Download Tumor suppressor genes

Cancer Biology
Bob Duronio
Gidi Shemer
metastatic tumors
Figure 20-1 Molecular Biology of the Cell (© Garland Science 2008)
Cells within a tissue are normally highly
organized and tightly regulated.
Cells of a certain type are restricted to proper area
Cell proliferation is tightly controlled
Cancer
Cells lose all controls
We are Making Progress !
US Mortality, 2004
Rank
Cause of Death
No. of
deaths
% of all
deaths
1.
Heart Diseases
652,486
27.2
2.
Cancer
553,888
23.1
3.
Cerebrovascular diseases
150,074
6.3
4.
Chronic lower respiratory diseases
121,987
5.1
5.
Accidents (Unintentional injuries)
112,012
4.7
6.
Diabetes mellitus
73,138
3.1
7.
Alzheimer disease
65,965
2.8
8.
Influenza & pneumonia
59,664
2.5
9.
Nephritis
42,480
1.8
10.
Septicemia
33,373
1.4
Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control
and Prevention, 2006.
2007 Estimated US Cancer Deaths*
Lung & bronchus
31%
Men
289,550
Women
270,100
26%
Lung & bronchus
15%
Breast
Colon & rectum
Prostate
9%
Colon & rectum
9%
10%
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
3%
Esophagus
4%
Non-Hodgkin
lymphoma
Urinary bladder
3%
3%
Uterine corpus
Non-Hodgkin
lymphoma
3%
2%
Brain/ONS
2%
Kidney
3%
Liver & intrahepatic
bile duct
All other sites
24%
ONS=Other nervous system.
Source: American Cancer Society, 2007.
23%
All other sites
This Lecture
properties of cancer cells
tumor progression
what causes cancer?
accumulation of mutations
oncogenes and tumor-suppressor genes
Cancer: an Aberration of Normal Development
Cancer cells exhibit behaviors found in normal
cells during development & differentiation.
However, these behaviors are separated from
developmental controls.
Properties of Cancer Cells
Most normal cells have a limited
potential to divide.
senescent cells
Normal Stem Cells can Divide
Indefinitely, but Under Tight Control
Properties of Cancer Cells
Cancer cells are "immortalized”,
just like stem cells, but w/o control.
tumor
Normal cells stop proliferating under
contact inhibition.
in vitro
in vivo
Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)
Properties of Cancer Cells
Cancer cells are not under contact inhibition.
Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)
Normal cells form differentiated tissues.
Properties of Cancer Cells
Cancer cells do not form differentiated tissues.
tumor
Properties of Cancer Cells
Normal cells may undergo apoptosis.
as part of a
developmental program.
when cells become “dangerous”
(e.g. DNA damage).
Properties of Cancer Cells
Cancer cells avoid apoptosis.
blue cells =
breast cancer cells
yellow cells = apoptotic
cells
Dave McCarthy and Annie Cavanagh
Properties of Cancer Cells
Cancer cells are invasive.
normal tissue
invasive tumor
Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)
Normal cells can be invasive at the
right time and place.
Dave McClay
Seward Hung
Properties of Cancer Cells
Cancer cells are "immortalized”.
Cancer cells are not under contact inhibition.
Cancer cells do not form differentiated tissues.
Cancer cells avoid apoptosis.
Cancer cells are invasive.
Naming Cancers
epithelial cells
connective
tissue
muscle tissue
epithelial cells: carcinoma
80-90%
connective tissues: sarcoma 1%
blood and lymphatic systems: lymphoma, leukemia, etc.
neuroectodermal system: neuroblastoma, retinoblastoma, etc.
Naming Cancers
Prefix
Meaning
adeno-
gland
chondro-
cartilage
erythro-
red blood cell
hemangio-
blood vessels
hepato-
liver
lipo-
fat
lympho-
lymphocyte
melano-
pigment cell
myelo-
bone marrow
myo-
muscle
osteo-
bone
Cancer develops through gradual changes
in cell morphology and properties.
benign tumor
malignant tumor
Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008)
Tumor Progression
tumor = abnormal growth of cells
benign- self
contained
malignantinvasive
Cancer Cells Induce Angiogenesis
consequences
1. Nutrients and oxygen are supplied to the tumor.
2. New blood vessels provide as easy way out.
Metastasis
Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)
Cellular Changes Required for Metastasis
Figure 20-44 Molecular Biology of the Cell (© Garland Science 2008)
Molecular Changes Required for Metastasis
Cells need to lose cell-cell adhesion contacts.
Cells need to penetrate through the matrix.
Molecular Changes Required for Metastasis
Loss of cadherins is detected in all tumors.
Metastatic cells produce high concentrations of MMPs
(matrix-metalloproteinases).
What Causes Cancer?
Cancer : Accumulation of Mutations
•
random mutations (mistakes at the assembly line)
• inherited mutations (pre-disposition)
• viral infections
• environmental factors (chemical;physical)
The first Association Between
Occupation and Cancer
Percivall Pott found that chimney sweeps show
substantially higher rates of skin cancer.
British chimney
sweeps didn’t do
anything about it.
Danish chimney
sweeps : a daily bath
after work.
A sad British chimney sweep
Result: significantly lower rates of skin cancer
amongst Danish chimney sweeps, compared with
British, even a century later.
A happy Danish Chimney Sweep
at work
with the family
Yamagiwa Took One Step Further
Coal tar condensates induced skin
carcinoma in rabbits.
Chemicals can directly
induce cancer.
Cancer can be studied in
the lab.
Yamagiwa
Figure 2.21b The Biology of Cancer (© Garland Science 2007)
Carcinogens = Agents that Contribute
to the Formation of a Tumor
Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008)
Carcinogens are not always mutagens.
+
=
100 fold increased risk for
head and neck cancers
One Mutation is Not Enough !!
A Process of Natural Selection
Cancer Cells Accumulate
Chromosomal Abnormalities
Figure 20-13 Molecular Biology of the Cell (© Garland Science 2008)
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)
One Mutation is Not Enough !!
A Process of Natural Selection
Cancer at the
Molecular Level
Signal transduction moves
information from the cell
surface to the nucleus
& other cellular targets.
What Types of Genes are Mutated in Cancers?
Two Broad Categories
Oncogenes
mutational activation of proteins
Tumor suppressor genes
mutational inactivation of proteins
Oncogenes
proto-oncogene
oncogene
They are similar, but NOT identical.
A proto-oncogene: a normal cellular gene that can become
an oncogene, upon DNA damage.
An Oncogene Acts in a Dominant Fashion
If oncogenes are dominant,
what is the normal functions of the proto-oncogenes?
Oncogenes
cellular signaling machinery stuck in the ON State
one mutated copy = over active protein = over
proliferation, over-survival, etc.
The c-myc Proto-oncogene is a Transcription Factor.
c-myc
cell proliferation
Normally, c-myc is stimulated by growth factors.
c-myc
c-myc
c-myc
c-myc
c-myc
cell proliferation
Acta Cytologica, 05
Gene amplification turns myc into an oncogene.
What Types of Genes are Mutated in Cancers?
Two Broad Categories
Oncogenes
mutational activation of proteins
Tumor suppressor genes
mutational inactivation of proteins
Oncogenes
The good guys become bad guys.
Tumor suppressor genes
We are losing the good guys.
dominant
recessive
Figure 20-27 Molecular Biology of the Cell (© Garland Science 2008)
Example
P53: the Master Guardian
Mutations in p53 can be found in >50% of tumors.
Figure 9.8 The Biology of Cancer (© Garland Science 2007)
Without 2 copies of P53:
no cell cycle arrest (over-proliferation)
angiogenesis
no apoptosis
no DNA repair (more mutations)
Before We Summarize
How to read a Paper
for the paper, as well as for each figure
1) What is the question addressed here?
2) How did the researchers address this question?
3) what are the results?
4) what are the conclusions?
Summary
Cancer cells exhibit behaviors found
in normal cells, but in cancer these
behaviors are not under control.
Cancer develops through gradual
changes in cell properties.
Various factors lead to accumulation
of DNA damage- cancer.
Oncogenes and tumor-suppressor genes
are the molecules behind cancer.
tumor