Cancer

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 Cancer
• As we have seen in this course, normal development is
characterized by controlled growth; cells undergo
controlled cell division and migration to their proper
destination is highly regulated

• In this lecture, I employ cancer is an example of

abnormal development in which cells exhibit uncontrolled
cell division and invasive properties

• Definition of transformation: a normal cell (with controlled

rate of cell division) ‘transforms’ into a cancer cell
(exhibiting uncontrolled cell division and often invasive
properties)
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 Cancer
• Occurs in all animals
• Can occur in any tissue type, although some are
more prone than others
• Can occur at any age but risk increases with age
• LOSS OF CONTROL OF CELL DIVISION is key
characteristic of cancer
• Invasiveness is another feature
Brain tumor Leukemia Skin cancer

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 States of Cancer

1. Tumour: mass of cancer cells in one

location (benign vs malignant tumour)

2. Invasive: cancer may start as a tumour,

but cancer cells then move away from
original site (metastasize) to other
locations (example: breast cancer tumour
mestastizing to lymph nodes and then to
other body locations)
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 Staging of cancer malignancy
Method of categorizing the development of cancer is called
staging. The development of tumour malignancy occurs in
three stages:

1. Initiation – mutation in a cell

2. Promotion – the mutant cell undergoes cell

division resulting into many cells (a tumour)
with the same mutation

3. Progression – additional mutations in the

tumour result in malignancy
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 What induces cancer?
Classes of inducing agents:

• Carcinogen – a chemical with strong ability to induce

cancer; found in the environment, diet,
habits (smoking)

• Radiation – ultraviolet (UV) rays from the sun, X-rays

• Viruses
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 Cancer and carcinogens in the environment: asbestos

• Asbestos- long fibrous crystals

• ~150 years ago, started to be used in
construction industry and by mid-20th century,
asbestos was used for different purposes due
to its characteristics (inert, fire resistant, good
insulation for walls and ceilings )
• Items made out of asbestos may not be
carcinogenic themselves, but over time, they
start to break down  tiny asbestos fibers
which can be inhaled or ingested
• Asbestos fibers are tiny (human hair is ~1200
times thicker) and stay suspended in the air for
a long time
• Accumulation of these fibers in the body over
time by inhalation or ingestion can lead to
cancer
• malignant mesothelioma (specific type of
cancer induced by asbestos fibers) – affects
the mesothelium – lining of chest cavity,
abdominal cavity, and the cavity around the 7
heart.
Cancer and carcinogens in the diet
Processed foods and trans
fats linked with colon cancer
(Western society has higher
incidence of colon cancer
because of nature of diet)
Acrylamide found in over-deep fried foods
(choose golden, not brown)
Mice given high doses of acrylamide
developed various cancers, but some
researchers did not detect a link between
acrylamide consumption and cancers, like
colon and breast
It has been found that women who ate more
fried foods are more likely to develop
uterine and ovarian cancer
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Cancer and carcinogens in the diet: mycotoxin and aflatoxin

• Naturally occurring mycotoxin (produced by the fungus Aspergillus)

• Highly toxic and among the most carcinogenic substances known
• Aspergillus contaminates grains before harvest (during drought) or
during storage (high humidity)
• Crops that are often affected: cereals (rice, wheat), oilseeds
(peanuts, soybean, sunflower) and spices (chili peppers, black
pepper, turmeric) and tree nuts
• Aflatoxin can be found in milk of animals that were fed contaminated
feed
• Peanut butter contains minute quantities of aflatoxin; usually far
below safe level
• High levels or chronic exposure = liver cirrhosis and/or cancer

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 Cancer and carcinogens in personal habits
• Drinking alcohol can increase the
risk of developing several types of
• Smokers are 20 times more likely cancer including breast, colon,
to develop lung cancer esophagus, larynx, liver and mouth
• Tobacco smoke contains cancer
thousands of chemicals, including • ↑ drink ↑ risk
over 60 substances that are
known to cause cancer

POLYCYCLIC HYDROCARBONS:
highly carcinogenic
 present in tobacco smoke, over-grilled foods, smoked
meat and air pollution
 Large, flat ring-like molecules that can insert between
base pairs of the DNA double helix and cause mutations
after DNA replication mutation passed on to daughter
cells
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Cancer and radiation: UV, X rays
• UVA – (tanning rays, premature wrinkling and sagging skin)
damages connective tissue cells by activation of photoactive
molecules

• UVB – (more harmful than UVA; associated with development of

skin cancer) does not penetrate as deep into the skin. Most is
absorbed by the earth’s ozone layer, but it is thinning. Damages
DNA and effect is directly related to dosage intensity. UVB can
cause DNA damage at lower levels than those causing sunburns

• UVC – extremely hazardous, but is absorbed by ozone layer

• Solutions- keep out of strong sun, use sun screen

• X rays – high energy waves that can pass through the body and
damage cells resulting in an increased risk of cancer development
(used in dental and medical localized therapy at controlled levels) 11
 Experimental induction of cancer:
problems with using chemical
carcinogens and radiation as inducers
• These agents often cause changes in addition to the cancer
‘transformation’ event

• Problem: hard to tell the difference between primary (cancer-

causing) effects and secondary (non-cancer changes) effects
on cells grown in culture

• In the lab, chemicals and radiation only transform a few cells in

the population of cultured cells (poor transformation efficiency)

• Thus in the lab, chemicals and radiation are not ideal 12

experimental inducers for studying cancer ‘transformation’
Viruses are efficient inducers of cancer
(and are used experimentally in the laboratory)
Two classes of tumour viruses:
1. DNA tumour viruses
2. RNA tumour viruses (retroviruses)

Method of viral replication is different in #1 and #2; both

are able to integrate their genome into the host
cell’s genome

A tumour virus can ‘transform’ a normal cell in two

ways:
1. The virus introduces a gene that causes the normal
cell to start dividing uncontrollably
2. The virus activates a gene that is normally turned
off in the normal cell, causing the cell to start
dividing uncontrollably 13
 Tumour viruses
• Specific cancer-inducing agents
• Tumours induced by viruses can be tissue-specific
• Can transform 100% of a cell population in vitro

Inject cell-free
chicken lung
cancer extract
Lung cancer Lung cancer

Chicken A Chicken B Chicken B

• Result: chicken B develops same cancer as chicken A in the same tissue

(lung)
• Conclusion: the cancer-inducing agent in the cell-free extract was small
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• Later experiments showed that the agent was a virus
 DNA tumour viruses involved in
human cancers
#1) Human papilloma viruses (HPVs)
– Group of 100+ viruses
– Cause warts (benign tumours)
– HPVs that cause common warts (on hands and feet) are different
from the ones that cause warts in genital or throat areas
– Some HPVs are associated with virulent forms of cancer and are
considered high-risk or carcinogenic HPVs
– Most HPV infections occur without any symptoms and go away
without any treatment over the course of a few years
– Persistent HPV infections are associated with cervical cancer
– Oral HPV is a strong risk factor for oropharyngeal cancer

#2) Polyoma DNA virus, small genome (5,000 nucleotides, codes for
1,500 amino acids, 1/3 encoded proteins are viral coat proteins). Used
widely in lab experiments to transform tissue culture cells into uncontrolled
cell division in cancer research. 15
 What types of cells in the body
can become cancerous?
1. Cells that are undergoing controlled division
(e.g. stem cells in bone marrow, epithelial skin
cells)

2. Post-mitotic (non-dividing) cells (e.g.

neurons)...although their odds of turning
cancerous is lower than rapidly dividing cells

In other words, a wide range of cell types may

become cancerous
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Carcinogenesis: how does a cell
become cancerous?
1. Malignant transformation: normal cell acquires the
properties of cancer

2. Malignant degeneration: benign tumour turns

malignant

Hence cancer is a HERITABLE

change (transferred to all daughter
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cells)
 Tumour-suppressor gene
• Function: these genes encode proteins that regulate the
cell cycle and/or promote apoptosis.
• If mutated, loss of function of a tumour-suppressor gene
enables a cell to progress towards cancer (usually other
changes are required as well)

• Example- p53:
– Activates DNA repair proteins
– Arrests the cell cycle long enough for repairs to be
made
– Initiates apoptosis if damage is too severe
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 Proto-oncogenes
• During normal development, proto-oncogenes are
highly expressed and are involved in controlling normal
cell division during embryonic growth
• In the adult, these genes are turned off (or expressed
at very low levels) in most cells
• A proto-oncogene’s protein product has the potential to
cause cancer if expressed at the wrong time or in
improper amounts
Proto-oncogenes encode for proteins that regulate cell
growth and differentiation during normal development

Proto-oncogenes can be:

1. Growth factors
2. Kinases
3. G coupled receptors
4. Membrane associated G proteins
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5. Transcription factors
Improper activation of proto-oncogenes

• During ‘transformation’, proto-oncogenes may

be changed into ONCOGENES (altered version
of the normal proto-oncogene in which the gene
is always turned on)

• Most oncogenes require another mutation in an

additional gene in order to cause cancer

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 Cancer at the gene level
Cancer is a heritable change. This suggests that
changes are occurring at the gene level.
How? Three mechanisms are-

1. Gene jumping (gene is translocated to a new

chromosomal site, changing its pattern on gene
expression)
2. Point mutation (base pair change/deletion/insertion)
3. Introduction of a regulatory DNA sequence into host
which turns on a gene that would normally be inactive

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 Comparison of
normal cells vs. cancer cells grown in
tissue culture
Normal cells exhibit- Cancer cells exhibit-
• Limited number of cell divisions • Unlimited cell divisions
• Contact inhibition • Loss of contact inhibition
• Normal cell recognition • Altered cell recognition
• Normal cell adhesion • Altered cell adhesion

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 Cell division: normal cells vs.
cancer cells
Normal cells:
• When grown in tissue culture, cells will proliferate at first, but as cell
density builds up, cell division slows and eventually stops
• Undergo a limited number (~70) of mitotic divisions
• Theory: ‘old’ cells stop expressing the enzyme telomerase, which is
responsible for maintaining telomeres at the ends of chromosomes,
and this stops cell division.

Cancer cells:
• Proliferate indefinitely in culture (said to be immortalized)
• Continue to express telomerase and consequently they are not
triggered into ceasing cell division
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 Contact inhibition in normal cells
• When two normal cells touch, 1) cell movement stops and 2) cell
division stops; this is a mechanism for controlling cell division
• As long as cell density is low, cells divide regularly
• Cell division occurs until all space on bottom of culture dish has
been filled and a monolayer has formed
• Transfer cells to a new dish  start dividing again

Cancer cells  loss of contact inhibition

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 How do normal cells know to
stop dividing once they come in
contact with a neighboring cell?
Normal cells have cell recognition molecules on
their surface so that when a cell comes in contact
with another cell, these molecules sense that cell
density is high and a cessation of cell division is
triggered

Cancer cells have altered cell recognition ability,

thus they continue to divide and pile up
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 Cell adhesion: normal cells
Cell adhesion molecules are involved in cell
recognition

Cell adhesion Cell adhesion

molecules are molecules are
lost regenerated

Result: normal cells re-aggregate into tissue

fragments 26
 Cell adhesion: mixing 2 types of normal cells

Result: Cells sort themselves into two populations such

that tissue fragments that are composed of only one cell
type, liver or kidney cells. Not both

Conclusion: normal cells only associate with their own cell

type 27
Cell adhesion: mixing cancer cells
with normal cells

Result: cancer and kidney cells clump together

Conclusion: The cancer cells exhibit altered cell adhesion

and cell recognition properties
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 Comparison of biochemistry of
normal and cancer cells
When studying cancer, a main goal is to identify
biochemical differences between cancer cells and
normal cells
Some proteins are present at higher or lower
concentrations in cancer cells than normal cells

Problems with a direct comparison of protein levels

between normal and cancer cells:
1. What caused the difference? The cancer inducing
event or secondary change?

2. What was the original cell that became cancerous?

(hard to tell in a complex tissue composed of many cell
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types)
Cancer cells exhibit the Warburg Effect

• Most tumours rely on anaerobic glycolysis even when oxygen levels

are high: this is called the Warburg effect
• This switch from aerobic to anaerobic glycolysis is inefficient (36-38
ATP/glucose vs. 2 ATP/glucose respectively)
• As a consequence of this switch, tumour cells consume glucose at a
much higher rate than normal cells
• The Warburg Effect is beneficial for tumours: it allows them to out-
compete surrounding normal cells for available resources (by soaking
up glucose) and invade normal tissue
• The Warburg Effect ALSO results in decrease in extracellular pH 
this triggers 1) apoptosis of normal cells, but not the tumour cells, 2)
enhanced angiogenesis and 3) decreased immune responses and
degradation of ECM
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• Warburg effect is vital for the cancer cell’s survival and growth
 Antigenic differences between
normal and cancer cells?
• Original belief: cancer cells do not have antigenic
differences (enabling cancer cells to escape the
immune system and grow out of control)

• Current belief: cancer cells DO have antigenic

differences

Why do most people not get cancer?

• Cancer occurs more frequently in our bodies than originally
thought
• It is estimated that many cancerous cells are produced in the
body but they are detected and removed by control
mechanisms in the body 31
 Immune surveillance
• Our normal immune system detects cancerous cells- and then
macrophages, natural killer cells or cytotoxic T cells remove them
• Tumours develop when the immune system is compromised or is
overwhelmed
• Support for this theory comes from studies on organ transplants. Patients
are often put on immunosuppressant drugs to minimize organ rejection.
Unfortunate side effect of these drugs is an increased in rate of tumour
formation in organ transplant patients receiving immunosuppresent drugs

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 Cancer Therapies
Traditional methods:
» Surgery (best for tumours)
» Chemotherapy
» Radiotherapy

(often used in combination sequence- surgery first

removes mass of tumour and chemo or radiotherapy
subsequently tries to knock out cancer cells missed in
the surgery):

Newer methods:

» Immunotherapy
» Angiotherapy
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 Chemotherapy
• Selective uptake of a harmful therapeutic chemical by
rapidly dividing cells that kills them
• For example, 5-fluorouracil: a modified nucleotide that
leads to cell death when incorporated into the DNA of
dividing cells
• Can be used topically for skin cancer or systemically
(i.v.) for internal cancers
• Many side effects (especially if given systemically)
because drug is not cancer-specific and affects other
dividing cells in the body (can induce vomiting, skin
problems, internal organ problems, hair loss)
• Chemotherapy is still one of our best cancer-fighting
methods
• New chemotherapy drugs are constantly being
developed 34
 Radiotherapy
• Focused radiation beam on tumour to kill cells directly or
by interfering with cell proliferation
• Different beams have different energy levels, which
determine the depth at which the radiation will penetrate
the body
• E.g. electron beams  treat skin cancers, whereas X-
rays  internal cancers
• Side effects (skin burns, vomiting, mouth ulcers, dry
eyes, etc.)
• Some cancers respond better (e.g. lymphomas) than
others (e.g. melanoma skin cancers)
• Advantage- radiotherapy beam can to focused on deep
body cancers that are difficult of dangerous to reach by
surgical methods (for example- brain tumours) 35
 Immunotherapy
• Methodology stemmed from discovery of
immune surveillance
• Still relatively new
• General stimulation of immune system does not
work as well as selective stimulation
• Therapeutic approaches-
• #1 Cancer vaccines (vaccines made to cancer
specific proteins)
• #2 Interleukin-2
• #3 Tumour necrosis factor 36
 Cancer vaccines
• Inject cancer antigen (a cancer specific protein)
to stimulate immune response against that
antigen

• Problem: vaccines are not always sufficient to

reverse the progression of cancer

• Benefit: minimal side effects and may provide

useful anti-cancer effects

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 Interleukin-2 (IL-2)
IL-2 is normally found in the body and is responsible for transforming
white blood cells into killer cells.

1) Produce IL-2 in bacteria (using biotechnology). Add mass-produced

IL-2 to blood taken from cancer patient, incubate (IL-2 converts white
blood cells into killer cells), then transfuse blood back into patient.
Result: decreased tumour size
Side effect: increased water retention in internal organs

2) Animal trial stage: Excise piece of tumour tissue. Mince tumour

tissue and add IL-2 (T lymphocytes become TUMOUR INFILTRATING
LYMPHOCYTES). Inject back into mouse.
Result: decreased tumour size

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 Tumour necrosis factor (TNF)
• Naturally occurring factor produced by white
blood cells
• Attacks and destroys cancer cells
• Known for some time for its cancer cell-killing
ability in lab experiments
• In vivo, tumours still arise in the body. Why? It is
thought that TNF is not made in large enough
quantities in the body to keep up with the tumour
growth
• Mechanism of action- TNF binds to a cell
surface receptor and triggers apoptosis
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 Attempts of using TNF for
cancer therapy
First attempt: Give extra TNF to
cancer patient to attach tumour.
Problem: doses needed to kill the
tumour triggers major toxic effects

Second attempt: Modify

molecular structure of TNF cell
surface recognition domain so
that modified TNF is not toxic to
normal cells, but retains its
tumour-killing ability. Tumour size
shrinks (in mice), but needs to be
tested in primates to see if
effective in higher order species
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 Angiotherapy
• Recent cancer fighting technique
• Developed to help kill resistant cancer cells. Cancer cells have
unique ways of destroying chemotherapeutic drugs that have been
developed to kill them (hence some cancer cells are resistant to
chemotherapy)
• Different approach: attack the blood vessel system that supplies
nutrients and oxygen to the tumour
• As tumour grows  the tumour stimulates growth of blood vessels
(angiogenesis) into the tumour (i.e. tumours develop their own
blood vessel system)
• Anti-angiogenic drugs hamper/knock out the growth of blood vessels
into the tumor, thus starving the tumour. The rationale is that the
weakened tumour cells will now be more sensitive to chemotherapy
and/or radiation treatment.

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The End

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