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Cancer
Tumor Cells and the Onset of Cancer
Metastatic Tumor Cells Are Invasive and Can
Spread
Benign; Malignant; Metastasis
Malignant tumors are classified as carcinomas
if they derive from endoderm or ectoderm and
sarcomas if they derive from mesoderm.
Alterations in Cell-to-Cell Interactions Are
Associated with Malignancy
Tumor Growth Requires Formation of New
Blood Vessels
DNA from Tumor Cells Can Transform Normal
Cultured Cells
When DNA from a human bladder carcinoma, mouse
sarcoma, or other tumor is added to a culture of 3T3 cells,
about one cell in a million incorporates a particular
segment of bladder carcinoma DNA that causes a
distinctive phenotype. Such cells, which continue to grow
when the normal cells have become quiescent, have
undergone transformation and are said to be transformed.
Ras protein, which participates in intracellular
signal transduction pathways activated by growth
factors, cycles between an inactive. Because the
mutated RasD protein hydrolyzes bound GTP very
slowly, it accumulates in the active state, sending a
growth-promoting signal to the nucleus .
Any gene, such as rasD or v-src, that encodes a
protein capable of transforming cells in culture or
inducing cancer in animals is referred to as an
oncogene. The normal cellular gene from which it
arises is called a proto-oncogene.
Development of a Cancer Requires Several
Mutations
Epidemiology
According to this "multi-hit" model, cancers
arise by a process of clonal selection not unlike
the selection of individual animals in a large
population. A mutation in one cell would give it
a slight growth advantage.
Somatic Mutations in Human Tumors
tumor-suppressor genes,
DNA from different human colon carcinomas generally
contains mutations in all these genes APC, p53, K-ras,
and DCC establishing that multiple mutations in the
same cell are needed for the cancer to form.
Inherited Mutations That Increase Cancer Risk
Overexpression of Oncogenes
Overexpression of Myc protein is associated with
many types of cancers, a not unexpected finding,
since this transcription factor stimulates expression
of many genes required for cell-cycle progression.
Cancers Originate in Proliferating Cells
SUMMARY
Cancer is a fundamental aberration in cellular
behavior, touching on many aspects of molecular
cell biology.
Cancer cells can multiply in the absence of growthpromoting factors required for proliferation of
normal cells and are resistant to signals that
normally program cell death (apoptosis).
Cancer cells invade surrounding tissues. Both
primary and secondary tumors require angiogenesis.
Certain cultured cells transfected with tumor-cell
DNA undergo transformation.
Colon cancer develops through distinct
morphological stages that commonly are
associated with mutations in specific tumorsuppressor genes and oncogenes.
Cancer cells, which are closer in their properties
to stem cells than to more mature differentiated
cell types, usually arise from stem cells and other
proliferating cells.
Proto-Oncogenes and Tumor-Suppressor Genes
two broad classes of genes proto-oncogenes (e.g., ras)
and tumor-suppressor genes (e.g., APC) play a key role in
cancer induction. These genes encode many kinds of
proteins that help control cell growth and proliferation;
mutations in these genes can contribute to the
development of cancer. Most cancers have inactivating
mutations in one or more proteins that normally function
to restrict progression through the G1 stage of the cell
cycle (e.g., Rb and p16).
Gain-of-Function Mutations
Oncogenes into Oncogenes
Convert
Proto-
An oncogene is any gene that encodes a protein able
to transform cells in culture or to induce cancer in
animals. Of the many oncogenes, all but a few are
derived from normal cellular genes (i.e., protooncogenes) whose products participate in cellular
growth-controlling pathways.
Point mutations in a proto-oncogene
gene amplification of a proto-oncogene
Chromosomal translocation
Oncogenes Were First Identified in CancerCausing Retroviruses
The v-src gene thus was identified as an oncogene.
A gene that is closely related to the RSV v-src gene,
normal cellular gene, a proto-oncogene, commonly
is distinguished from the viral gene by the prefix
"c" (c-src).
Slow-Acting Carcinogenic Retroviruses Can
Activate Cellular Proto-Oncogenes
Many DNA Viruses Also Contain Oncogenes
Loss-of-Function Mutations in Tumor-Suppressor
Genes Are Oncogenic
Intracellular proteins, such as the p16 cyclin-kinase
inhibitor, that regulate or inhibit progression through
a specific stage of the cell cycle
Receptors for secreted hormones (e.g., tumorderived
growth factor b) that function to inhibit cell
proliferation
Checkpoint-control proteins that arrest the cell cycle
Proteins that promote apoptosis
Enzymes that participate in DNA repair
The First Tumor-Suppressor Gene Was Identified
in Patients with Inherited Retinoblastoma
Loss of Heterozygosity of Tumor-Suppressor Genes
Occurs by Mitotic Recombination or Chromosome
Mis-segregation
Proteins that promote apoptosis
Enzymes that participate in DNA repair
SUMMARY
Dominant gain-of-function mutations in protooncogenes
and recessive loss-of-function mutations in tumorsuppressor genes are oncogenic.
Among the proteins encoded by proto-oncogenes are
positive-acting growth factors and their receptors, signaltransduction proteins, transcription factors, and cell-cycle
control proteins.
An activating mutation of one of the two alleles of a
proto-oncogene converts it to an oncogene.
Activation of a proto-oncogene into an oncogene can
occur by point mutation, gene amplification, and gene
translocation.
The first recognized oncogene, v-src, was identified in Rous
sarcoma virus, a cancer-causing retrovirus. Retroviral
oncogenes arose by transduction of cellular protooncogenes into the viral genome and subsequent mutation.
The first human oncogene to be identified encodes a
constitutively active form of Ras, a signal-transduction
protein.
Slow-acting retroviruses can cause cancer by integrating
near a proto-oncogene in such a way that gene transcription
is activated continuously and inappropriately.
Tumor-suppressor genes encode proteins that slow or inhibit
progression through the cell cycle, checkpoint-control proteins
that arrest the cell cycle, receptors for secreted hormones that
function to inhibit cell proliferation, proteins that promote
apoptosis, and DNA repair enzymes.
Inherited mutations causing retinoblastoma led to the
identification of RB, the first tumor-suppressor gene.
Inheritance of a single mutant allele of many tumor-suppressor
genes (e.g., RB, APC, and BRCA1) increases to almost 100
percent the probability that a tumor will develop.
Loss of heterozygosity of tumor-suppressor genes occurs by
mitotic recombination or chromosome missegregation.
Oncogenic
Proliferation
Mutations
Affecting
Cell
Misexpressed Growth-Factor Genes Can Autostimulate
Cell Proliferation
Virus-Encoded Activators of Growth-Factor Receptors
Act as Oncoproteins
Activating Mutations or Overexpression of GrowthFactor Receptors Can Transform Cells
Constitutively Active Signal-Transduction Proteins Are
Encoded by Many Oncogenes
Deletion of the PTEN Phosphatase Is a Frequent
Occurrence in Human Tumors
Cells lacking PTEN have elevated levels of phosphatidylinositol
3,4,5-trisphosphate and protein kinase B, which acts to prevent
apoptosis.
Inappropriate Expression of Nuclear Transcription
Factors Can Induce Transformation
SUMMARY
Certain virus-encoded proteins can bind to and activate host-cell
receptors for growth factors, thereby stimulating cell proliferation
in the absence of normal signals.
Mutations or chromosomal translocations that permit growth factor
receptor protein-tyrosine kinases to dimerize lead to constitutive
receptor activation in the absence of their normal ligands. Such
activation ultimately induces changes in gene expression that can
transform cells. Overexpression of growth factor receptors can
have the same effect and lead to abnormal cell proliferation.
Most tumors express constitutively active forms of one or more
intracellular signal-transduction proteins, causing growthpromoting signaling in the absence of normal growth factors.
A single point mutation in Ras, a key transducing protein in many
signaling pathways, reduces its GTPase activity, thereby
maintaining it in an activated state.
The activity of Src, a cytosolic signal-transducing protein-tyrosine
kinase, normally is regulated by reversible phosphorylation and
dephosphorylation of a tyrosine residue near the C-terminus. The
unregulated activity of Src oncoproteins that lack this tyrosine
promotes abnormal proliferation of many cells.
Deletion of the PTEN phosphatase promotes the PI-3 kinase
pathway and activation of protein kinase B, which inhibits
apoptosis. Loss of this tumor suppressor, which is common in
many human cancers, reduces apoptosis.
Inappropriate expression of nuclear transcription factors, such as
Fos, Jun, and Myc can induce transformation.
Mutations Causing Loss of Cell-Cycle Control
Passage from G1 to S Phase Is Controlled by ProtoOncogenes and Tumor-Suppressor Genes
Overexpression of Cyclin D1
Loss of p16 Function
Loss of Rb Function
Loss of TGFb Signaling Contributes to Abnormal Cell
Proliferation and Malignancy
SUMMARY
Overexpression of the proto-oncogene encoding cyclin D1 or
loss of the tumor-suppressor genes encoding p16 and Rb can
cause inappropriate, unregulated passage through the restriction
point in late G1, a key element in cell-cycle control. Such
abnormalities
are
common
in
human
tumors.
TGFb induces expression of p15, leading to arrest in G1, and
synthesis of extracellular matrix proteins such as collagens and
plasminogen
activator
inhibitor-1.
Loss of TGFb receptors or Smad 4, a characteristic of many
human tumors, abolishes TGFb signaling. This promotes cell
proliferation and development of malignancy.