What is Cancer?
Cancer is a genetic disease:
Inherited cancer
Sporadic cancer
Cancer typically involves a change in gene
expression/function:
Qualitative change
Quantitative change
Any cancer causing genetic alteration typically results in
loss of cell growth control.
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What is Cancer?
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What is Cancer?
Malignant Vs. Benign growth
Benign: called a tumor
Well circumscribed, slow growing, non invasive, non metastatic.
Malignant: called a cancer
Not well organized, irregularly shaped, fast growing, infiltrative
growth, metastatic.
Initial stages of malignant cancer may typically show
benign growth;
further accumulation of mutations may make it malignant.
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Benign Vs. Malignant Tumors
Benign tumors are
tumors that cannot
spread by invasion
or metastasis;
hence, they only
grow locally.
Malignant tumors
are tumors that are
capable of spreading
by invasion and
metastasis.
By definition, the
term "cancer"
applies only to
malignant tumors.
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From: National Cancer Institute : http://press2.nci.nih.gov/sciencebehind/cancer/cancer00.htm
Cancer: Loss of Cell
Growth Control
Cancer arises from a loss of
normal growth control.
In normal tissues, the rates of
new cell growth and old cell death
are kept in balance.
In cancer, this balance is
disrupted. This disruption can
result from uncontrolled cell
growth or loss of a cell's ability to
undergo "apoptosis."
Apoptosis, or "cell suicide," is the
mechanism by which old or
damaged cells normally self-
destruct.
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From: National Cancer Institute : http://press2.nci.nih.gov/sciencebehind/cancer/cancer00.htm
Tumor Cell Formation
Loss of Cell Cycle Regulation at Checkpoints
Increased growth rate, escape from
apoptosis
Accumulation of DNA damage, errors in
replication, introduction of mutations,
chromosomal translocations, aneuploidies
Normal Cell Tumor Cell 6
Properties of Cancer Cells
Cancer cells exhibit several characteristics that are distinct from
normal cells.
Multiple changes are involved in the conversion of a normal cell
to a cancer cell:
Autocrine stimulation; grow in the absence of growth factors
Lack of gap junctions;
lack of contact inhibition
Resistance to cell death; persistent telomerase activity
Rapid growth; overtake population, invade other tissues.
Angiogenesis
Clonal nature of cancer
Genomic Instability: Accumulation of successive mutations
A germline mutation causes a hereditary cancer.
A somatic mutation causes a sporadic cancer.
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Properties of
Cancer Cells:
Autocrine
stimulation,
Lack of contact
inhibition,
Lack of cell
death,
Lack of gap
junctions
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Properties of
Cancer Cells:
Lack of
contact inhibition
Normal skin cells
Grow in monolayer
Skin cancer cells
Do not grow in monolayer
Pile up on each other
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Properties of
Cancer Cells:
Lack of
Apoptosis
(Programmed
cell death)
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Properties of
Cancer Cells:
Genomic
Instability
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Properties of Cancer Cells:
Changes that produce a potential for immortality
Loss of limitations on the number of cell divisions
Ability to grow in culture normal cells do not grow well in culture
Restoration of telomerase activity
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Feature Figure 18.16 c
Properties of Cancer Cells:
Changes that enable tumor to disrupt local tissue and invade
distant tissues
Ability to metastasize Feature Figure 18.16 d
Angiogenesis secrete substances that cause blood vessels to
grow toward tumor
Evasion of immune surveillance 13
Properties of Cancer Cells:
clonal descendents of one cell
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Fig. 18.18
Most cancers result from exposures to mutagens
If one sib or twin gets cancer, other usually does not
Populations that migrate profile of cancer becomes more like people
indigenous to new location
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Cancer develops over time
Males began frequent smoking after 1940
Females began frequent smoking after 1960
Fig. 18.19 16
Cancer develops over time
Mutations accumulate over time
Incidence of cancer increases with age
Fig. 18.19 17
Sporadic Vs. Familial Cancer
Familial:
inherited form. The family has a predisposition through a
germline mutation.
Increases the probability that further mutations will occur.
Sometimes the initial germline mutation may be responsible
for different cancers:
e.g. same family may have individuals with breast, bone, lung, ovarian
cancer because of a single inherited germline mutation:
e.g.: p53.
Sporadic cancers:
new mutations arising in somatic cells of the body.
Could result in any type of cancer, depending on the where the
mutation occurs.
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Familial Cancer
Inheritance of a mutation in a "cancer protection" gene in a germ
cell (egg or sperm). The offspring will have both a faulty copy and a
correct copy of the "cancer protection" gene in all the cells of their
body, and will be predisposed to develop cancer.
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From: The Center for Genetics Education Website: http://www.genetics.com.au/
Sporadic Cancer
Mutations that occur during life in the body cells (somatic
mutations) such as the cells of the breast are confined to the
breast tissue. These mutations will not be passed on to the next
generation.
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From: The Center for Genetics Education Website: http://www.genetics.com.au/
Genes and Cancer
Two classes of genes are mutated frequently in cancer:
Tumor suppressor genes: loss of function mutations.
Normal function is to prevent cell proliferation.
So-called cancer protection genes
Protooncogenes: gain of function mutations.
quantitative change in expression of these genes common in cancer
Normal function is to promote cell proliferation.
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Tumor Suppressors vs. Oncogenes
Oncogenes
dominant
mutations
Mutant tumor-
suppressor genes
recessive
mutations
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Multistep Nature of Cancer
Cancer develops progressively as mutations accumulate.
Experimental evidence in mice with either the ras OR the myc
protooncogenes mutated: fewer tumors develop than when BOTH
genes are mutated.
Mice with only one allele of the tumor suppressor p53 mutated are
not as cancer prone as when both alleles are mutated.
Hereditary adenomatous polyposis or Familial adenomatous
polyposis (FAP):
a typical example of the multi-step pathway for cancer.
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Multistep Nature of Cancer
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The Multi-Step
Model for
Colon Cancer
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The Multi-Step Model
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Genomic Approaches to Cancer
Diagnostics and Therapies
Cancer Diagnostics Goal:
Properly classify the type of cancer
To properly treat that specific type
Usually done by morphology,
Certain tumor surface markers,
and Identification of translocations
Now, genomic approaches can help
Determine the gene expression array of the tumor
Compare to tumors with known patient outcome
Gene profiling
Example: Non-Hodgkin Lymphoma, DLBCL 29
Non-Hodgkin Lymphoma, DLBCL
Normal B lymphocytes Diffuse Large B Cell Lymphoma
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Non-Hodgkin Lymphoma, DLBCL
Higher patient survival rate correlates
with GC B-like RNA profile
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Homework
Chapter 22
# 15, 16,
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