Download Cancer-Principles and overview

Chapter 13
Cancer—Principles and overview
By
Robert A. Weinberg
13.1 Tumors are masses of cells derived
from a single cell
• Cancers progress from:
– a single mutant cell
– to a tumor
– then to metastasis
• Tumors are clonal.
• Tumors are classified by cell type.
13.2 Cancer cells have a number of
phenotypic characteristics
• Cancer cells are characterized by
several distinct properties.
• Unlike normal cells, cancer cells do not
stop dividing when they contact a
neighboring cell when such cells are
propagated in a Petri dish.
13.2 Cancer cells have a number of phenotypic
characteristics
• Cancer cells have a greatly reduced
requirement for growth factors to
sustain growth and proliferation.
• Unlike normal cells, cancer cells in
culture do not require attachment to a
physical substrate in order to grow.
– The trait of anchorage independence
13.2 Cancer cells have a number of phenotypic
characteristics
• Unlike normal cells in culture, which halt
division after a certain number of
growth-and-division cycles:
– cancer cells are immortal
– they do not stop dividing after a
predetermined number of generations
• Cancer cells often have chromosomal
aberrations, including changes in
chromosome number and structure.
13.3 Cancer cells arise after DNA
damage
• Agents that cause cancer may do so by
damaging DNA.
• Mutations in certain genes cause a cell
to grow abnormally.
13.3 Cancer cells arise after DNA
damage
• Ames devised a test to determine the
carcinogenicity of chemical agents.
• Cancers usually arise in somatic cells.
13.4 Cancer cells are created when
certain genes are mutated
• Oncogenes promote cell growth and
division.
• Tumor suppressors inhibit cell growth
and division.
13.4 Cancer cells are created when certain genes are
mutated
• Cellular genomes harbor multiple protooncogenes.
• Tumor viruses carry oncogenes.
• Genetic alterations can convert protooncogenes into potent oncogenes.
13.5 Cellular genomes harbor a number
of protooncogenes
• Gain-of-function mutations can activate
protooncogenes.
• Overexpression of proto-oncogenes can
cause tumors.
• Translocations can create hybrid
proteins that are oncogenic.
13.6 Elimination of tumor suppressor
activity requires two mutations
• Both copies of a tumor suppressor gene
must usually be inactivated to see a
phenotype.
13.6 Elimination of tumor suppressor activity requires two
mutations
• Mechanisms that result in loss-ofheterozygosity are often responsible for
the loss of the remaining normal copy of
the tumor suppressor gene.
• Cancer susceptibility can be caused by
the inheritance of a mutant copy of a
tumor suppressor gene.
13.7 The genesis of tumors is a complex
process
• Cancer is a multistep process that
requires four to six different mutations to
reach the tumor state.
• Tumorigenesis progresses by clonal
expansion, where increasingly abnormal
clones of cells outgrow their less mutant
neighbors.
13.8 Cell growth and proliferation are
activated by growth factors
• Cell signaling requires extracellular
factors, receptors, and other proteins
that transmit the signal to the nucleus.
13.8 Cell growth and proliferation are activated by growth
factors
• Extracellular signals may be:
– growth promoting or
– growth inhibiting
• Many genes encoding cell signaling
molecules are proto-oncogenes and
tumor suppressor genes.
13.9 Cells are subject to growth inhibition
and may exit from the cell cycle
• Cells that have differentiated have
reached their final specialized form.
• Differentiated cells are usually
postmitotic.
– Thus, differentiation reduces the pool of
dividing cells.
13.9 Cells are subject to growth inhibition and may exit from the cell
cycle
• Cells can commit suicide by apoptosis.
• Apoptosis eliminates healthy cells
during development and at other times
in an organism’s lifetime.
13.9 Cells are subject to growth inhibition and may exit from the cell
cycle
• Apoptosis eliminates damaged cells that
can pose a threat to the organism.
• Mutations that compromise a cell’s
ability to carry out apoptosis can result
in malignancy.
13.10 Tumor suppressors block
inappropriate entry into the cell cycle
• Cells decide whether or not to divide at
the restriction point.
• pRb is a tumor suppressor that can
prevent passage through the restriction
point.
13.10 Tumor suppressors block inappropriate entry into the
cell cycle
• pRb can be inactivated by:
– mutations
– sequestration by oncoproteins
– hyperactivity of the Ras pathway
13.11 Mutation of DNA repair and
maintenance genes can increase the
overall mutation rate
• DNA repair proteins keep the spontaneous
mutation rate low.
• Defects in DNA repair genes increase the
basal rate of mutation in the cell.
• Mutations in checkpoint proteins compromise
chromosome integrity.
13.12 Cancer cells may achieve
immortality
• Cancer cells avoid senescence by
inactivating tumor suppressor genes.
• Cancer cells reach a crisis point at
which many of them die off.
13.12 Cancer cells may achieve
immortality
• Cells that survive the crisis are
immortalized.
• Telomeres become shorter each
generation unless telomerase is
activated.
13.12 Cancer cells may achieve
immortality
• When telomeres become too short to
protect the chromosomes, the
chromosomes fuse.
– This provokes crisis.
• Most cancer cells activate telomerase
transcription, thereby escaping death.
13.13 Access to vital supplies is provided
by angiogenesis
• Tumor growth is limited by access to
nutrients and waste removal
mechanisms.
• Tumors can stimulate blood vessel
growth (angiogenesis), which enables
them to expand.
13.14 Cancer cells may invade new
locations in the body
• Some cells from a primary tumor can
gain entrance to blood and lymphatic
vessels (intravasation).
• The process of intravasation often
requires breaking through barriers of
neighboring tissue.
13.14 Cancer cells may invade new locations in the
body
• Cells that survive the trip through the
blood vessels may colonize other
organs.
• Metastasis, or colonization of other
tissues, usually results in death of the
individual.