at a basic level, mutations accumulate in cells
so one of the basic properties of cancer cells is uncontrolled cell division
what happens to these cells to allow this to occur?
regulation of mitosis
what is mitosis? what are the phases?
cell cycle
cell replication is primarily controlled by regulating the timing of 2 critical events in the cell cycle
mutations in critical genes that regulate the cell cycle can lead to
mitosis can be regulated in 2 ways:
1)
these genes are known as tumor suppressor genes
they act at either the G1/S or G2/M control points
if these genes are lost or inactivated by mutation
2)
these regulatory genes are known as proto-oncogenes
when these genes are active
if these genes become permanently activated or overproduce their products
mutant forms of proto-oncogenes are called
present several examples of how mutations in a number of different tumor suppressor genes are involved in the development of cancer
A) retinoblastoma (RB)
there is a mutation in the RB gene
can distinguish 2 forms of RB
1) hereditary RB
2) sporadic RB
the RB gene encodes a protein that is confined to the nucleus
this protein is present at all stages of the cell cycle
it acts as a molecular switch
if the protein is active during G1 it will prevent passage of cells from
if this protein is inactive
if both copies of the RB gene are deleted or become mutated in a retinal cell
what happens if both copies of the RB gene become mutated?
this does happen in bone cells
it is interesting to note that if a copy of the RB gene is transferred into these
osteosarcoma cells, RB protein is produced and cell division stops
(reinforces the idea that the retinoblastoma protein plays a central role in the
regulation of the cell cycle)
B) 2 genes that have been implicated in the development or predisposition to breast
cancer have been identified
BRCA1 and BRCA2
if have mutations in these genes, cell division is altered
seems to be a genetic predisposition to breast cancer; mutations in the BRCA1
gene account for about half of all hereditary forms and the BRCA2 gene is
responsible for the majority of those cases not caused by a BRCA1 mutation
C) colon cancer is also thought to be influenced by heredity
this type of cancer is characterized by an accumulation of mutations over time
each mutation confers a slight growth advantage on the cell
it is the sum of the accumulated changes that is critical to the development of
colon cancer
oncogenes
these genes induce or maintain uncontrolled cell division
first discovered by work on a virus that causes cancer in chickens
forms a type of sarcoma
over the years, many other forms of animal tumors were shown to be caused by viral infection
so what is it about viruses that give them this transforming ability?
viruses can cause colds, herpes, AIDS, etc.
viruses have a protein-containing capsid
viruses can be grouped into 2 classes: DNA or RNA viruses
polyoma –
RNA viruses – known as retroviruses
ex: Rous sarcoma virus (RSV)
ex: mouse mammary tumor virus
ex: others have been found in chicken, mouse, rat, hamster
the results of work with RSV and other similar viruses have been important in understanding the origins of human cancer
the ability of many retroviruses to cause tumor formation is due to
since this gene is associated with the ability to of the virus to induce tumors, it is known as
the discovery of an oncogene was an important event in cancer research
more than 20 different oncogenes have been identified
the version of the oncogenes carried by retroviruses are called
retroviruses that carry a v-onc gene are able to infect and transform a host cell
into a malignant tumor cell
since not all retroviruses carry oncogenes, where did such genes originate?
are they viral in origin?
or might they represent genes captured by the virus from host animal cells?
the normal version of these genes are called
these genes are normal genes that are present in all cells but they have the ability
to cause cancer
what is the normal function of proto-oncogenes? why would they cause cancer?
these genes are associated with
ex: the DNA sequence of the sis oncogene closely matches that of a proto-
oncogene that encodes a growth factor called PDGF
ex: the DNA sequence of the erb-B oncogene is related to a proto-oncogene that
encodes a cellular receptor for another growth factor
** the majority of proto-oncogenes regulate cell growth and division
although oncogenes were originally discovered in viruses, only a few forms of human cancer are caused by
in most cases, the conversion from proto-oncogene to oncogene takes place in a somatic cell
what is the difference between a proto-oncogene in a normal cell and a mutant version of that gene (oncogene) in a cancer cell?
many differences are possible, including mutations that produce
ex:
ex:
this protein receives and transfers growth-inhibiting signals across the plasma
membrane and when analyzed, ras oncogenes from human tumors were found to
contain a single nucleotide change which differentiates the mutant oncogene
from the proto-oncogene found in normal cells
this amino acid substitution occurs at either amino acid 12 or 61 (very specific)
in the polypeptide
this alteration changes the structure of the protein
the altered protein can’t function in signal transfer across plasma membrane
knowledge about the molecular organization of oncogenes and their products is being used to develop
if altered oncogenic proteins are released into the bloodstream
ex: tests have been developed for a particular type of protein that is secreted into
the bloodstream by breast cancer cells
extract DNA from cancer cells and sequence the DNA
also, it has been determined from laboratory studies on cultured cells that if an active oncogene is switched off, the cell reverts to a nonmalignant state
do this by developing new anticancer drugs
or alternatively, since the protein products of oncogenes have been characterized,
it may be possible to block or reduce the action of such proteins