Download Biology of Cancer

Cancers
Identification of genes
Function of genes
Defining of the pathways
Integration of the pathways
Identification of
Molecular Therapeutic Targets
Genes related with cancer;
What genes are mutated in cancers ?
Tumor suppressor, --suppress cell divisions; cell cycle controller
Ex) G1/S, G2/M checkpoint controller
?
Mutation(loss of function); uncontolled cell divisions &
other mutations events
Oncogene : promote the cell divisions
Gain of functions; hyperactive
Ex) Ras, EGFR active
Caretakers
Gatekeepers
( ATM, Brca1,
( p53, Rb, ARF ets)
PMS,MSH etc)
Telomerase
activation
Oncogene activation
( Ras, Src ets)
Mitogenic
Signals
Proliferations
DNA damage
Signals
Cell cycle arrest
& Apoptosis
The protein Networks
Robert A. Weinberg
The Biology of Cancer
First Edition
Chapter 3:
Tumor Viruses
Copyright © Garland Science 2007
Cancer is an infectious Disease ?
• No.
– Virus-induced cancers represent only a minority of human cancers
• Study of tumor virus open many of the secrets of human
cancer, even majority of cancer have no connection with
tumor virus in human cancers.
• Studying tumor virus, identification of oncogenes, changed
the direction of cancer research .
• 1876, Russian research reported that the transmission of a
tumor from one dog to another by xonografting.
Questionable ?
• 1908, filtered extracts from Chicken leukemia cells induced
tumors in other birds
•1910, Peyton Rous discovered that the Rous Sarcoma
virus (RSV) is able to induce tumors in chicken
•
•
•
1913, Dane Johannes Grib Figiber
reported that stomach cancers in
rats could be traced to spirochete
worms that they harbored. Thus, he
received Nobel Prize, direct
validation of the idea that cancer
was an infectious disease
But Metastatic stomach epithelia in
those rats were present in the
normal stomach with Vitamin
deficient. Misinterpretation? Fraud ?
Things easily go wrong
Since then, Peyton Rous report had
been disregarded for two decades
Figure 3.2 The Biology of Cancer (© Garland Science 2007)
•
In the Lab of Renato Dulbercco in
CalTech, Harry Rubin found
that stocks of RSV infected in
Chicken Embryonic Fibroblast
and some of these cells survived
indefinitely.
•
The RSV infected cells in cultures
showed many traits of cancers.
•
Form a foci, round shape, highly
metabolic stage etc
Figure 3.6 The Biology of Cancer (© Garland Science 2007)
•Howard Temin showed the ability of RSV to
transform cells in vitro.
• In the Lab of Renato Dulbercco
in CalTech, Graduate student
Howard Temin showed RSV
can transform normal cells to
cancer cells.
• Cancer formation could be
studied at the level of individual
cells and these processes could
be traced easily
• Loss of contact inhibition, foci
formation
Figure 3.6 The Biology of Cancer (© Garland Science 2007)
Transformation In vitro
•Proposed the processes of transformation
•Loss of contact inhibition, foci formation,
an anchorage independent growth
•Tumorigenicity can be tested in a host nude mice
Figure 3.7b The Biology of Cancer (© Garland Science 2007)
Question is whether RSV is required for maintenance of
transformation or simply initial infection is sufficient ?
•
The continued presence of RSV is
needed to maintain transformation
•
How prove it
? Tem-sensitive mutant and the
maintenance of transformation
•
Viral transforming gene is required
to both initiate and maintain the
transformed phenotype of virusinfected cells ?
This finding is also true In vivo ?
•
Figure 3.8 The Biology of Cancer (© Garland Science 2007)
Viruses have simple life cycles
Figure 3.3 The Biology of Cancer (© Garland Science 2007)
Retroviral genome become integrated into the chromosome of infected
cells
•
•
•
•
•
How did RSV RNA virus succeed in transmitting in genome through many generations
within a cell lineage ?
Late 1960, Temnin proposed a radical idea explaining that RSV made ds DNA from RNA
and become a part of chromosomal DNA by integration
How was DNA made from RNA ? Central Dogma can not explain this phenomenon ?
Reverse trasnscriptase was found within a year
Retrovirus re-infection can explain the stable transformation ? No. RSV virus with no ability
to replicate was still able to transform cells
Figure 3.16 The Biology of Cancer (© Garland Science 2007)
Src gene from RSV is responsible for transformation
•
•
•
•
•
Retrovius has small number of genes (gag,
poly,env genes.
Several mutant of RSV
– No replication with transformation
activity
– Replication without transformation
activity
In 1974, Bishop and Varmus defined the
transformation-associated sequences of RSV
genome by making probes. How did they
found ?
Src gene was found, but interestingly, this src
was also clearly present in the uninfected
chicken cells ? There are two copies of the
src-related gene in normal cells
C-src play a role in cellular processes in
normal cells, but v-src is able to transform
normal cells to tumors
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
ALV (avian leukosis virus) may kidnapp cellular Src
gene during lysogenic life cycle and become RSV ?
•
Viral Oncogene would be changed,
acquire the tranformation activity
•
What is the different action of
Cellular oncogene and Viral
Oncogene ?
•
How one Viral Oncogene can
induce multiple change during
tumorigenesis ?
•
C-oncogene might be modified in
many non-viral induced tumors ?
•
How do other retrovirus without
oncogene induce tumors ?
Figure 3.22 The Biology of Cancer (© Garland Science 2007)
Retroviruses cause cancer by kidnapping
mutated versions of normal cellular genes
The structures of c-src and v-src and
Deletion of the C-terminal region
leads to activation of v-Src
Binds polyproline motifs
Binds peptides phosphorylated on Tyr
DNA viruses are able to induce cancer
• 1960, Shope found that
papillomas can be induced a
virus (papillomavirus). This
Virus contain DNA molecule
• Several tumor DNA tumor
viruses were found.
• Papillomavirus, the mouse
polyomavirus and SV40 are
grouped together as the
Pavovavirus (papilloma, polyoma
and Vacuoles); Circular ds DNA
• Adenovirus and herpesvirus have
long linear ds DNA
Figure 3.9a The Biology of Cancer (© Garland Science 2007)
SV40 tumor virus
• SV40 virus (the 40th simian
virus monkey virus) was
discovered as a contaminant of
the polyovirus vaccine stocks
• SV 40 induces cell lysis in
permissive host cells, but can
not replicate in Nonpermissive
cells and instead transform
these cells
• SV40 contaminant might
trigger cancer (mesothelioma)
in many people who were
vaccinated, but no evidence ?
Figure 3.10a The Biology of Cancer (© Garland Science 2007)
Table 3.2 The Biology of Cancer (© Garland Science 2007)
Tumor Virus become part of host cell DNA in virus transformed cells
•
•
•
•
Discovery of tumor virus-associated
proteins were found in cancers induced
by DNA virus; indicating that the viral
genome place in tumor cells encoded a
protein (SV40 T Ag)
How could viral genomes be replicated
and transmitted for many generations of
cells ?The virus are replicated as
extranchromosomal molecules in
permissive cells.
1968, found that the viral DNA in SV40transforned cells was associated with
chromosomal DNA, suggesting a
integration of viral DNA into
chromosome
Viral genome become a part of cell’s
genome.
Figure 3.14 The Biology of Cancer (© Garland Science 2007)
T Ag
in cancer
Integrated SV40 genomes
How can you find this integrated SV40 genome in
chromosomes ?
Table 3.3 The Biology of Cancer (© Garland Science 2007)
How do other retrovirus without any oncogene induce tumors ?
Slowly tranforming retrovirus activates proto-oncogene by
inserting their genomes adjacent cellular genes
•
Avian Leukosis virus(AVL) or murine
leukemia virus (MVL) with no concogen
induce a malignancy ?
•
Map the site of integration of viral
genome. Myc was a target site of viral
integration of tumors induced by these
viruses ?
Insertinal mutagenesis
•
•
Is it possible to transform cells with
random integration of DNA or Viral
DNA in vitro ?
•
These insertional mutagenesis provided
a powerful tool to find new oncogenes
Figure 3.23a The Biology of Cancer (© Garland Science 2007)
Retroviruses also cause cancer by randomly
inserting next to, thus activating the expression of proto-oncogenes
Retroviral insertion
sites in different tumors
Transcribe to mRNA
5 kilobases
exons
Table 3.4 The Biology of Cancer (© Garland Science 2007)
• Some retroviruses naturally carry oncogene HTLV (human T cell
leukemia virus) were transmitted via milk-borne from mother to
infants. In Kysu, 1 % infection in the population. Tax gene product
from viral genome appears to activate the two cellular genes (IL-2,
GM-CSF), which stimulates the proliferation of hematopoietic cells
• Gene therapy can induce the tumors
• Immune deficiency (AIDS) can induce the some types of viral-induced
tomors ‘ Kaposi’s Sarcoma in endotherial lining of lymphduct. Related
with human herpesvirus-8 (HHV-8).
• How about the helicobacter ? HBV, HCV ?
Retrovirus
•
•
•
•
Summary
The causative agents of transplantable tumors in chickens, mice, and rats
RNA virus
The virus carries genetic information responsible for transforming a normal
cell into tumor cell.
Retrovirus : RNA-containing animal virus that replicate through a DNA
intermediate
: Two classes based on the latent period of tumorogenesis
1) Acute transforming retrovirus rapidly produce tumors in newborn animals
and carry genetic information capable of inducing tumors directly.
2) The slowly transforming retroviruses do not carry oncogenes and induce
tumors by integrating themselves adjacent to a cellular gene and altering its
transcriptional regulation.