APP Cancer I (part 2) Flashcards
Lecture 2: APP
Carcinomas originate in what cell line?
Carcinomas are cancer of epithelial origin
If the cells are well differentiated, is it most likely a benign or malignant tumor?
Benign - well differentiated cells, specialized features of the parent cell is preserved (e.g. hormone release)
What kind of cells proliferate in adults?
- Bone marrow myeloblasts - Immune Cells - Epidermal cells - Epithelial cells (e.g. gut) - Regenerating Tissues
If a tumor is well demarcated, it is probably….. (benign or malignant)?
Benign - usually well demarcated/encapsulated masses - no invasion of the surrounding tissue
lack of differentiation indicates that a tumor is ____
malignant (Lack of differentiation = anaplasia)
Proto-oncogenes encode for proteins that normally___ cell proliferation
stimulate
In cancers, the oncogenes have sustained gain-of-function alterations resulting from 3 possible events….
- point mutations - chromosomal rearrangements - gene amplification
Protooncogenes are affected by ____ factors
Growth Factors
Proto-oncogene mutations usually arise somatically in tumor cells and are _____ (dominant or recessive?)
dominant
What are the mechanisms of oncogene activation?
- Point mutation - Gene amplification - Chromosomal Translocation
Describe protooncogene assoication with growth factor receptors?
- Mutated or truncated forms of the receptors with constitutive activity - Epidermal growth factor (EGF) receptor - ERBB1 is truncated in glioblastoma
2 types of cancer caused by overexpression of autocrine growth factors:
- Platelet-derived growth factor (PDGF) in glioblastomas. - Transforming growth factor α (TGF-α) in sarcomas.
Overexpression of growth factor RECEPTORS in 2 types of cancers:
- ERBB1 in squamous cell carcinomas of the lung - ERBB2 (HER2) in breast cancer
RAS encodes?
p21 G-protein
_____ mutations are the most common abnormalities in human cancer, particularly high incidence in colon and pancreatic cancers.
RAS
How is p21 G-protein involved in GF signaling?
- p21 transmits mitogenic signal from an activated GF receptor to the nucleus - (through phosphorylation cascade of transducing proteins)
_____ mutations changing amino acids in the pocket binding GTP and region essential for GTP hydrolysis lead to constitutive activation of RAF-MAPK mitogenic cascade
Point mutations (RAS pathway)
Describe ABL and what it promotes
Non-receptor tyrosine kinase, promotes apoptosis;
The BCR-ABL fusion protein retains in cytoplasm and, due to its high _______ activity, stimulates several pathways, including RAS-RAF mitogenic cascade.
Tyrosine kinase activity
What do nuclear transcription factors stimulate?
Stimulate expression of several growth-related genes, such as cyclin-dependent kinases (CDKs)
Describe the nuclear transcription factor MYC…
The most commonly involved in human cancer
In burkitt lymphoma, what is overexpressed due to a translocation to the chromosome 14, in close proximity to an Ig gene.
MYC nuclear transcription factor
In breast, lung and other cancers, what is overexpressed due to gene amplification?
MYC nuclear transcription factor
Amplification of related genes _____ and _____ are common in neuroblastoma and small cell cancer of lung, respectively.
N-MYC.
L-MYC.
Dysregulation of cyclin and ____ expression or their mutations occur often in cancer cells and promote proliferation
CDK
The most common perturbations affect proteins involved in G1-S transition?
Overexpression of cyclin D (breast, esophagus, liver cancers, lymphomas) Amplification of CDK4 (melanomas, sarcomas, glioblastomas)
Tumor supressor genes encode proteins, which normally ____ cell proliferation or stimulate apoptosis upon cell damage
inhibit cell proliferation
Tumor Suppressor genes are _____ in cancer cells
inactivated
TSGenes are inactivated in cancer cells by _______ leading to uncontrolled growth. (4)
mutations, truncation, deletions or methylation
Mutations of TSGs are usually _____ - two alleles must be altered to lose their function
Recessive
Inherited mutations of the TSGs contribute to _______ cancers
Familial cancers
_______ cancers develop earlier in age than sporadic malignancies and often arise in multiple locations
Hereditary
Mechanisms of Tumor suppressor gene inactivation? (list 3)
Point mutations, deletions, epigenetic changes (methylation of the promoter)
RB (Tumor suppressor gene) encodes DNA-binding protein, which controls ______ checkpoint
G1 - S checkpoint
In quiescent cells, an active hypophosphorylated RB prevents activation of ______ genes
S-phase
Upon growth factor stimulation, Rb protein is ________ by cyclin-dependent phosphorylation, which allows progression of cell cycle
Inactivated
Deregulation of _____ checkpoint by mutations in one of these tumor suppressor genes has been found in majority of cancers
G1-S checkpoint
Retinoblastoma - pediatric tumor developing in retina due to deletion of ______ gene.
RB tumor suppressor gene.
What are the two forms of Retinoblastoma?
Sporadic and Familial
In the sporadic form of retinoblastoma, both mutations in RB gene are acquired ____ birth, thus frequency of the tumor is relatively ____.
acquired after birth; frequency is low.
In the familial form, one mutation in RB protein is ______, therefore only one additional mutation has to occur in one of the retinal cells. Due to this, frequency of retinoblastoma is very ______ and the tumors often arise bilaterally.
inherited; high frequency
APC gene stands for?
Adenomatous polyposis coli
APC gene encodes a cellular protein regulating ______ and adhesion
cell proliferation
APC protein interacts with ______, a signaling molecule in WNT pathway
Beta-catenin
In the absence of _____, APC binds beta-catenin and stimulates its degradation
WNT
Upon WNT stimulation, APC releases Beta-catenin, which translocates to the ______ and activates genes _______ cell cycle
nucleus; promoting
Germline mutations of APC gene lead to development of multiple benign tumors (polyps) in colon, which in almost 100% of cases transform to the malignant cancer; this trasformation is associated with loss of the ______
second APC allele
APC mutations also occur in majority of _________ colorectal cancers.
sporadic
p53 is a _____ _____ gene
tumor suppressor gene
p53 controls cell proliferation and apoptosis; it “_________” cellular stress and prevents propagation of damaged cells
“detects”
Under normal conditions, p53 is bound to MDM2 gene, which causes its ________ and short half-life;
degradation by MDM2 gene
Upon cellular stress (hypoxia, DNA damage, overexpression of mitogenic factors), p53 is released from the complex with MDM2, which increases its half-life and activates its ______ _____activity;
transcription factor
Active p53 stimulates transcription of CDK inhibitor - _______, which leads to G1 growth arrest; simultaneously DNA repair systems are activated (GADD45);
CDK inhibitor - p21,
_____ is the one of the most commonly mutated genes in human cancer (over 70%)
p53
Mutations or loss of p53 leads to accumulation and propagation of mutated and damaged cells; it also allows survival of the cells with _______ or ________ mitogenic factors;
overexpressed or deregulated mitogenic factors
Germline mutations in the p53 gene cause _____, associated with high risk of multiple tumors.
Li-Fraumeni Syndrome (LFS-dominant)
Tumors associated with p53 induced LFS?
- Soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer. - tumors develop at a younger age than sporadic and often in multiple locations.
p53 protein
- a transcription factor - binds to DNA in promoter region of genes encoding proteins responsible for cell cycle arrest and apoptosis
p53 in its functional form is a ____
tetramer
tumor-associated mutations of P53 genes often affect which domain?
DNA-binding domain (DBD)
What is loss of function (due to p53 mutation)?
mutant p53 is not functional, but does not interfere with actions of normal p53 allele.
What is dominant negative mutant (due to p53 mutation)?
mutant p53 forms a complex with the wild type allele and prevents it from binding to target gene promoters
What is gain of function due to mutated p53?
mutant p53 binds to and activates different target genes, can lead to stimulation of cell proliferation, instead of cell cycle arrest and apoptosis
What other factors contribute to Li-Fraumeni Syndrome? (mutations of what gene and polymorphism of what?)
Mutations of CHK2 Gene. Polymorphism of WT p53.
Mutations of BRCA1 have been found in 40 - 50% of families with multiple ______ cancer cases
breast cancer
BRCA1 gene (TSG)
Germline mutation (truncation, inactivating frameshift mutations) of this gene is associated with increased risk of breast cancer and ovarian cancer (85% and 50%)
Germline mutations (truncation, inactivating frameshift mutations) of what gene can lead to increased risk of breast cancer (80%), while ovarian cancers are not as common (~10%)
BRCA2 gene (TSG)
BRCA2 mutations are associated with increased risk (6%) of male _____ cancer
male breast cancer
Both BRCA1 and BRCA2 encode nuclear proteins involved in response to DNA _____ and in DNA ______
DNA damage and DNA repair
____ ______ genes (TSG) usually are not directly involved in cell cycle regulation. However, lack of DNA repair activity leads to genetic instability and facilitates mutations in other genes, including oncogenes and tumor suppressors.
DNA repair genes
Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with defects of?
Defects of DNA mismatch repair genes
Xeroderma pigmentosum is increased risk of UV induced skin cancers due to defects in the _____ _____ repair system responsible for removal of UV-crosslinked residues
Nucleotide excision repair system
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase preferentially expressed in ______ and _____ nervous systems
central and peripheral nervous systems
Germline activating mutations of ALK have been associated with familial ________, which segregates as autosomal-dominant diseases with limited penetrance
Neuroblastoma
The mutations and amplification of _____ occur also in sporadic cases of neuroblastoma
ALK (anaplastic lymphoma kinase)
oncogenic miRNAs target _____ ____
tumor suppressors
Tumor Supressor miRNA target _____
oncogenes
Alteration of the balance of Micro RNAs can trigger/facilitate ______ transformation
Malignant transformation
Deregulation of apoptosis leads to propagation of _____, _____ cells
damaged mutated cells due to deregulation of apoptosis
Deregulation of apoptotic mechs: What can happen at the receptor level?
Reduced levels of CD95
Deregulation of apoptotic mechs: What can happen with death-induced signaling?
Inactivation of death-induced signaling complex by FLIP protein
Deregulation of apoptotic mechs: What can happen to anti-apoptotic molecules of mitochondrion?
Up-regulation of anti-apoptotic BCL2 (e.g. due to translocation near Ig genes in B-cell lymphoma)
Deregulation of apoptotic mechs: Down regulation of what is due to lack of p53
Proapoptotic BAX (downregulation of this is due to lack of p53)
Deregulation of apoptotic mechs: Loss of what can occur by cytochrome C.
APAF-1 loss Deregulation of apoptotic mechs: Loss of what can occur by cytochrome C.
methylation of Caspase 8 gene causes what?
methylation inactivates caspase 8 gene, resulting in deregulation of apoptotic mechanisms.
most normal cells only replicate 60-70 times; after that they enter _________. Why?
- non-replicative senescence. - replicative potential due to shortening of telomeres.
Telomerase in stem cells?
telomerase maintains telomere length, preventing senescence (aging)
Telomerase is responsible for what feature of cancer cells?
- up-regulation of telomerase enzyme allows unlimited division of cancer cells.
