IMMUNOLOGY

OF CANCER
I gede andika sukarya
Making a cancer cell
1. Cancer cells  are transformed cell
2. Cancer cells  can survive in

unfavorable situation
3. Using energy efficiently

4. escape from immune surveillance

Cellular Senescence
 When normal ploid cells cease to divide
 Replicative senescence of “Hayflick

limit”
Mortal and immortal cell line
 Normal cells : mortal  senescence
 Transformed cells: immortal  can divide

continuously  become a continuous cell

line
 Cancer cells  immortal  continuous cell

line
Property of continuous cell line
1. Reduced serum requirement
2. Decrease density limitation of growth
3. Can grow in semi-solid media
4. Aneuploid  bear many genetic alteration
How to become a cancer cell
1. Genetic mutations
2. Inflammation  promote cell
tumor
Genetic Mutation in Cancer
1. Inherited mutation  germline
mutation
2. Acquired mutation  somatic
mutation
Caused of mutation
 Chemical compound or
drug
 Ionizing radiation

 Oncogenic viruses

 Spontaneous mutation
ROS and mutation
Stress signaling in normal
cells

Initiation of
DNA mutation

Promote
neoplastic
transformat
 ROS in cancer cells
 amplify the tumorigenic phenotype
 accelerate the accumulation of additional

mutations  that lead to metastatic behaviour

Genetic mutation in cancer cell
Cancer occur when there are several genetic
mutation:
 Knudson’s Two-Hit Hypothesis of

Oncogenesis
 Vogelstein Progression Model
Knudson’s Two-Hit Hypothesis of Oncogenesis
A Genetic Model for Colorectal
Tumorigenesis

Fearon and Vogelstein, 1990

Vogelstein Progression Model
The hallmarks of cancer
1. Sustaining proliferative signaling
2. evading growth suppressors
3. resisting cell death
4. enabling replicative immortality
5. inducing angiogenesis
6. activating invasion and
metastasis
Mutation in cancer cells
1. Hereditary mutation
2. Acquired mutation
1. Germline
mutation
2. Somatic mutation
Sustaining proliferative signaling
Mutation in:
1. Growth factor

2. Growth factor receptor

3. signal transducers

4. transcription factors

5. cell cycle components

Mutation in growth factor receptor
 Mutation or over-expression
 GIST  mutation in the receptor

tyrosine kinase c-KIT or PDGFR  Tx

imatinib
Overexpression of normal forms of growth
factor
receptors :
 ERBB1 (EGF-R) gene overexpressed in 80%

of squamous cell carcinomas of the lung, in

50% of glioblastomas and in 80% - 100% of
head and neck tumors  Tx Gefitinib
 ERBB2 gene (HER-2/NEU), EGF receptor

family, is amplified in 25% of breast cancers

and in adenocarcinomas of the ovary, lung,
stomach, and salivary glands  Tx
Mutation in signal-transducing Protein

 carcinomas (particularly from colon and pancreas) have mutations of

KRAS, bladder tumors have HRAS mutations, and hematopoietic tumors
bear NRAS mutations.
 mutations in BRAF (members of the RAF family) have been detected in >
60% of melanomas and in > 80% of benign nevi.
 Mutation in Transcription Factors

 oncoproteins, products of the MYC, MYB, JUN, FOS, and REL

oncogenes, are transcription factors that regulate the expression of
growth- promoting genes, such as cyclins
Mutation in cell cycle components
 Cell cycle component : Cyclin &
CDK
Apoptosis
 Intrinsic
Pro-apoptotic
Anti-
apoptotic
 Extrinsic
Pro-apoptosis vs Anti-apoptosis
 Pro-apoptosis: BAX and BAK
 Anti-apoptosis: BCL2, BCL-XL and MCL1

 BH3-only proteins: BAD, BID, PUMA 

promote apoptosis by neutralizing the actions

of anti- apoptotic proteins like BCL2 and
MCL1.
Extrinsic Pathway
 CD95/Fas binds to its ligand: CD95L/FasL
 attract the intracellular adaptor protein

FADD
 recruits procaspase 8  caspase 8
Limitless Replicative Potential: becoming
Immortal
1. evasion of senescence
2. evasion of mitotic crisis
3. the capacity for self-renewal
The role of HIF-1 and VEGF
 Relative lack of oxygen due to hypoxia
stabilizes HIFla (an oxygen-sensitive
transcription factor)  activates VEGF
and bFGF  proliferation of endothelial
cells
VEGF expression in human cancer
Action of VEGF in angiogenesis
Anti-VEGF therapy
1. Monoclonal-antibody anti-
VEGF : bevacizumab
2. Tyrosine kinase inhibitor 
inhibit downstream signaling –
sorafenib

VEGF blockade leads to unwanted effects and

toxicities, as VEGF is an important mediator
of angiogenesis in healthy tissues too
Invasion and Metastasis
 E-cadherin
 Matrix metalloproteinases

(MMPs)
 cathepsin D

Epithelial – mesenchymal transition (EMT)

Cancer-enabling Inflammation
 most tumors are infiltrated by
infiltrating immune cells (IIC)
 IIC can variously supply proliferative and

survival signals, pro-angiogenic factors,

and facilitate local invasion and blood-
borne metastasis
 some of IIC: T-regulatory cells and myeloid-

derived suppressor cells can actively

suppress the cytotoxic T lymphocytes
(CTL)
Cancer-enabling Inflammation
1. Release of factors that promote proliferation
2. Removal of growth suppressors.
3. Enhanced resistance to cell death.
4. Inducing angiogenesis.
5. Activating invasion and metastasis.
6. Evading immune destruction.
Tumor-associated macrophage

Macrophage

M M
1 2

Supressin Promotin
g g
cancer cancer
 Tumor Antigens

1. Products of mutated genes: mutated

oncoproteins such as RAS, p53, and
BCR- ABL
2. Over-expressed or aberrantly expressed
cellular proteins: tyrosinase, melanoma
antigen gene (MAGE) family
Tumor Antigens
3. Tumor antigens produced by
oncogenic viruses: proteins produced
by latent
DNA viruses – human papilloma virus
(HPV) and Epstein-Barr virus (EBV)
4. Oncofetal antigens: carcinoembryonic
antigen (CEA) and -fetoprotein (AFP).
Tumor Antigens
5. Altered cell surface glycolipids and
glycoproteins: CA-125 & CA-19-9,
expressed on ovarian Ca, MUC-1, expressed
on both ovarian and breast carcinomas.
6. Cell type-specific differentiation antigens:
normally present on the cells of origin
(tissue specific Ag): CD20, PSA
 tugas

1. AFT 7. MCA

2. CEA 8. NSE

3. CA15-3 9. SCC

4. CA125 10.B-HCG

5. CA 19-9 11.CYFRA 21-1

6. PSA 12.VEGF