Oncology
Cancer
• More than 100 forms of the disease
• Almost all tissues can spawn cancer and
some tissues can produce several types
• Each type of cancer has some unique
features but
• Basic processes appear to be quite similar
Cancer
• One cell with genetic mutations
• Uncontrolled cell reproduction
• Additional genetic mutations in daughter
cells as abnormal cells multiple
• Tumor
• Additional mutations
• Metastasis
Multistage Theory of
Carcinogenesis
• Initiation
• Promotion
• Progression
Multistage Theory of
Carcinogenesis
Initiation
– Alteration in structure and function of DNA
with little change in structure or function
caused by exposure to carcinogen which may
include
• Radiation
• Chemical exposures
• Viral infections
Multistage Theory of
Carcinogenesis
Promotion
– Process in which initiated cell is stimulated to
become malignant
– May affect initiated cell by
• Stimulation of cell division
• Interfering with differentiation
– Promoters may include: chemicals, drugs,
hormones, nutritional factors, wound healing,
developmental stage
Multistage Theory of
Carcinogenesis
Tumor Progression
– Evolution of progressively more malignant
cells and development of metastatic colonies
– May be influenced by
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Hormone responsiveness
Growth rate
Invasiveness
Additional mutations
Drug resistance
Host defense response
Multistage Theory of
Carcinogenesis
Initiated /cell
Differentiated
cell
Cell Death
Pre-malignant
Cell
Cancer Cell
M etastatic
Cell
Characteristics of Cancer Cells
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Altered Cell Structure
Altered Cell Interactions
Reduced Requirements for Growth
Immortality
Production of different proteins
Altered Metabolism
Increased uptake of glucose
Circumvent normal controls on growth
Secrete enzymes that enable them to invade
neighboring tissues and move through tissue
Cancer is a Genetic Disorder
• Abnormal behaviors in cancer cells are the
result of genetic mutations
• Cells become progressively more
abnormal as more genes become
damaged
• Genes that are responsible for DNA repair
eventually become damaged creating
more genetic havoc
Genetic Mutations
• Two main categories of mutation
– Point mutations: changes that alter only a few
nucleotides in the DNA
– Chromosomal mutations: changes involve the
breakage and movement of chromosome
fragments.
Chromosomal Mutations: Translocations
Breakage and repositioning of chromosomal segments
BCL-2 codes for a membrane protein. In B cell leukemia, the gene is translocated from the normally
quiet area on 14 to a very actively transcripted area on chromosome 18 and the BCL-2 protein is
expressed at very high levels. Normally B lymphocytes do their job and die. In B cell leukemia, the
abnormal cells persist and reproduce.
Chromosome 18
14
Chromosomal Mutations: Translocations
Philadelphia Chromosome
– Occurs in chronic myelogenous leukemia
– Results from a translocation between chromosomes 9
and 22
– The abl gene from chromosome 9 is repositioned next
to the bcr gene on chromosome 22. Together these
form the Philadelphia chromosome
– The two genes are fused and produce a hybrid
abl-bcr protein
– Abnormal protein acts to increase rate of mitosis and
prevent cell death
Chromosomal Mutations: Amplification
Many copies of a segment of a chromosome are produced
leading to multiple copies of selected genes. If overexpressed area contains an oncogene, dysregulation of cell
growth can occur.
Epigenetic Changes
• These changes do not alter the DNA or
chromosome but do influence activity of
the genes
– Methylation: addition of methyl group to DNA
inactivate the gene
– Acetylation: addition of an acetyl group
causes loosening of the DNA-Histone
interaction and allows more gene expression
Mutations
DNA can be altered by
• Spontaneous mutations
• Unrepaired replication errors
• Random molecular events
• Induced mutation
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Radiation
Chemical mutagens
Chronic inflammation
Oxygen radicals
• Viral Mutations
• Inherited Mutations
• BRCA 1 and BRCA 2 associated with breast and ovarian cancers
• MSH2 mutation leads to hereditary non-polyposis colorectal cancer
• Rb mutation leads to retinoblastoma, osteogenic sarcoma and
others types of cancer
Viruses Associated with Cancer
RNA Viruses
Cancer
Human T cell leukemia virus T cell leukemia
(TCLV )
Lymphoma
Mammary tumor virus
Breast carcinoma
DNA Virus
Human papilloma virus
Cervical cancer
Ebstein-Barr virus
African Burkett’s lymphoma
Nasopharyngeal carcinoma
Hepatocellular carcinoma
Hepatitis B
Mutations Accumulate Over Time
The Genes of Cancer
• Two main groups
– Genes whose products stimulate division and
survival of cells
• Normal copies of these genes are called
proto-oncogenes
• Mutated copies of these genes are call
oncogenes
– Genes whose products prevent cell division or
lead to cell death are called suppressor genes
The Genes of Cancer
• Normal regulation of cell function depends
on a balance between
– genes that stimulate cell division and survival
and
– genes that prevent cell division or regulate
cell death (apoptosis)
The Genes of Cancer
Proto-oncogenes are like the gas pedal of the car.
When functioning properly, the car moves only
when the gas pedal is pushed.
Oncogenes cause the gas pedal to be stuck in the
“on” position
Suppressor genes act like the brakes. Each copy
of the suppressor gene acts like one part of the
brake system. If both copies of a suppressor
gene is mutated, the car has no brakes
Oncogenes produce proteins that
function as:
Oncogenes: HER 2/Neu
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Gene that codes for epidermal
growth factor receptor 2 found on
cell membranes
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Amplified in 30% of breast tumors
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Over-expression of this gene in
tumor cells is associated with poor
cellular differentiation and
decreased patient survival
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Trastuzumab (Herceptin) is a
monoclonal antibody that binds
the HER 2/NEU protein and
blocks its activity, thereby
preventing cellular replication
Oncogenes: RAS
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The RAS protein acts like relay
switch that leads to activation of
genes that regulate cell division
and differentiation
When a growth factor binds a
receptor, the RAS protein sends a
message to divide to the nucleus
When RAS is over-expressed
the positive signals for cell division
outweigh the negative signals and
the cell divides
When RAS is mutated the relay
switch is stuck in the “ON”
position, continually telling the cell
to divide even when it should not
Oncogenes: RAS
• Mutated RAS has been found in many
tumor types
– Pancreas
90%
– Colon
50%
– Lung
30%
– Thyroid
50%
– Ovarian
15%
– Breast, skin, liver, kidney and some leukemias
Other Important Oncogenes
• MMPs: matrix metalloproteases
• Mdr: multiple drug resistance
– Codes for pump that removes toxins from cell.
May be amplified in cancer cells, pumping out
chemotherapeutic agents and decreasing
their effectiveness
Suppressor Genes
• Act to inhibit cell division
• A loss of function of the gene leads to
cancer
• Act as the brakes on cell division
• Generally both copies must be ineffective
for cancer to develop/progress
Suppressor Gene: p 53
• Found to be defective in ~50%
of tumors
• Functions as the guardian of
the genome and conductor of a
network of proteins that
monitor the health of a cell
• Acts a transcription factor for
several genes, including p21
which prevent cell division
• This allows a cell time to repair
its DNA.
• If repair is not successful, p53
promotes apoptosis
Suppressor Gene: Rb
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Normally function includes:
– binds with transcription factors
to prevent cell division
– promotes apoptosis
– post-translational processing
of proteins
Mutated in several types of cancer
including retinoblastoma,
osteosarcomas and carcinomas
Mutations may be sporadic or
familial
Suppressor Gene: BRCA
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Mutations associated with subsets
of breast and ovarian cancer but
also found in prostrate, pancreatic,
colon and other cancers
Mutations may be inherited or
arise spontaneously
An important BRCA function is the
repair of DNA. When this function
is impaired, cells are more
vulnerable to new mutations in
DNA
Genetic Mutations and
Development of Cancer
• For cancer to occur at least three genetic
aberrations must be present
– One to push cell to unrelenting cell division
– One to inactivate signals for cell to stop dividing
– One to release “brake” on cells life span
• Other genetic derangements are usually present
as well
• Additional mutations develop as rapid cell
divisions proceeds
Tumor Progression
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Hyperplasia
Dysplasia
In situ tumor
Invasive tumor
Metastasis
Summary
• Cancer is caused by genetic mutations
which
– Promote cell division
– Prevent cell death
– Promote tumor survival and spread
• Identifying the specific mutations
– Predicts progression and prognosis
– Identifies molecular targets for better
treatments
Mr. B’s Story
Mr. B. is a 56 year old man who fell while cleaning
the gutters. An x-ray, taken to rule out a
fractured rib, revealed a small shadow in the
upper lobe of his right lung. A subsequent CT
scan indicated the spot was suspicious for
cancer and surgery was performed to remove
the mass.
Analysis of the tumor revealed non-small cell lung
carcinoma. Based on clinical and pathologic
characteristics the tumor was staged as IA.
Mr. B’s Story
• Mr. B’s physicians explain that
– Stage IA indicates a small, early tumor without evidence of
spread
– The current standard for treatment of patients with stage IA
NSCLC is surgical resection without adjuvant chemotherapy.
– Studies show that 25% of these patients will relapse after initial
surgery and have a poor prognosis. This subgroup of patients
would probably benefit from chemotherapy.
– However, chemotherapy poses significant risks also.
• The physicians believe that, based on clinical staging of
IA, the risks of chemotherapy outweigh the benefits and
they recommend close follow up without chemotherapy.
• Mr. B. and his wife accept their advice but are very
worried about recurrence of the cancer.
Question
Since the current clinical staging system for
NSCLC has limitations in determining
prognosis and optimal treatment, is there a
way to identify whether Mr. B. is among
the 25% at risk for relapse who would
benefit from chemotherapy?
Question
• Similarly, patients with stages IB, IIA, and
IIB routinely receive chemotherapy after
surgery even those a subgroup of these
patients are unlikely to relapse. Is there a
way to identify these low risk patients and
eliminate their exposure to the risks of
chemotherapy?