Cancer Biology

• Objectives of the lesson:

• At the end of this lesson students will be able to:
 Recognize the basic biology of cancer

 Differentiate environmental vs genetic role in

cancer pathology

 Appreciate the different types of cancers

 List down the basic treatment strategies

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 Cancer origin and terminology

 From Molecular immunology perspective, cancer

cells can be viewed as altered self-cells that have
escaped normal growth-regulating mechanisms.

 In most organs and tissues of a mature animal, a

balance is usually maintained between cell renewal
and cell death.

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 Cancer origin and terminology

 The various types of mature cells in the body have

a given life span; as these cells die, new cells are
generated by the proliferation and differentiation of
various types of stem cells.

 Under normal circumstances, the production of

new cells is regulated so that the number of any
particular type of cell remains constant.

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 Cancer origin and terminology
 Occasionally, though, cells arise that no longer
respond to normal growth-control mechanisms.

 These cells give rise to clones of cells that can

expand to a considerable size, producing a tumor,
or neoplasm.

 A tumor that is not capable of indefinite growth

and does not invade the healthy surrounding
tissue extensively is benign.

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 Cancer origin and terminology

 A tumor that continues to grow and becomes

progressively invasive is malignant; the term cancer
refers specifically to a malignant tumor.

 In addition to uncontrolled growth, malignant

tumors exhibit metastasis

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 Cancer origin and terminology

 In this process, small clusters of cancerous cells

dislodge from a tumor, invade the blood or
lymphatic vessels, and are carried to other tissues,
where they continue to proliferate.

 In this way a primary tumor at one site can give

rise to a secondary tumor at another site

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 Cancer origin and terminology

 Malignant tumors or cancers are classified

according to the embryonic origin of the tissue
from which the tumor is derived.

 Most (>80%) are carcinomas, tumors that arise

from endodermal or ectodermal tissues such as
skin or the epithelial lining of internal organs and
glands.

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 Cancer origin and terminology

 The majority of cancers of the colon, breast,

prostate, and lung are carcinomas.

 The leukemias and lymphomas are malignant

tumors of hematopoietic cells of the bone marrow
and account for about 9% of cancer incidence in the
developed counterie.

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 Cancer origin and terminology

 Leukemias proliferate as single cells, whereas

lymphomas tend to grow as tumor masses

 Sarcomas, which arise less frequently are derived

from mesodermal connective tissues such as bone,
fat, and cartilage.

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 Malignant Transformation of Cells

 Treatment of normal cultured cells with chemical

carcinogens, irradiation, and certain viruses can
alter their morphology and growth properties.

 In some cases this process, referred to as

transformation, makes the cells able to produce
tumors when they are injected into animals.

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 Malignant Transformation of Cells

 Such cells are said to have undergone malignant

transformation, and they often exhibit properties in
vitro similar to those of cancer cells.

 A second category of cancer-associated genes

called tumor suppressor genes, or anti-oncogenes
encodes proteins that inhibit excessive cell
proliferation.

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 Inhibition of cellular proliferation

 Inactivation of these results in unregulated

proliferation.

 The prototype of this category of oncogenes is Rb,

the retinoblastoma gene.

 Hereditary retinoblastoma is a rare childhood

cancer, in which tumors develop from neural
precursor cells in the immature retina.

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 Inhibition of cellular proliferation

 The affected child has inherited a mutated Rb

allele; somatic inactivation of the remaining Rb
allele leads to tumor growth.

 Probably the single most frequent genetic

abnormality in human cancer is mutation in p53,
which encodes a nuclear phosphoprotein.

 Over 90% of lung cancers and over 50% of breast

and colon cancers have been shown to be
associated with mutations in p53.
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 Cancer Associated genes

 Homeostasis in normal tissue is maintained by a

highly regulated process of cellular proliferation
balanced by cell death.

 If there is an imbalance, either at the stage of

cellular proliferation or at the stage of cell death,
then a cancerous state will develop.

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 Cancer Associated genes

 Oncogenes and tumor suppressor genes have

beenshown to play an important role in this
process, by regulating either cellular proliferation
or cell death.

 Cancer-associated genes can be divided into three

categories that reflect these different activities,

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 Cancer associated genes

• CATEGORY I: GENES THAT INDUCE CELLULAR

PROLIFERATION
Type/ Name Nature of gene product
Growth factors
sis A form of platelet-derived
growth factor (PDGF)
Growth-factor receptors
fms fms Receptor for colony-
stimulating factor 1 (CSF-1)
erbB Receptor for epidermal growth
factor (EGF)
neu Protein (HER2) related to EGF
receptor
erbA Receptor for thyroid hormone
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 Cancer Associated genes
• CATEGORY II: TUMOR-SUPRESSOR GENES, INHIBITORS
OF CELLULAR PROLIFERATION

Rb Suppressor of retinoblastoma
p53 Nuclear phosphoprotein that
inhibits formation of small-cell
lung cancer and colon cancers
DCC Suppressor of colon carcinoma
APC Suppressor of adenomatous
polyposis
NF1 NF1 Suppressor of
neurofibromatosis
WT1 Suppressor of Wilm’s tumor

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 Cancer Associated genes

 CATEGORY III: GENES THAT REGULATE

PROGRAMMED CELL DEATH

 The activity of the normal products of the category

II genes inhibits progression of the cell cycle.

 Loss of a gene or its inactivation by mutation in an

indicated tumor-suppressor gene is associated with
development of the indicated cancers.

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 Cancer origin and terminology

 The development from a normal cell to a cancerous

cell is usually a multistep process of clonal
evolution driven by a series of somatic mutations
that progressively convert the cell from normal
growth to a precancerous state and finally a
cancerous state.

 The presence of myriad chromosomal

abnormalities in precancerous and cancerous cells
lends support to the role of multiple mutations in
the development of cancer.
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 Tumor Antigens
 The subdiscipline of tumor immunology involves
the study of antigens on tumor cells and the
immune response to these antigens.

 Two types of tumor antigens have been identified

on tumor cells: tumor-specific transplantation
antigens (TSTAs) and tumor-associated
transplantation antigens (TATAs).

 Tumor-specific antigens are unique to tumor cells

and do not occur on normal cells in the body.

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 Tumor Antigens
 They may result from mutations in tumor cells that
generate altered cellular proteins; cytosolic processing
of these proteins would give rise to novel peptides that
are presented with class I MHC molecules, inducing a
cell-mediated response by tumor-specific CTLs

 Tumor-associated antigens, which are not unique to

tumor cells, may be proteins that are expressed on
normal cells during fetal development when the
immune system is immature and unable to respond
but that normally are not expressed in the adult.

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 Tumor Antigens

 Reactivation of the embryonic genes that encode

these proteins in tumor cells results in their
expression on the fully differentiated tumor cells.

 Tumor-associated antigens may also be proteins

that are normally expressed at extremely low levels
on normal cells but are expressed at much higher
levels on tumor cells.

 It is now clear that the tumor antigens recognized

by human T cells fall into one of four major
categories:
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Tumor antigens
 Antigens encoded by genes exclusively expressed
by tumors

 Antigens encoded by variant forms of normal

genes that have been altered by mutation

 Antigens normally expressed only at certain stages

of differentiation or only by certain differentiation
lineages

 Antigens that are over expressed in particular

tumors
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 Tumor antigens

 Many tumor antigens are cellular proteins that give

rise to peptides presented with MHC molecules;
typically, these antigens have been identified by
their ability to induce the proliferation of antigen-
specific CTLs or helper T cells.

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 Etiology
• Nature
– Inherited cancer syndromes
• p53, BRCA1 and 2, MMR
– Immune deficiency syndromes
• Inherited/Congenital or acquired
• Nurture
– Radiation (cosmic, fallout, radon)
– Chemotherapy
– Viruses and bacteria HTLV-I/II, H. pylori
– Repeated injury (Acid reflux, hepatitis)

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 Cancer pathogenesis

 Oncogenes (In some cases, retrovirus-induced

transformation is related to the presence of
oncogenes, or “cancer genes,” carried by the
retrovirus
– myc, ras, src, abl, bcl2
 Tumor suppressor genes
– p53, Rb, APC, MEN1, NF1
 MicroRNA
– Transcriptome control

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 The path to cancer
 Clonal proliferation

 Starts from a single cell

 Expansion in steps

 Pre-malignant states

 Serial accumulation of mutations

 Clonal evolution
 Resistance

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 “Hallmarks of cancer”
 Self-sufficiency in growth signals

 Insensitivity to anti-growth signals

 Evading apoptosis

 Limitless reproductive potential

 Sustained angiogenesis

 Tissue invasion and metastases

 Genomic instability
Hanahan & Weinberg, 2000
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 Hallmarks of Cancer Cells

 Self-maintained – Apoptosis down-

replication regulation
 Longer survival
– Lack of response to
 Genetic instability inhibitory factors

 Capable of inducing – Self-sustained

neoangiogenesis proliferation
 Capable of invasion and
metastasis
 Hallmarks of Cancer Cells

 Self-maintained – Apoptosis down-

replication regulation
 Longer survival
 Genetic instability – Telomerase
 Capable of inducing reactivation
neoangiogenesis
 Capable of invasion
and metastasis
 Hallmarks of Cancer Cells

 Self-maintained – Cooperative
replication
 Longer survival
genetic damage
 Genetic instability – Mutagenic
 Capable of inducing agents
neoangiogenesis
– Defective repair
 Capable of invasion
and metastasis systems
 Tissue and tumor architecture

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32
 Cancer stem cells
 Present in most (all) tumors

 Small fraction of population

 No universal marker

 Often resistant to therapy

 May be important target of therapy

 Cancer initiating cells in mice

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 Genomic instability
 Chromosomal instability
Gross translocations, loss and gain of
chromosome parts
 Mutator phenotype
Repair genes
Xeroderma pigmentosum
Other repair genes

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 Genetic Lesions in Tumors

 Activating or inactivating

 Dominant / Recessive / Dominant negative

 Somatic or germline

 Genetic targets (oncogenes, tumor suppressor

genes, mismatch repair genes)

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 Genetic Mechanisms of Tumors

• Gene deletions / amplifications

• Mutations
• Insertional
• Point Mutations
• Genetic Instability
• Microsatellite Instability (MSI)
• Chromosomal Instability (CIN)

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 Gene Inactivation
Genetic Changes
Inactivating mutation
Interstitial DNA deletion

Epigenetic Changes
Promoter hypermethylation

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 Genetic Instability in Tumors

 (+) Oncogenes  Chromosomal

 (-) Tumor suppressor Instability
genes
 Telomere shortening

 Mismatch repair
(MMR) genes  Microsatellite
Instability

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 Telomeres and Cell
Senescence

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 Telomeres, Telomerase, and Cancer

Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603

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 Telomeres and
Chromosomal Anomalies

Invasive
carcinoma

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Mismatch Repair and
Microsatellites

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 Basic Mechanisms in
Neoplasms

• Genetic bases

• Basic aspects of tumorigenesis

– Correlation between genetics and kinetics

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 Alterations of Specific Cellular
Functions in Cancer
DNA Repair

Tumor Suppressor Genes Oncogenes

Inactivation
Activation

Differentiation Apoptosis/Proliferation

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CANCER
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 Specific Cellular Functions in
Cancer: Genetic Alterations
Genetic Instability

DNA Repair

CANCER
Tumor Suppressor
Genes Oncogenes

Interstitial Deletion Gene Amplification

Inactivating Mutation Gene Overexpression
Hypermethylation Activating Mutation
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 Progressive Acquisition of
Neoplastic Features

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 Self-sufficiency in growth signals

 Autocrine loops
 Over-expression
of receptor
 Receptor is
always ‘on’
 Downstream
signals

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 Insensitivity to antigrowth signals

01/25/24 Biot 611 Nega B Hanahan & Weinberg, 2000

48
 Evading apoptosis

 External triggers
 Intracellular
triggers
 Death receptors
 Caspases
– Sensors (8, 9)
– Executioners (3)

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 Sustained angiogenesis

• VEGF
• FGF1/2

• Thrombospondin
• Thalidomide
• Avastin

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 Tissue invasion and metastases

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 Tumor burden - Staging

• Tumor
– Size, capsule invasion
• Nodes
– Involved, how many?
• Metastases
– Present/absent

– “Unknown primary”

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 Imaging

• CT scan
• PET/CT
• SPECT/CT
• MRI

• Staging
• Response

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 Prognostic scoring systems
 Host vs Disease

 Disease burden
 Disease biology
 Co-morbid conditions
 Performance status

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 Therapy

 Surgery
 Radiation
 Chemotherapy
 Antibodies
 Small molecules
 Adjunctive

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 Surgery

 Diagnosis
 Therapy
– Curative
– Palliative
• Debulking
• Symptoms control
• Prevent complications

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 Radiation

 External beam radiation

– Gamma photons
– Neutron beams
 Radioimmunoconjugates
– Antibody targeted radiation
 Radioconjugates
– Isotope tagged to bone seeking material
 Free isotopes
– 131I, Gallium
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 Radiation targets

 DNA
 Water
 Free radical generation
– Oxygen is required
– Anti-oxidants are not helpful
 Direct and indirect effects
 Not all cells are created equal
 Geometry important

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 Radiation

 Consolidation
– “Mantle radiation”
– “Axillary radiation”
 Palliation
– Spinal cord compression
– Pain relief

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 Radio(immuno)conjugates
 or -emitters

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 Free isotopes

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 Chemotherapy

Antimetabolites
Antifolates, Purine nucleosides,
nucleoside synthesis inhibitors
Alkylators
Direct DNA damage (Many), platinum
Spindle poisons
Vinca alkaloids, taxanes
Topoisomerase inhibitors
Anthracyclines, Etoposide

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 Chemotherapy
 Often used in combinations
– “CHOP”, “ABVD”, “AC”, “Taxol/Carbo”
 Minimizes resistance
 Reduces toxicity
– Different side effects
 Can be curative in specific cases
– AML, ALL, HD, NHL, Testicular cancer

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 Antibodies

 Target specific antigen

 Specificity is relative
 Various mechanisms of action
– Complement activation
– ADCC
– Calcium entry
– May synergize with chemotherapy
• R-CHOP and CHOP
– Expected or unexpected toxicities

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 Antibodies

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 Small molecules
 Target oncogene product
Bcr-Abl, PML-RARA,
 Inhibit signaling at key steps

 Safer than chemotherapy

 Specific side effects

 Specificity is often relative

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 Small molecules

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 Adjuncts
 Glucocorticosteroids

 Estrogens/anti-androgens/SERMs

 Bisphosphonates

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 The target

Tumor cells do not live in isolation

– Stroma
• Adhesion resistance
– Blood vessels
• Angiogenesis inhibitors
– Antibodies (Avastin)
– Small molecules (Thalidomide, other IMiDs)
– Immune system
• Transplantation
• Vaccines

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