Download 03.30.11 Cancer Biology

03.30.11
Cancer Biology
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Outline
1.How do cancer cells differ
from normal cells?
2.Tumor progression
3.Molecular basis for cancer
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Cancer is the second leading cause
of death in the U.S.
Cancer accounts for nearly one-­‐quarter of deaths in the United States, exceeded only by heart diseases. In 2004, there were 553,888 cancer deaths in the US.
Cancer may be derived from many
tissues
Epithelial cells
ConnecIve Issue
Muscle Issue
Epithelial cells: carcinomas 80-­‐90%
ConnecIve Issues: sarcomas 1%
Blood and lymphaIc systems: leukemias, lymphomas Neuronal system: neuroblastoma, reInoblastoma, etc.
The most common types of cancer involve epithelial cells. These compose 80-­‐90% of cancers.
A cancer like this would be called Carcinoma.
There are also cancer that evolve from transformaIon of non-­‐epithelial cells. There are three main groups:
Cancer of the connecIve Issues: Sarcoma (1%)
Cancer of the blood and lymphaIc system: Leukemia, Lymphoma, Myeloma
Cancer of the neuroectodermal system system: Neuroblastoma, Re?noblastoma
Cells within a tissue are normally highly
organized and tightly regulated
e.g. intesIne
e.g. skin
Cancer: an aberration of normal
development
Cancer cells exhibit behaviors found in normal
cells during development differentiation, and
homeostasis
Cancer cells exhibit behaviors found in normal cells during development & differen?a?on.
However, in cancer cells these proper?es are separated from normal developmental controls
& combined in unique & troublesome ways.
Cancer: an aberration of normal
development
Cancer cells exhibit behaviors found in normal
cells during development differentiation, and
homeostasis
However, cancer cells put together suites
Of cell behaviors in problematic ways
And do so out of normal regulatory controls
Cancer cells exhibit behaviors found in normal cells during development & differen?a?on.
However, in cancer cells these proper?es are separated from normal developmental controls
& combined in unique & troublesome ways.
Properties of Cancer Cells
Most normal cells have a limited potential
to divide
senescent cells
In what ways cancer cells differ from normal cells?
1. Cancer cells are "immortalized"-­‐ i.e. conInue to divide indefinitely
without differenIaIng-­‐ a normal property of body's stem cells
Normal stem cells can divide
indefinitely, but under tight control
Differen?ated cells
Self-­‐renewing stem cell
In what ways cancer cells differ from normal cells?
1. Cancer cells are "immortalized"-­‐ i.e. conInue to divide indefinitely
without differenIaIng-­‐ a normal property of body's stem cells
Properties of Cancer Cells
Cancer cells are "immortalized”,just like stem
cells, but w/o control
Differen?ated cells
Self-­‐renewing stem cell
In what ways cancer cells differ from normal cells?
1. Cancer cells are "immortalized"-­‐ i.e. conInue to divide indefinitely
without differenIaIng-­‐ a normal property of body's stem cells
Cancer cell
Most Normal cells
differentiate
3. Cancer cells fail to form differenIated Issues like epidermal sheets, or specific blood cells But stem cells
do NOT
differentiate
3. Cancer cells fail to form differenIated Issues like epidermal sheets, or specific blood cells Like normal stem cells cancer
cells do not differentiate
tumor
3. Cancer cells fail to form differenIated Issues like epidermal sheets. Most normal cells stop proliferating
under contact inhibition
in vitro
Figure 20-­‐29 Molecular Biology of the Cell (© Garland Science 2008)
2. Cancer cells not under contact inhibiIon
Normal cells stop dividing when come into contact with neighbors. Normal blastocyst stage embryonic cells share this property.
in vivo
Cancer cells do not exhibit contact
inhibition
Figure 20-­‐29 Molecular Biology of the Cell (© Garland Science 2008)
2. Cancer cells not under contact inhibiIon
However cells of early embryos
also lack contact inhibition - thus cancer
cells exhibit properties off embryonic
cells
Cancer cells exhibit altered cell
adhesion and cytoskeletal
organization
Normal
“Transformed”
These changes in cell shape and
behavior are shared by many
migrating cells,including those that
migrate into wound sites
Late stage cancer cells are
invasive
normal ?ssue
invasive tumor
Figure 20-­‐17 Molecular Biology of the Cell (© Garland Science 2008)
5. Cancer cells are invasive
Normal cells can be invasive at
the right time and place
5. Normal cells can also be invasive (inflammatory response, EMT).
A neutrophil penetrates through blood vessels and the extra-­‐cellular matrix as part of an inflammatory response
Normal cells that are starved for O2
Induce Angiogenesis
Can’t breathe!
Send Blood vessels
Consequences
1. Nutrients and oxygen are supplied to the tissue
Cancer Cells also Induce Angiogenesis
Consequences
1. Nutrients and oxygen are supplied to the tumor
2. New blood vessels provide as easy way out
Normal cells may undergo
apoptosis
As part of a
developmental
program
4. Cancer cells do not undergo normal programmed cell death.
when cells become
“dangerous” (e.g.
DNA damage)
Properties of Cancer Cells
Cancer cells escape apoptosis
Blue cells = breast cancer cells
Yellow cells = apopto?c cells
Dave McCarthy and Annie Cavanagh
4. Cancer cells do not undergo normal programmed cell death.
Properties of Cancer Cells
• Immortalized
• Do not differentiate
• Fail to exhibit contact inhibition
• Invasive
• Escape apoptosis
Cancer develops through gradual
changes in cell morphology and
properties
Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008)
Tumor progression, from over-­‐proliferaIon, to –”taking over” the Issue and eventually-­‐ invasion through the basal lamina
Tumor Progression
Tumor = abnormal growth of solid tissue
Benign- self
contained
Malignantinvasive
Tumor progression: Hyperplasia: cells divide in an uncontrolled manner
Dysplasia: more abnormal growth. Cells and Issues don’t look normal anymore. They sIll “Respect” the boundary of their Issue (e.g. basal lamina) UnIl now, these abnormaliIes are defined as a benign tumor. A benign tumor is not too problemaIc, as it is self-­‐contained and can be removed surgically. In the majority of the cases it does not cause death. SomeImes, benign tumors can put pressure on organs and Issues and cause problems. The big problem, however, is that one of those cells can acquire the ability to penetrate and becomes malignant. Carcinoma in situ: high risk of malignancy
Malignancy
In many cases (especially from the clinical prospecIve) only cells at this stage and on will be defined as cancer. From our prospecIve, as cell biologists, we are interested also in the early stages as they lead to cancer.
Metastasis: cell penetrate the blood vessels and sefle in foreign Issues. As the tumor is growing is needs more nutrients and oxygen and then it signals to starts angiogenesis. The forming blood vessels not only supply what the cells need but provide a way to “get out”.
Metastasis is a difficult and dangerous
process both for the tumor cell and the
host
Cellular changes required for metastasis
All cancers have a genetic basis and
are diseases caused by mutations in
normal signaling pathways
•
Random mutations (mistakes during
DNA replication)
•
Inherited mutations (pre-disposition)
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Viral infections
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Environmental factors (chemical;
physical)
Other factors that can cause mutaIons are radia?on (e.g. sun screen) and viral infec?on.
Cancer from viral infecIon is common in animals and less in humans. However there are cancers that are caused by viral infecIons, wither indirectly, like in HIV, where the body defense mechanism is compromised, or directly: human papilloma virus causes carcinoma of the uterine cervix.
That being said, the fact that viruses do cause cancer in animals was the basis for our understanding on the cellular and molecular mechanisms that are involved in human cancers
Inherited mutations may predispose
individuals towards cancer e.g.,
Familial adenomatous polyposis
(FAP)
Cancer results from a series of
mutations, each cumulatively altering
the cell
Hypothetical progression of colon
cancer
• Mutations in 4 key genes
• Progressive changes in cancerous
tumor cells
Carcinogens are chemical agents that
contribute to tumor formation
Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008)
Carcinogens contribute to cancer. We need to remember that the data are based on staIsIcal correlaIon (it is hard to prove that someone who smoked 60 cigarefes a day for 30 year dies because of that, but staIsIcal analysis in a populaIon, together with known biological carcinogenic effects of specific chemicals (e.g. in cigarefes) do not allow us to give the benefit of the doubt.
Tumors evolve by repeated rounds
of mutation and proliferation
AccumulaIon of mutaIons
The fact that cancer
is a multi-step
process is reflected
in correlation
between age and
incidence of
cancers
Figure 20-­‐7 Molecular Biology of the Cell (© Garland Science 2008)
This mulI-­‐step process and accumulaIon of mutaIons in Ime is reflected in correlaIon between old age and incidence of cancers
Especially late in the process,
Cancer cells also accumulate
chromosomal abnormalities
Karyotype from breast cancer cell
• Total of 48 chromosomes (instead of 46)
• Multiple chromosomal translocations
Two classes of genes are
mutated in cancer:
1. Oncogenes
2. Tumor suppressor genes
Oncogenes
Proto-oncogene: a normal cellular gene that
can become an oncogene, upon DNA damage
Following this discovery, many genes from infecIous viruses that can transform animal (not human) cells , were found in animal (and human) normal cells. We disInguish between them as oncogenes (e.g. v-­‐src) and proto-­‐oncogenes (c-­‐src). Oncogenes result from rare dominant
mutations that lock signaling machinery in
the ON state
Examples of oncogenic
mutations
Mutations that cause ligandindependent receptor
activation
(dimerization)
The molecular basis of cancer.
When v-­‐src was introduced to chicken, the cells became cancerous, although there was sIll a normal, endogenous copy of c-­‐src. This is also true for proto=oncogenes that become oncgones due to mutaIons and not because of viruses. Thus, a cellular Oncogene is dominant.
One mutated copy is enough.
If a proto-­‐oncogene has a normal, cellular role and when it is mutated into an oncogene, it can promote cancer, what would you expect its cellular role is?
AffecIng funcIons that are criIcal for cell proliferaIon and survival, but funcIons that are normally under control. In a cell that carries an oncogene, the same “normal” funcIon lost its control.
Oncogenes result from rare dominant
mutations that lock signaling machinery in
the ON state
Examples of oncogenic
mutations
Mutations that lock Ras into
the GTP-bound form
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Tumor suppressor inactivation result from
rare recessive mutations that lock signaling
machinery in the OFF state
Examples of oncogenic mutations
Mutations that inactivate the Retinoblastoma protein (Rb)
Tumor suppressor inactivation result from
rare recessive mutations that lock signaling
machinery in the OFF state
Examples of oncogenic mutations
Mutations that inactivate p53
Also promotes cell death