Lecture 15 Flashcards
Characteristics of cancer cells
- divide continually and quicker than normal cells
- contain heritable mutations
- transplantable
- dedifferentiated
- have a different appearance
- cell surface has different types and/or number of antigen
- lack contact inhibition
- induce angiogenesis
- invasive
- metastasize
dedifferentiated (characteristic of cancer cell)
lose their specialized identity
angiogenesis
formation of local blood vessels
invasive (characteristic of cancer cell)
squeeze into any space available
metastasize (characteristic of cancer cell)
move to new location in body
origins of cancer cell (4)
- activation of stem cells that produce cancer cells
- dedifferentiation - lose their specialized identity
- increase in proportion of a tissue that consists of stem cells or progenitor cells
- faulty tissue repair
cancer by loss of specialization
specialized cells lose some of their distinguishing features as mutations occur when they divide
-result: dedifferentiation
what can cause cancer?
- loss of specialization
- shifting balance of cell types in a tissue
- uncontrolled tissue repair
acute vs chronic injury
acute: resting epithelium –> injury and activation of tissue –> repair (–> injury and activation of tissue)
chronic: persistent activation of stem cells –> cancer
proto-oncogenes
normal versions of genes that promote cell division
What happens when expression is at the wrong time or in the wrong cell type?
it leads to cell division and cancer
oncogenes
proto-oncogenes in their mutated form
how many copies of an oncogenic mutation is sufficient to promote cell division?
one copy
oncogenes: overexpression of a normal function
overexpression of the proto-oncogene is caused by moving a proto-oncogene next to a highly transcribed gene
when is an oncogene activated?
when a proto-oncogene moves next to another gene. the gene pair is transcribed together
fusion protein
the double gene product
-it activates or lifts control of cell division
Chronic Myelogenous Leukemia (CML)
-Most patients have a translocated Philadelphia chromosome (tip of 9 on 22)
-Abl (chromosome 9) and bcr (chromosome 22) genes produce a fusion protein
-BCR-ABL oncoprotein is a tyrosine kinase that excessively stimulates cell division
-Understanding cellular changes allowed development of new drug, Gleevec, for
treatment
Her-2/neu
-Product of an oncogene
Excessive levels in approximately 25% of breast cancer patients
-Too many receptors
-Too many signals to divide
-Monoclonal antibody drug, Herceptin, binds to receptors, blocking signal to divide
tumor suppressor genes
- Cancer can be caused by loss of genes that inhibit cell division
- Tumor suppressor genes normally stop a cell from dividing
- Mutations of both copies of a tumor suppressor gene is usually required to allow cell division
- Genes can also be lost by deletion or silenced by promoter hypermethylation
Retinoblastoma (RB)
-The RB gene is on chromosome 13
-The RB protein binds transcription factors so that they cannot activate genes that carry
out mitosis. Normally halts the cell cycle at G1
-Study of RB was the origin of the “two-hit” hypothesis of cancer causation
two-hit hypothesis
-Two mutations or deletions are required. One in each copy of the RB gene
-For sporadic cases (non-inherited). Retinoblastoma is a result of two somatic
mutations
-For familial cases (inherited), individuals harbor one germline mutant allele for the RB gene in each of their cells. This is followed by a somatic mutation in the normal allele
p53
-The p53 gene is the “guardian of the genome”
-Determines if a cell has repaired DNA damage
-If damage cannot be repaired, p53 can induce apoptosis
-More than 50% of human cancers involve an abnormal p53 gene
-Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome
- Family members have many different types of
cancer at early ages
What are the two main forms of breast cancer?
- Familial form: A germline mutation is inherited and then a somatic mutation occurs in a breast cell
- Sporadic form: Two somatic mutations affect the same cell
Mutations in many genes can cause cancer
BRCA
-The two major breast-cancer susceptibility genes are BRCA1 and BRCA2
- Encode proteins that join two others to form a complex that allows repair of double-stranded DNA breaks
-Mutations in these genes have different incidences in different populations
-Inheriting BRCA mutations increases the risk
of other types of cancer
Other genes
genes whos protein products affect those of BRCA1, BRCA2, and p53 can cause breast cancer
gatekeeper genes
directly control mitosis and apoptosis
caretaker genes
control mutation rates and may have an overall effect, when mutant, in destabilizing the genome
How can people lower the chance of developing cancer?
- avoiding high-risk environmental factors, such as smoking and excess sun exposure
- taking “chemopreventative” nutrients such as folic acid and vitamin D
- cruciferous vegetables
method to study cancer - population study
compares incidence of a type of cancer among different groups of people
method to study cancer - case control
identify differences between patients with a type of cancer and healthy individuals matched for mutiple characteristics
method to study cancer - prospective studies
two or more groups of individuals follow a specific regimen (e.g. , det or activity plan) and are checked regularly for cancer
Cancer treatment
New types of cancer drugs: - Stimulate cells to regain specialized characteristics - Inhibit telomerase - Induce apoptosis - Inhibit angiogenesis Genomics information is increasingly used - Enables physicians to better matchpatient to treatment
cytogenetics
a subdisipline within genetics. deals with chromosome variations.
- excess genetic material has a milder effects on health than a deficit
- still, most large-scale chromosomal abnormalities present in all cells disrupt or halt prenatal development
what are the essential parts of a chromosome?
telomeres
origins of replication sites
centromere
portrait of a chromosome - heterochromatin
darkly staining
-consists mostly of repetitive DNA
portrait of a chromosome - euchromatin
lighter straining
-contains most protein-encoding genes
portrait of a chromosome - telomeres
chromosome tips composed of many repeats of TTAGGG
-shorten with each cell division
centromeres
the largest constriction of the chromosome and where spindle fibers attach
- the bases that form the centromere are repeats of a 171-base DNA sequence
- replicated at the end of S-phase; facilitated by centromere protein
- CENP-A is passed to next generation - an example of an epigenetic change
subletelomeres
the chromosome region between the centromere and telomeres
- consists of 8,000 to 300,000 bases
- near the telomere, the repeats are similar to the telomere sequence
- contains at least 500 protein-encoding genes
- about 50% are multigene families that include pseudogenes
how many chromosome types do humans have?
- autosomes are numbed 1-22 by size
- sex chromosomes are X and Y
karyotype - a chromosome chart
centromere positions
At tip – Telocentric
Close to end – Acrocentric
Off-center – Submetacentric
At midpoint – Metacentric
how are karyotypes useful
1) can confirm a clinical diagnosis
2) can reveal effects of environmental toxins
3) can clarify evolutionary relationships
how to visualize chromosomes
chromosomes are extracted then stained with a combination of dyes and DNA probes
how is tissue obtained from a person?
Tissue is obtained from person - Fetal tissue: Amniocentesis Chorionic villi sampling Fetal cell sorting Chromosome microarray analysis - Adult tissue: White blood cells Skinlike cells from cheek swab
Amniocentesis
how fetal (15-16 months) tissue is obtained
- detects about 1,000 of the more than 5,000 known chromosomal and biochemical problems
- fetal cells suspended in the fluid around the fetus are sampled
- ultrasound is used to follow needle’s movement
chrionic villi sampling
-Performed during 10-12th week of pregnancy - cels of the chorion are sampled
-Provides earlier results than
amniocentesis
-However, it does not detect metabolic problems
- And has greater risk of spontaneous
abortion
fetal cell sorting
-Fetal cells are distinguished from maternal cells by a fluorescence-activated cell sorter
- Identifies cell-surface markers
-A new technique detects fetal
mRNA and DNA in the bloodstream of the mother
FISH (fluorescene in situ hybridization)
DNA probes labed with fluorescing bind complementary DNA
-fluorescent dots correspond to copies of chromosome 21
