancer. Independently
of the existence of risk factors, malignant transformation of cells
arises against a background of chronic inflammation. The network
of cytokines and molecules present in high concentration during
this chronic inflammatory process triggers and maintains the
multistep process of carcinogenesis (Figure 1). This process is
characterized by a progressive accumulation of chromosomal,
genetic and epigenetic alterations (Figure 1). The final result is a
sustained overproduction of cytokines, stimulatory or inhibitory
growth factors and hormones that drive altered cells to irreversible
changes in cell physiology, i.e. (1) dysregulated growth, (2) high
capacity of invasiveness; and (3) capacity to metastasize.
 GENETIC ALTERATIONS
Genetic alterations are followed by specific changes in
cell physiology such as:
(1) stimulation of growth induced by autocrine signals;
(2) dysregulated of the mechanisms of replication;
(3) insensitivity to growth inhibitory mechanisms;
(4) escape from cell apoptosis; and
(5) neo­angiogenesis, tissue invasiveness and metastasis.

The final result of these altered processes is an

uncontrolled cell growth. The principal genes altered
during the development of Carcinogenesis, such as K-ras,
p53, p14ARF, p16INK4a and β -catenin, are also
altered in many cancer types.
 K-ras and p53
Mutations of K-ras and p53 oncogenes are described in
several epithelial carcinomas. Moreover, K-ras and p53
oncogenes are also often mutated in CC cells[7,17­19].
Such point mutations are located in codon 12 and consist
of changes from glycine (GGT) to aspartic acid (GAT) or,
less frequently, to valine. Furthermore, mutations have
been located at codon 13, involving GGT to GAT, and
codon 61, involving CAA to CAC changes[20]. In addition,
some Authors described that the expression of K-ras
correlates with the gross morphology and location of the
tumor in the liver[7,20]. In summary, these differences in
K-ras mutations could be due to the existence of different
subtypes of cancers, racial and geographical differences
of the patients or use of different assay techniques.
 p53
p53 is a fundamental tumor suppressor gene with two
important functions: the induction of cell cycle arrest and
suppression of Bcl­2 protein expression with consequent
blockage of apoptosis. The incidence of p53 gene
mutation is high and varies from 20 to 80% of cases. The
evidence that this mutation is more frequent in the mass­
forming type tumors means that p53 mutation could be
related to the development of intrahepatic CCs of the
peripheral small bile ducts [in case of
cholangiocarcinoma]. In many cases, the p53 protein
forms complexes with other molecules such as WAF­1 and
mdm­2, which favor its inactivation. p14ARF and
p16INK4a are cell cycle regulator genes implicated in the
genesis of CCs. However, their mutation or deletion is not
frequent in CCs.
 NKG2D
Natural killer (NK) cells are implicated in tumor surveillance by cell­
mediated cytotoxicity. The natural killer group 2, member D cell
receptor, also known as NKG2D, is expressed by NK cells and T­
lymphocytes and is involved in their cytotoxic activity. The role of
these cells is highly relevant since some studies have suggested
that high levels of cytotoxicity protect PSC patients from the
development of CCs in a background of chronic inflammation of
the biliary tract. Melum et al. recently evaluated the NKG2D gene
in PSC­affected patients and showed that two single nucleotide
polymorphisms (SNPs) of the gene were associated with an
increased risk of CCs. In addition, a homozygous condition for the
non­risk alleles is linked to an extremely low risk of CCs. This finding
could be helpful in identifying low risk CC­patients. The
development of cancer is a complex biological process, and other
yet unknown polymorphisms are likely to be associated with CC
risk. Combining NKG2D SNPs with other polymorphisms in a panel
of markers may be useful in creating a test to assess Cancer risk.
 MOLECULAR STEPS OF CARCINOGENESIS
Enhanced proliferation signaling
Deregulation of several molecular mechanisms such as
ErbB­2, MUC­1, Met, β­catenin, interleukin­6 (IL­6),
transforming growth factor­β (TGF­β), signal transducer
and activator of transcription­3 (STAT­3), Bcl­2, DCP4/
Smad4, hepatocyte growth factor (HGF), reduced
glutathione (GSH), Notch­1, tumor necrosis factor­related
apoptosis­inducing ligand (TRAIL), p16INK4a, Ras/Raf and
WISP1v have been described in transformed cells as a
consequence of the activation of cellular oncogenes or
the inactivation of TSGs.