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Source (American Cancer Society)

http://www.cancer.org/cancer/cancerbasics/what-is-cancer
Basic Properties of a Cancer Cell
Basic Properties of Cancer Cells
Loss of Growth Control
Normal Cells Cancer Cells
Growth Control
Normal cells proliferate to the point
where they cover the bottom of the
culture dish, their growth rate decreases
markedly, and they tend to remain as a
single layer (monolayer) of cells.
Loss of growth Control
They continue to grow, piling on top of
one another to form clumps
Not responsive to the types of signals
that cause their normal counterparts to
cease growth and division
Ignores Inhibitory Growth Signals
Basic Properties of Cancer Cells
Growth w/o Stimulatory Growth Signals
Normal Cells Cancer Cells
Normal cells depend on growth factors Growth in the absence of Stimulatory
Growth Signals
The cell cycle of cancer cells does not
depend on the interaction between
growth factors and their receptors, which
are located at the cell surface.
Basic Properties of Cancer Cells
Indefinite Cell Division, Immortalization
Normal Cells Cancer Cells
Limited Capacity for Cell Division
After a finite number of mitotic
divisions, they undergo an aging process
that renders them unfit to continue to
grow and divide;
Absence of telomerase from most types
of normal cells is thought to be one of
the body's major defenses that protects
against tumor growth.
Indefinite Cell Division, Immortalization
Attributed to the presence of telomerase
(enzyme that maintains the telomeres at
the ends of the chromosomes, allowing
cells to continue to divide) in cancer cells
Shows uncontrolled mitotic divisions
causing unorganized growth and later on,
tumors (neoplasms)
Basic Properties of Cancer Cells
Highly Aberrant Chromosome Complements: Aneuploidy
Normal Cells Cancer Cells
Normal cells maintain their diploid
chromosomal complement as they grow and
divide, both in vivo and in vitro.
Cancer cells are genetically unstable and
often have highly aberrant chromosome
complements, a condition termed
aneuploidy
Occurs primarily as a results of defects in
the mitotic checkpoint or the presence of
an abnormal number of centrosomes.
The growth of cancer cells is much less
dependent on a standard diploid
chromosome content than the growth of
normal cells
Basic Properties of Cancer Cells
Protection from Apoptosis
Normal Cells Cancer Cells
When the chromosome content of a normal
cell becomes disturbed, a signaling pathway
is usually activated that leads to the self-
destruction or apoptosis of the cell.
Protection from Apoptosis.
Cancer cells typically fail to elicit the
apoptotic response even when their
chromosome content becomes highly
deranged.
Basic Properties of Cancer Cells
Cancer Cells
Metastasis
Ability to invade new sites
They grow at an increase rate and will slowly overtake the good cells and then
effect internal parts until they have consumed all that is available unless treatment
is sought.
Cancer cells often depend on glycolysis, which is an anaerobic metabolic pathway;
reflects the high metabolic requirements of cancer cells and an inadequate blood
supply within the tumor;
under hypoxia, cancer cells activate a transcription factor called HIF that induces
the formation of new blood vessels and promotes the migratory properties of the
cells, which may contribute to the spread of the tumor.
Basic Properties of Cancer Cells
Cancer Cells
Ability to spread
Cancer cells are far less adhesive than the normal cells, so these generally wander
through the tissues to cause cancerous growth in different parts of the body
The Causes of Cancer
Percivall Pott
- 1975
- British surgeon
- Made the first known correlation between an
environmental agent and the development of cancer.
- Concluded that the high incidence of cancer of the
nasal cavity and the skin of the scrotum in chimney
sweeps was due to their chronic exposure to soot.
All carcinogenic agents have one thing in common: they
alter genome.
- Carcinogenic chemicals
- Ionizing radiation
- DNA- and RNA-containing viruses.
Also mutagenic.
A number of viruses can infect mammalian cells
growing in cell culture, transforming them into
cancer cells.
Two groups of viruses: DNA tumor viruses and
RNA tumor viruses.
- Classified depending on the type of nucleic acid
found within the mature virus particle.
DNA tumor viruses
- Polyoma virus, simian virus 40 (SV 40), adenovirus,
and herpes-like viruses.

RNA tumor viruses or retroviruses
- Similar in structure to HIV
- Subject of Experimental Pathways
Tumor viruses
- Can transform cells because they carry genes whose
products interfere with the cells normal growth-
regulating activities.
- Invaluable tool in identifying numerous genes
involved in cell transformation.
- Associated with only a small number of human
cancers.
Other types of viruses are linked to as many as 20
percent of cancers worldwide.

In most cases, these viruses greatly increase a
persons risk of developing the cancer, rather than
being the sole determinant responsible for the
disease.
This relationship between viral infection and cancer
is illustrated by human papilloma virus (HPV),
which can be transmitted through sexual activity
and is increasing in frequency in the population.
- Present in 90% of cervical cancers.

HPV is also linked as a primary causative agent of
cancers of the mouth and tongue in both men and
women.
Other viruses linked to human cancers include:
- hepatitis B virus, which is associated with liver
cancer;
- Epstein-Barr virus, which is associated with
Burkitts lymphoma in areas where malaria is
common;
- and a herpes virus (HHV-8), which is associated
with Kaposis sarcoma.
Certain gastric lymphomas are associated with
chronic infection by the stomach-dwelling
bacterium Helicobacter pylori, which can also cause
ulcers.
Recent evidence suggests that many of these
cancers linked to persistent viral and bacterial
infections are actually caused by the chronic
inflammation that is triggered by the presence of
the pathogen.
Inflammatory bowel disease (IBD), which is also
characterized by chronic inflammation, has been
associated with an increased risk of colon cancer.
Epidemiologists
- Researchers who study disease patters in
populations.
- Determines the causes of different types of cancers.

Causes of certain cancers: smoking causes lung
cancer, exposure to ultraviolet radiation causes skin
cancer, and inhaling asbestos fibers causes
mesothelioma.
But despite a large number of studies, we are still
uncertain as to the causes of most types of human
cancer.

Diet can play a major role in the risk of developing
cancer.

Cancer rates are higher among obese individuals
than the non-obese population and studies in
primates suggests that a calorie-restricted diet
protects against cancer.
Elevated levels of insulin and insulin-like growth
factor (IGF-1)
- Primary cause of increased cancer incidence in
obese individuals.

There is also evidence that some ingredients in the
diet, such as animal fat and alcohol, can increase the
risk of developing cancer.
Examples of the latter include isoflavones found in
soy, sulforaphanes found in broccoli, and EGCG
found in tea.

Drugs that interfere with the action of estrogen
(e.g., tamoxifen or raloxifene) or the metabolism of
testosterone (e.g., finasteride) can reduce the
incidence of breast cancer or prostate cancer,
respectively.

Long-term use of nonsteroidal anti-inflammatory
drugs (NSAIDs) such as aspirin and indomethacin
has been shown to markedly decrease the risk of
colon cancer.

They are thought to have this effect by inhibiting
cyclooxygenase-2, an enzyme that catalyzes the
synthesis of hormone-like prostaglandins, which
promote the growth of intestinal polyps.

The cancer-suppressing action of NSAIDs supports
the idea that inflammation plays a major role in the
development of various cancers.
Persons who have taken the antidiabetes drug
metformin also appear to have a significantly
reduced risk of developing cancer.
The Genetics of Cancer
16.3 Genetics of Cancer
Cancer
1 out of 3 individuals have cancer
Monoclonal
Arises from the uncontrolled proliferation of once cell
Anyone can develop cancer
Billions of cells divide each day; one mutation in one cell can
make a hell lots of difference
2 types of gene mutations
1. Germ-line mutations
Inherited from parents
Plays a significance whether an individual will develop
cancer, but not very much
2. Somatic mutations
Occurs during lifetime
Has the greatest impact on whether an individual
would develop cancer

Tumors
Most common solid tumors occur at either
epithelial tissue or blood-forming tissues
These tissues have a high amount of cell divisions
Can be divided into 3 types of cells
1. Stem cells
2. Progenitor cells
3. End-products
Carcinogenesis: Formation of
Cancer
The tumor accumulates cells that have properties
favorable for the tumors growth
Telomerase-containing abnormal cells
Epigenetic
Cancer cells develop more mutations throughout
its lifetime
It becomes more and more abnormal
Drug Resistant Cancer Cells
Histological changes (Physical Appearance)
Some cancers can be detected early and prevented
Pap smear Cervix cancer

Benign Tumors
Moles
Senescence
INK4a
Disabled in human cancers
Encodes p16 and ARF

Genes Responsible for
Carcinogenesis
1. Tumor-suppressor genes
Negative regulators of cell proliferation
Elimination of these genes results in
uncontrolled growth
Play a major role in the development of many
cancers
2. Oncogenes
Encode proteins that promote loss of growth
control
Converts cells to malignant state

Retinoblastoma (Hereditary Cancer)
Childhood cancer of the retina
Caused by deletion of RB gene
Dominant genetic trait
Though unlike other dominantly inherited conditions
Both RB genes have to be mutated
Tumor-Suppresor Genes
Why RB gene?
Its deletion is present in other cancers

The Role of pRB in Cell Cycle Regulation
Helps regulate the passage of cells from G1 to S
phase
As a cell goes from G1 to S phase, many genes that
encode proteins activate
pRB forms a complex with E2F transcription
factors
Acts as a gene repressor
When the pRB-E2F
complex gets
phosphorylated, the
complex gets broken,
allowing a cell to
undergo S phase
Important as a
negative regulator
DNA tumor viruses
blocks pRB function;
no pRB, no regulation
to replication
TP53
TP 53 absence causes Li-Fraumeni Syndrome
High incidence of various cancers in victims
Similar to inheritance of retinoblastoma
Most commonly mutated gene in human cancers
Mutated TP53 has a low survival rate compared to wild-
type
TP53 needs to be eliminated for tumorigenesis to proceed
Produces p53


Importance of p53
A gene activated by p53 produces p21
p21 arrests a genetically-damaged G1 cell from proceeding to S
Enables cell time to repair genetic damaged before replicating
DNA; no p53, no p21
No p21, leads to production of abnormal cells which may lead to
malignant state
Mutations in both TP53 genes stop production of p53
p53 activated BAX gene, whose encoded protein Bax
initiates cell death or apoptosis
Drugs that restore p53 function (i.e. PRIMA1) are being
developed
Also leads cell to senescence


How does p53 work?
Healthy cell=low p53
Damaged cell=high p53
In healthy cells, p53 has a half-life of a few
minutes
Binds with M2D2, which releases the complex
into the cytosol, and then destroyed by
proteasome
In damaged cells, ATM levels rise, which
phosphorylate p53, forming a more stable form of
the protein

M2D2
Some tumor cells, although may have functional
TP53 genes, have extra copies of M2D2.
A lot of M2D2 doesnt allow accumulation of
enough p53 to lead to apoptosis
Overexpression of M2D2 has the same effect as
the absence of p53
Other Tumor-Suppressor Genes
APC
Similar function to the RB gene
Mutation leads to the formation of polyps in colon cancer
BRCA1 and BRCA2
Mutated forms promote breast cancer, and even ovarian cancer
PI3K/PKB pathway
Allows a cell to survive otherwise deadly environments
Balance of proaptotic and antiaptotic signals determines cell life
or cell death
PTEN
Prevents PKB from becoming activated
Oncogenes
Comes from mutated proto-oncogenes
Proto-oncogenes produce functional proteins present in a
normal cell
RAS
Most commonly mutated oncogene
Produce Ras (a GTP-binding protein) which serves as an on-
off switch for cell proliferation

3 Types of Oncogenes
1. Oncogenes that Encode Growth Factors or Their
Receptors
2. Oncogenes that Encode Nuclear Transcription
Factors
3. Oncogenes that Encode Products that Affect
Apoptosis
Oncogenes that Encode Growth
Factors or Their Receptors

PDGF (Platelet-Derived GF)
Sis-simian sarcoma virus
Cells affected by sis produce a lot of PDGF
EGFR (Epidermal Growth Factor Receptor)
erbB family
Encodes EGF with missing portion
Seen in lung cancer
Malignant cells contain a lot of mutated EGFR
More receptors. Fewer growth factor, more division


Oncogenes that Encode Nuclear
Transcription Factors
MYC
Cells enter G
0
stage (dormant state, readily available
for reactivation for cell division)
MYC regulates a huge number of miRNA and protein
expression
Another commonly mutated oncogene
Mutation results in overexpression of MYC; more
MYC, more cells out of G
0
stage, more division
Oncogenes that Encode Products
that Affect Apoptosis

BCL-2 (B-cell lymphoma 2)
Encodes protein that inhibits apoptosis
More BCL-2, lesser apoptosis
Leukemia

The Mutator Phenotype: Mutant
Genes Involved in DNA Repair
Cells with misfunctioning DNA repair proteins
These kind of cells are more likely to incur
secondary mutations in tumor-suppressor genes
and oncogenes
MicroRNAs
Play a role in tumorigenesis
miR-15 and miR-16 inhibit the expression of an
mRNA that produce BCL-2
Mutated misfunctioning miR-15 and miR-16 allow the
overexpression of BCL-2
New Strategies for Combating Cancer
Traditional Treatments
Surgery
Chemotherapy
Radiation

*May not be completely successful for widespread
cancer and may have serious side effects (attacks
both cancer cells and normal cells)

Targeted Therapies
affects only the cancer cells or particular proteins
relevant to the malignant cells
1. Immunotherapy
2. Inhibiting the activity of cancer-promoting
proteins
3. Inhibiting the formation of new blood vessels
(angiogenesis)
Immunotherapy
Uses antibodies or immune cells to attack tumor
cells

1. Passive Immonotherapy
2. Active/Adoptive immunotherapy
Passive Immunotherapy
Introduce antibodies as therapeutic agents; bind
to specific proteins on target cells surface
Was not successful at first because it was
produced using mouse cells, and so was seen by
human immune system as foreign
Developed humanized antibodies later on
Mice can now be genetically engineered to produce
fully human amino acid sequence

Passive Immunotherapy
Rituxan
Most effective humanized antibody
Binds to cell surface protein, CD20, to inhibit cell
growth and leads to cell apoptosis
CD20 is present in malignant cells of non-Hodgkins B-cell
lymphoma

Passive Immunotherapy
Other drugs
Vectibix- binds to EGF receptor to combat EGFR-
expressing metastatic colon cancer
Arzerra- chronic lymphocytic leukemia

Active Immunotherapy
Induces persons own immune system to fight
malignant cancer cells
Under normal conditions, the immune system does not
recognize the harmful cells
Immune cells (dendritic cells) are isolated from
patient, modified, then cultured to be
reintroduced later on

Active Immunotherapy
Limited effectivity
Time consuming and expensive since each patient
has a personalized treatment, but there have been
some cases of reduction of tumor size and
prolonging patients life
Provenge- prostate cancer treatment
DCVax- brain cancer treatment

Inhibiting Activity of Cancer-
Promoting Proteins
Block activity of cancer-promoting proteins to
kill cancer cells
oncogene addiction- tumor cells depend on
continued activity of abnormal proteins
Drugs used to target cancer cells
Drugs used to target normal cells that may
contribute to cancer cells

Inhibiting Activity of Cancer-
Promoting Proteins
Gleevec- inhibits the tumor-inducing Abl kinase
of patients with chronic myelogenous leukemia
May not always be effective due to the varied
oncogene protein sources, may not be targeting
the appropriate cells (cancer stem cells: argued to
sustain the tumor life)

Inhibiting the Formation Of New
Blood Vessels
Angiogenesis- the formation of new blood vessels
angiogenesis is stimulated with tumor growth
These blood vessels are essential to supply the necessary
materials for cell growth as well as remove cell waste
Also provide means for cancer cells to spread to other
locations
VEGF, a growth factor secreted by cancer cells promote
angiogenesis

Inhibiting the Formation Of New
Blood Vessels
Endostatin, thrombospondin, and other lab-
developed antibodies/compounds inhibit
angiogenesis
Avastin- used on VEGF and blocks it from binding to
cell its cell receptor VEGFR
Sutent and Nexavar

Inhibiting the Formation Of New
Blood Vessels
Inhibitors target normal endothelial cells
No drug resistance because normal cells do not mutate and form
resistance like cancer cells
Do not interfere with physiological processes of the body
Not curative, but may prolong life
Some debate because O
2
deprived tumor cells may
end up seeking out other sites in body

Source: http://www.miamiherald.com/2013/07/29/3529382/doctors-use-engineered-hiv-to.html
Source: http://www.theguardian.com/environment/2010/jun/07/china-cancer-villages-industrial-pollution
Source: http://pediatrics.aappublications.org/content/122/2/e305.full
Source: http://www.imb.uq.edu.au/protein-holds-key-to-cancer-spread
So why havent we cured cancer?
http://www.sciencebasedmedicine.org/persona
lized-medicine-vs-evolution/