 Etiology of cancer

 Mechanisms by which immune system

recognize tumors

 Understand tumor escape mechanisms

 Learn how to manipulate the immune
system to kill tumors: immunotherapy
 Cells that continue to replicate,
fail to differentiate into
specialized cells, and become
immortal.

1. Malignant: A tumor that grows

indefinitely and spreads
(metastasis)--also called
cancer: kills host
2. Benign: A tumor that is not
capable of metastasis: does not
kill host muscle, nerve, bone,
blood
 Carcinoma: arising from epithelial tissue, such as glands,
breast, skin, and linings of the urogenital, digestive, and
respiratory systems (89.3% of all cancers)
 Sarcoma: solid tumors of muscles, bone, and cartilage that
arise from the embryological mesoderm (1.9% of all cancers)
 Leukemia: disease of bone marrow causing excessive
production of leukocytes (3.4% of all cancers)
 Lymphoma, Myeloma: diseases of the lymph nodes and
spleen that cause excessive production of lymphocytes (5.4%
of cancers)
1. Genetic factors: mutations, translocation,
amplifications
2. Environmental factors: UV, chemicals,
viral infections
3. Conversion of proto-oncogenes (potential for cell
transformation) to oncogenes (cell transformation)
4. Alteration in tumor suppressor genes
Oncogene: gene expression causes a
cell to be cancerous

Proto-oncogene: normal cell gene

which when altered becomes an
oncogene

Tumor Supressor: gene expression

causes a cell to be normal
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Cancer begins with a mutation in a single cell.

However, a single mutation is not sufficient to

cause cancer. It takes 5-6 serial mutations to
progress from a normal cell to metastatic cancer.

People with hereditary cancer already have the

first mutation.

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 The underlying cause of cancer is
somatic mutations leading to deregulated
mitosis. What are these mutations and
what are their consequences?

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 The cell's progress
from normal to
malignant to
metastatic follows a
series of distinct
steps, each controlled
by a different gene or
set of genes.

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10
 Control of cell
growth

Growth-promoting Growth-restricting
Proto-oncogenes Tumor-suppressor genes

Conversion of proto-
oncogenes to oncogenes:
• amplification of c-erbB2 in
breast cancer
• point mutation of c-ras in
kidney and bladder cancers
• chromosome translocation of
c-myc in Burkitt’s lymphoma
Uncontrolled
cell growth
Altered tumor-suppressor
genes:
• P53 mutation in prostate cancer:
failure in cell cycle arrest or
apoptosis of prostate tumors
• Rb mutation: fail to prevent
mitosis
 Damage or mutation of DNA:
 Melanoma: metastatic, highly immunogenic,
spontaneous rejection
 Non-melanoma cancers:
1. Basal cell carcinoma: rarely spreads
2. Squamous cell carcinoma: can spread
 Free radicals and other oxidants steal electron
from DNA and cause cancer: anti-oxidants
(vitamins A, C)
DNA viruses: papova (papilloma, SV40), hepatitis,
EBV
RNA viruses: retroviruses---> Human T-
lymphotropic viruses (HTLV-I and HTLV-II)
cause T cell leukemia

Highly immunogenic because of viral antigens

 1. Spontaneous regression: melanoma, lymphoma
2. Regression of metastases after removal of primary
tumor: pulmonary metastases from renal carcinoma
3. Infiltration of tumors by lymphocytes and
macrophages: melanoma and breast cancer
4. Lymphocyte proliferation in draining lymph nodes
5. Higher incidence of cancer after
immunosuppression, immunodeficiency (AIDS,
neonates), aging, etc.
  Cancer immunosurveilance:
immune system can recognize and destroy
transformed cells

 Cancer immunoediting:
immune system kill and also induce changes in
the tumor resulting in tumor escape and
recurrence (epigenetic changes or Darwinian
selection)
 Antibodies recognize intact antigens while T cells
recognize processed antigens associated with MHC
 Repertoire of T cells with low affinity against
self proteins exist because of positive and
negative selections in the thymus
 Expression of altered self proteins by tumors
will increase the affinity of T cells for tumor
antigens
 Mutated self antigens
 Antigen mimicry: viral antigens
 Expression of cryptic or hidden
epitopes

 Expression of co-stimulatory
molecules in tumors or cross
presentation of tumor antigens
by antigen presenting cells (APC)
 antigen function cancers
CTA MAGE1 normal testicular Melanoma
MAGE3 protein Breast & Glioma
(Cancer Testis Antigen)

TDA Tyrosinase melanin Melanoma

synthesis
(Tumor Differentiation Antigen)
HER-2/neu receptor tyrosine Breast, ovary,
ERBB3 kinase GI, lung,
TAA ERBB4 prostate
(Tumor Associated Antigen) epithelia
MUC-1
CEA cell adhesion Breast
Colorectal
gp100 melanin Melanoma
cancer
polymerization
HPV (E7) viral transforming Cervical cancer
TSA gene product
(Tumor Specific Antigen)
 Cross Presentation of
Tumor Antigens
Effector T cells: killers

Signal I
T cells

Tumor
Signal II
Non-specific: NK cells,  T cells
(NKG2D), macrophages, NK T cells

Antigen-specific: Antibody (ADCC,

opsinization); T cells (cytokines, Fas-
L, perforin/granzyme)
 NK T cells

MIC A, B
NKG2D
NKT
Tumor
IFN-
apoptosis Perforin/granzyme B
Fas-L/Fas
 Tumor

sIg

Macrophage/
Complement opsinization

Tumor

Fc Fab FcR
NK cells &
ADCC
 T cell leukemia

IL-2R Anti-IL-2R Ab
IL-2
T cell receptor (TCR)

MHCI
CD8 Tumor

peptide
IFN-
Granzyme B

Apoptosis
There are a number of specific tumour markers which are found in
serum which help confirm diagnosis and can be used to monitor
response to treatment and disease progression
 -Fetaprotein (AFP)
 Testicular tumours, hepatacellular carcinoma
  human chorionic gonadotrophin (-HCG)
 testicular tumours, choriocarcinoma
 Prostate specific antigen (PSA)
 prostate cancer
 CA125
 ovarian, gut, pancreatic cancer
 Carcinoma embryonic antigen (CEA)
 colonic cancer
 CA19-9
 gut, pancreatic cancer

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