Transcript Hormones and Behavior and Immunology and Behavior

Chapter 25
Cancer
박준오
Cancer is due to failures of the mechanisms that
usually control the growth and proliferation of cells.
Cancer
1) Normal development and throughout adult life.
2) Intricate genetic control systems regulate the
balance between cell birth and death in response to
growth signals, growth-inhibiting signals, and
death signals.
Mutations in two broad classes of genes have been
implicated in the onset of cancer : proto-oncogenes
and tumor-suppressor genes.
Proto-oncogenes normally promote cell growth ; they
are changed oncogenes by mutations.
Cancer forming process : oncogenesis
Tumor-suppressor genes are normally restrain growth,
so mutations that inactivate them allow
inappropriate cell division.
Cancer forming process : tumorigenesis
Caretaker genes are also often linked to cancer,
normally protect the integrity of the genome.
Cancer-causing mutations occur mostly in somatic
cells, not in the germ-line cells, and somatic cell
mutations are not passed on to the next generation.
Cancer commonly results from mutation that arise
during a lifetime’s exposure to carcinogens,
substances encountered in the environment, which
include certain chemicals and ultraviolet radiation.
In some cases cells from the primary tumor migrate to
new sites where they form secondary tumors, a
process termed metastasis.
-Tumor cells and the onset of cancerthe change from a normal cell into a cancer cell
commonlly involves multiple steps, each one adding
properties that make cells more likely to grow into a
tumor.
Hypoxic tumors : oxygen-staved
carcinomas : epithelia, ectoderm
sarcomas : mesoderm (leukemia : white blood cell)
lymphomas : another type of malignant tumor
(lymphocites)
glioblastomas : glial cell (brain)
carcinomas are by far the most common type of
malignant tumor. (more than 90%)
Benign tumor
- most pose little risk to their host because they are
localized, and of small size.
(ex : warts, benign skin tumor)
- serious medical problems only if their sheer bulk
interferes with normal functions or if they secrete
excess amounts of biologically active substances like
hormones.
Malignant tumor
- usually grow and divide more rapidly than normal,
and fail to die at the normal rate. (e.g., chronic
lymphocytic leukemia)
- malignant cells is their ability to invade nearby
tissue, spreading and seeding additional tumors while
the cells continue to proliferate.
Most tumors induce the formation of new blood
vessels that invade the tumor and nourish it, a
process called angiogenesis.
Many tumors produce growth factors that stimulate
angiogenesis; other tumors somehow induce
surrounding normal cells to synthesize and secrete
such factors. Basic fibroblast growth factor (bFGF),
transforming growth factor α (TGFα), and vascular
endothelial growth factor (VEGF), which are secreted
by many tumors.
rasD, where the “D” stands for dominant. The
mutation is genetically dominant because the
active protein has an effect even in the presence
of the other, normal ras allele. Normal Ras
protein, which participates in many intracellular
signal-transduction pathway activated by growth
factors.
the p 53 protein is a sensor essential for the
checkpoint that arrests cells with damaged DNA
in G1. The arrest can be temporary, allowing
correction of cell defects, or permanent,
resulting in cell senescence.
The p 53 protein has several functions, and
which of them is most relevant to its tumorsuppressing function remains unclear. For
example, a mutation p 53 protein that is unable
to activate transcription can nonetheless
suppress tumor formation.
-Gain-of-Function Mutation Recall That an oncogene is any gene that encodes a
protein able to transform cells in culture, usually in
combination with other cell alterations, or to induce
cancer in animals.
Conversion, or activation, of a proto-oncogene into
an oncogene generally involves a gain-of-function
mutation.
1) point mutation.
2) chromosomal translocation that fuses two genes
together to produce hybrid genes.
3) chromosomal translocation that brings a growth
regulatory genes.
4) amplification.
Pioneering studies by Peyton Rous beginning in
1911 led to the initial recognition that a virus
could cause cancer when injected into a suitable
host animal.
Rous sarcoma virus (RSV) is retrovirus whose is
incorporated into the host-cell genome. In
addition to the “normal” genes present in all
retroviruses, oncogenic transforming virus like
RSV contain an oncogene.
-Loss-of-Function Mutation Tumor-suppressor genes generally encode proteins
that in one way or another inhibit cell proliferation.
Loss-of-function mutations in one or more of these
“brakes” contribute to the development of many
cancer.
1) intracellular proteins that regulate, or inhibit
progress.
2) receptors or signal transducers for secreted
hormones or developmental signals that inhibit cell
proliferation.
3) checkpoint-control proteins that arrest the cell
cycle if DNA is damaged.
4) protein that promote apoptosis.
5) enzyme that participate in DNA repair.
Cell circuitry that is affected by cancer causing mutation.
-Oncogenic mutation in growth promoting proteinGenes encoding each class of cell regulatory protein have
been identified as proto-oncogenes or tumor-suppressor
genes. Mutation that result in the unregulated, constitutive
activity of certain proteins or in their overproduction
promote cell proliferation and transformation, there by
contributing to carcinogenesis.
- oncogenic receptors can promote proliferation
in the absence of external growth factorsReceptor tyrosine kinase (RTKs) leads to their
dimerization and activation of their kinase activity,
initiating an intracellular signaling pathway that
ultimately promotes proliferation.
- viral activators of growth-factor receptors
act as oncoproteinsa retrovirus called spleen focus-forming
virus (SFFV) induced erythroluekamia in
adult mice by manipulating a normal
developmental signal. The proliferation,
survival, and differentiation of erythroid
progenitors into mature red cells absolutely
require erythropoietin (Epo) and the
corresponding Epo receptor.
- many oncogenes encode constitutive
active signal-transduction proteinsa large number of oncogenes are derived
from proto-oncogenes whose encoded
protein aid in transducing signals from an
activated receptor to a cellular target.
1) Ras pathway components
2) Src protein kinase
3) Abl protein kinase
-Mutations causing loss of growth-inhibiting
and cell-cycle controls-
just as critical are mutations that decrease
the activity of growth-inhibiting pathways
when they are needed.
TGFβ inhibits proliferation of many cell
types, including most epithelial and immune
system cells.
-mutations that promote unregulated
passage from G1 to S phase are
oncogeniccyclin-dependent kinase (CDKs), and the
Rb protein are all elements of the control
system that regulate passage through the
restriction point.
-loss-of-function mutations affecting
chromatin-remodeling proteins contribute
to tumors-
SWI/SNF complex, in transcriptional control
has become increasingly clear. These large
and diverse multiprotein complexes have at
their core an ATP-dependent helicase and
often control histone modification and
chromatin-remodeling.
-loss of p 53 abolishes the DNA-damage
checkpointCells with functional p 53 become arrested
in G1 when exposed to DNA-damaging
irradiation, whereas cells lacking functional
p 53 do not.
- apoptotic genes can function as protooncogenes or tumor-suppressor genesCells can receive instructions to live and
instructions to die, and a complex
regulatory system integrates the various
kinds of information.
-Carcinogenes and caretaker genes in
cancercarcinogenes, which can be natural or
produced by humans, are chemicals that
cause cancer. Carcinogenes cause
mutations that reduce the function of
tumor-suppressor genes, create
oncogenes from proto-oncogene, or
damage DNA repair systems.
-carcinogens induce cancer by damage
DNAcarcinogens to induce cancer is due to the
DNA damage that they cause as well as the
errors introduced into DNA during the cell’s
efforts to repair this damage.
- some carcinogens have been linked to
specific cancerstobacco (benzo (a) pyrene) -> damaging
chromosomes
-loss of DNA-repair systems can lead to
cancerDNA damage is due to depurination
reactions, to alkylation reactions and to the
generation of reactive species such as
oxygen radicals, all of which alter DNA.
-telomerase expression contributes to
immortalization of cancer cellsThe physical ends of linear chromosomes,
consist of tandem arrays of a short DNA
sequence, TTAGGG in vertebrates.
(replication problem)