Carcinogenesis I Flashcards
Describe the properties of malignant cancer cells (5).
- Unresponsive to normal signals for proliferation control
- Dedifferentiated
- Invasive – can grow into neighboring normal tissues, extending the boundaries of the tumor
- Metastatic
- Clonal in origin – all derived from a single cell
What is the multi-step process for carcinogenesis?
While cancer in and of itself is not considered to be. A genetic disease, susceptibility to cancer is often inherited.
Carcinogenesis is a multi-step process characterized by the accumulation of many somatic, genetic alterations or mutations. It has been estimated by analyzing the DNA sequence of micro-satellite repeats in some colon cancers that a tumor has over 100,000 somatic mutations!
Tumor initiation, promotion, conversion and progression are four of these steps.
Carcinogenesis is a multi-step process characterized by _________
the accumulation of many somatic, genetic alterations or mutations.
list the steps of multi-step carcinogenesis: (4)
- Tumor initiation
- promotion
- conversion
- progression
What types of genes are usually mutates in tumor initiations?
- oncogenes
2. tumor suppressors
oncogenes function to
normally stimulate cell proliferation.
When they are mutates, they are activated
Tumor suppressors normally act to
inhibit cellular proliferation. They are deactivated when they are mutated
Mutations in proto-oncogenes, can______,
modify their expression and function, increasing the amount or activity of the product protein.
oncogenes
proto-oncogenes
are the normally quiescent counterparts of oncogenes
when proto-oncogenes mutate, they become
oncogenes
the result of the transition of proto-oncogenes to oncogenes is
that is upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible.
An example of an oncogene
Ras
Mutated members of the Ras family of proto-oncogenes are found in______% of human tumors.
20-30
The chance of cancer cannot be reduced by removing _______ from the genome, even if this were possible, as they are critical for ____________.
proto-oncogenes
growth, repair and homeostasis of the organism
It is only when proto-oncogenes are mutated that_________
the signals for growth become excessive.
Tumor suppressor genes code for _________
anti-proliferation signals and proteins that suppress mitosis and cell growth
Generally, tumor suppressors are _________
transcription factors that are activated by cellular stress or DNA damage.
Often DNA damage will cause the presence of _________
free-floating genetic material as well as other signs, which
will trigger enzymes and pathways which lead to the activation of tumor suppressor genes.
The functions of tumor suppressor genes is to_______
arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells.
An example of a tumor suppressor is _________,
p53
p53 is a
is a transcription factor activated by many cellular stressors including hypoxia and UV damage.
What type of cytogenetic abnormalities are associated with malignancy?
- translocations
2. aneuploidies
Translocations and gene deletions may
activate oncogenes or inactivate tumor suppressors.
For example, chronic myelocytic leukemia (CML) is associated with the Philadelphia
chromosome (BCR-ABL)
CML is associated with
philadelphia chromosome (BCR-ABL)
Aneuploidy correlates ________
with a poor prognosis in many cancers
Inactivation of tumor suppressors may occur by________, which is associated with many cancers.
LOH (loss of heterozygosity)
LOH examples
retinoblastoma (RB) and APC gene in FAP (Familial Adenomatous Polyposis).
Loss of heterozygosity represents the _______
the loss of normal function of one allele of a gene in which the other allele was already inactivated.
In oncogenesis, after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent’s germline cell, ________.
it is passed on to the zygote resulting in an offspring that is heterozygous for that allele
As long as the offspring still has one good copy of the allele, that person will not have cancer.
If heterozygous functional allele in a somatic cell of the offspring becomes inactivated by mutation
this could cause a normal tumor suppressor to no longer be produced. It is this second, somatic mutation that could result in tumorigenesis.
LOH can occur by several different ways but the end result is the same: ________
loss of a tumor suppressor.
Knudson’s theory has
two hits
Knudson’s first hit
The first hit is classically thought of as a point mutation that inactivates one copy of a tumor suppressor gene (TSG), such as Rb1.
In hereditary cancer syndromes, individuals are born with the first hit.
The individual does not develop cancer at this point because the remaining TSG on the other allele is still functioning normally.
Knudson’s second hit
The second hit is classically thought of as a large deletion that results in loss of functioning TSG allele.
This leaves only a non-functioning copy of the TSG, and the individual goes on to develop cancer.
Are cancers associated with both dominant and recessive syndromes?
Yes, cancers are associated with both dominant and recessive syndromes.
Dominant Syndromes are explained by:
Inherited oncogenes generally have a dominant effect at the cellular level, resulting in over-expression or over-activation of a single mutant allele that changes the phenotype of the cell from normal to malignant.
Multiple Endocrine Adenomatosis results from
a mutation in the RET genes which encodes a receptor tyrosine kinase that becomes constitutively active.
Multiple Endocrine Adenomatosis are an example of
dominant syndromes
Inherited tumor suppressors can also be inherited in a ______ fashion as in the case of _____
dominant
retinoblastoma (Rb gene), Familial Adenomatous Polyposis (APC gene), familial breast cancers (BRCA1 and BRCA 2 genes) and Wilms tumor syndromes.
when inherited tumor suppressors are inherited in a dominant pattern, it is recognized because
the disease is present in every generation.
Only one mutant allele is inherited from the germ line, but the cell populations in which these cancer syndromes occur have a rapid rate of proliferation and/or large numbers of cell divisions.
with inherited tumor suppressors in dominant fashion, there is a strong probability that ______
a somatic mutation will occur in one of these cells resulting in a loss of heterozygosity.
Recessive Syndromes examples are
Familial cancer syndromes can also be inherited in a recessive fashion,
like: Xeroderma Pigmentosa (XP genes),
Ataxia telangiectasia (AT gene), Bloom’s syndrome
Fanconi’s congenital aplastic anemia (FA genes).
How was RB first idenitified
When cytogenetically examined, retinoblastoma tumor cells were observed to have an abnormal structure at Chromosome 13q14.
This indicated to scientists that an important gene in retinoblastoma was in this region. When PCR analysis and Southern blots were used, complete or partial deletions of Rb could be detected.
properties of protein product of RB gene? (5)
- Rb protein is hyper-phosphorylated in rapidly proliferating cells
- hypophosphorylated RB protein represses the entrance of cells into S phase
- is a tumor suppressor
- phosphorylation by CDKs inactivate RB protein
- it is a target for animal tumor viruses such as HPV
Rb protein function
Rb protein inhibits proliferation by preventing cells from entering S phase of the cell cycle.
how does Rb protein inhibit proliferation?
- binding the E2F family of transcription factors.
For a cell to divide, _______ must interact with __________
EGFR growth factors
with CDK4/6 and cyclin D1-3
CDK4/6 and cyclin D1-3 phosphorylate
CDK2 and Cycin E, which phosphorylate Rb and inactivate it.
Mutant Rb causes an ______
increase in proliferation, which when other genes are mutant can lead to malignant cancers.
When Rb is mutant, the connection between ____________. Which causes ______ and results in _________
Rb and the growth factors outside the cell are is lost.
The Rb protein is non-functional, and thus cannot bind the E2F transcription factors.
In constitutively active E2F and increased drive to S phase (i.e. increased proliferation)
The hallmark of tumor suppressor genes is _______
acquired homozygosity for the susceptibility to malignancy and then a clonal population of cancerous cells descends from one cell that lost the Rb function.
Non- malignant cells remain heterozygous for Rb.
Cancer cells are _______
poorly regulated for growth and division, resulting in uncontrolled proliferation in inappropriate locations.
De-differentiated is:
lack many of the specialized structures and functions of the tissue in which they grow.
Invasive:
capable of outgrowth into neighboring normal tissues to extend the boundaries of the tumor.
Metastatic
capable of shedding cells that can drift through the circulatory system and proliferate at other sites in the body.
Clonal
derived from a single cell.
A benign tumor is made up of ________
cells that are not invasive or metastatic, but like the cancer cells have lost many of the growth controls and specialized functions of normal cells. They are immortalized.
For a cell to change from a normal to neoplastic state, changes in ________ must be involved.
cellular heredity
Early in life, mutagenic events in somatic cells will produce _______.
For example, __________
tumors many years later
increased UV light exposure at an early age is associated with an increased incidence of melanoma.
cancer is not considered to be an inherited disease, in that, it is not _______
inherited as a single, Mendelian gene.
The etiology of cancer is related to the accumulation of ______
somatic mutations produced by environmental factors. As this accumulation takes time, age is a big factor as well.
An early event may be a mutation in a DNA repair gene that increases the rate of __________ examples are _________
obtaining further mutations;
p53, BRCA1 and BRCA2
Tumor initiation occurs by mutations in at least two types of genes:
- Oncogenes, which normally stimulate cellular proliferation (analogous to the “gas pedal” of your car), are activated.
- Anti-oncogenes or tumor suppressors, which normally inhibit cellular proliferation (analogous to the “brake pedal” of your car), are inactivated.
________ to study cancer gave first clues to genetic abnormalities in cancer cells and is used in clinical diagnosis.
Cytogenetic analysis
Susceptibility to cancer can be inherited in a _______ fashion.
dominant or recessive fashion.
In cases of “inherited” retinoblastoma, ______
(i.e. when there was a parent and other family members who also had the disease), the DNA from normal tissue of the patient or from other unaffected family members often shows a defect in the retinoblastoma gene, but has one normal copy of the gene per cell.
The Rb protein is hyperphosphorylated in ______,
rapidly proliferating cells at S or G2 of the cell cycle
In fact, susceptibility to cancer is _______
inherited
Carcinogenesis is a ________
multi-step process characterized by the accumulation of many somatic, genetic alterations or mutations.
It has been estimated by analyzing the DNA sequence of micro-satellite repeats in some colon cancers that a tumor has over _______ somatic mutations!
100,000
In these patients with heterozygous rb gene, the tumor cells have descended as a _______
clone from a single cell that has acquired homozygosity for the retinoblastoma susceptibility gene. This is the hallmark of a antioncogene or tumor suppressor gene
The hypophosphorylated form of the RB protein normally functions to ______
repress the entry of cells into the S phase of the cell division cycle.
When RB becomes hyperphosphorylated, ____
it no longer inhibits this transition and the cells begin a cell division cycle. Thus, when there is no RB protein or it is all nonfunctional, cells cannot down regulate their cell division and grow out of control.
Because RB is an inhibitor of cell proliferation, it is an
anti-oncogene or tumor suppressor.
Phosphorylation by CDKs (cyclin-dependent protein kinases)
inactivates the RB protein, thereby allowing the cell to proceed from G1 to the S phase of the cell cycle.
The ______ is a target for many animal tumor viruses, for example, _______. These viruses drive a quiescent cell into the ______
RB protein
SV40 and HPV (human papilloma virus).
S phase of the cell cycle and to proliferate by producing a viral protein(s), SV40 T antigen (T stands for transforming) or HPV E7 protein, that binds to and inactivate the RB protein.
HeLa cells were isolated from a ______and have been growing in culture for over ___ years. These cells express _______.
cervical carcinoma
60 years.
HPV E7 and E6 protein (E6 inhibits p53, another important tumor suppressor).
If E7 and E6 expression is blocked,
the cells return to normal phenotype. This bodes well for therapy as affecting just two proteins can have a drastic effect.
people who are heterozygotes for the RB gene are likely to ____________
develop the disease and will pass on the defective gene to 1/2 of their children,
so it appears to be autosomal dominant in its inheritance.
a cell must have a _______ RB mutation in order to become malignant, because _______
homozygous
because both RB genes in that cell must be inactivated, if it is to grow out of control.
Sporadic cases of retinoblastoma (i.e. cases that occur without prior family
history) are attributable to ___________
two independent events occurring in a retinal cell.
Persons who survive inherited retinoblastoma have an increased risk for developing ______
a second neoplasm,
which is typically mesenchymal in origin
example: osteosarcoma.
Cells of these tumors are also defective in RB function.
Cells derived from a _________ carry a defect in the RB gene.
high frequency of small cell lung tumors and from some breast tumors carry
In Rb -/- knockout mice, loss of RB results in
pituitary tumors with 100% penetrance.
