Exam 4: Cancer Flashcards Preview

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Flashcards in Exam 4: Cancer Deck (54):

Epigenetic changes

process that alters gene activity without changing DNA sequence and leads to modifications that can be transmitted to the cell's progeny - can lead to cancer



gene associated with control of cell division, act to promote cell growth



mutated proto-oncogene
excessively active in growth promotion - enhanced gene expression, production of hyperactive protein product, etc.
preserves activity of protein but results in excessive protein production or disrupts normal control of function
typically dominant mutation


Tumor suppressor genes

normally function to inhibit cell growth and division
mutations that inactivate tumor suppressor genes allow for inappropriate cell division


Caretaker genes

protect integrity of genome
ie DNA repair enzymes
when inactivated by mutation cells accumulate damaged DNA at a higher rate


Metastatic cancer

cancer that spreads to other parts of body


6 capabilities that cell must acquire to be transformed into invasive tumor

Self-sufficiency in growth signals
Insensitivity to antigrowth signals
Evading apoptosis
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis


Self-sufficiency in growth signals

oncogene products act to send inappropriate growth signals


Insensitivity to antigrowth signals

Loss of tumor suppressor fuction leads to loss of sensitivity to antigrowth signal


Evading apoptosis

needs to block cell death to become cancerous
mutations of components of pathway that lead to apoptosis


Limitless replicative potential

need to not senescence - which limits replication
Reactivates telomerase to lead to unlimited cell division potential


Sustained angiogenesis

cells achieve ability to promote and sustain angiogenesis (growth of blood vessels) to deliver oxygen and nutrients to tumor


Tissue invasion and metastasis

changes in expression of cell surface molecules leads to ability to migrate & invade nearby tissues
increase in expression of proteases that degrade extracellular matrix


dominant mutation

only one allele needs to be mutated for effect to be seen
i.e. gain of function like oncogenic


ErbB1/HER 1

receptor for epidermal growth factor (EGF), tyrosine kinase
activates MAP kinase cascade & cell growth/proliferation
proto-oncogene - mutation converts to consitutively active forms


ErbB1 constitutively active mutation

truncates protein & removes extracellular binding domain - activation of kinase domain
signal to grow delivered in absence of appropriate stimulus


HER2 constitutively active mutation

point mutation allows receptor dimerization and autophosphorylation in absence of ligand


Overexpression of HER2 protein seen in

many breast cancers
Overabundance of receptors allows cell to respond to very low concentrations of EGF = active more often


Ras constitutively active mutation

dominant mutations that favor GTP binding
Ras turned on without ligand binding
Very common in human cancers, especially pancreas & intestinal


c-Fos and c-Myc

transcription factors that activate genes needed for cell cycle progression (cyclins)
mutations stabilize mRNA/encoded protein, stays longer, inappropriate activation of growth promoting genes


Burkitt's lymphoma

caused by inappropriate Myc activity
translocation moves c-myc gene from chromosome 8 to chromosome 14
myc gene now continually expressed (close to new promotor regions) and B-cell becomes cancerous


recessive mutation

damage to both alleles of gene required to give rise to unregulated cell proliferation
typically found in tumor suppressor genes


two hit model

same gene in same cell needs to get both alleles mutated for affect to be seen - somatic mutation - more rare



Hereditary: inherit one mutated copy of RB1 gene, second somatic mutation results in retinal cell with no functional Rb protein = tumor formation more likely because lack of inhibition of cell division cyclins
Tumors develop in both eyes
Sporadic: two separate mutations required in cell


Mutations in p53

most common genetic alterations found in human cancers (over 50%)
Absence of p53 causes cells to divide with many problems (can't activate p21 used in cell cycle arrest or signal apoptosis of damaged cell)
homotetramer - mutation in one allele will reduce p53 activity


Li-Fraumeni syndrome

heritable, increased susceptibility to a variety of cancers
dominant inheritance, early onset of tumors, presence of multiple tumors and multiple affected family members
Inheritance of mutant TP53 allele - disrupts function of p53 tetramer & cells with damaged DNA free to divide & accumulate more damage, leading to tumor development


HPV-induced cervical cancer

caused by HPV
virus produces two proteins, E6 & E7
E6 inhibits p53 by binding to it
E7 inhibits Rb by binding to it (and displacing E2F which increases cell proliferation)
E6 & E7 induce cell proliferation in absence of mutations


Neurofibromatosis 1

due to loss of function mutations in NF1 gene - codes for neurofibromin, which accelerates rate at which Ras hydrolyses bound GTP to inactive GDP
Loss of NF1 means slower inactivation of Ras and longer Ras signaling (increased cell proliferation)
causes hyperpigmented skin patches, neurofibromas, benign growths on iris
Loss of both alleles develop neurofibromatosis - tumors of sheath cells that surround nerves


HBOC (hereditary breast and ovarian cancer)

inherited autosomal dominant
mutations in BRCA1 and BRCA2 lead to increased risk of breast and ovarian cancer
Loss of BRCA1/BRCA2 function impedes delivery of effector proteins to sites of double-stranded DNA breaks = accumulation of mutations



involved in HBOC
repair of double-stranded DNA breaks through homologous recombination (both) and other repair pathways/checkpoints (BRCA1)
Deliver various effector proteins to sites of double-stranded DNA breaks
lack of function allows for accumulation of mutations



stimulates oxygen-sensitive transcription factor HIF-1-alpha-beta
pairing of alpha/beta HIF-1 promotes angiogenesis & encoding of vascular endothelial growth factor (VEGF)


VEGF (vascular endothelial growth factor)

production results in development of angiogenic gradient, stimulating growth of new blood vessels
activated by HIF-1 alpha/beta



hold epithelial cells together
in cancer cells breaks down and cells are freed from primary tumor


matrix metalloproteases (MMPs)

secreted by tumor
breaks down basement membrane



tumor cells enter circulation



exit from bloodstream
begins with adhesion to and digestion of blood vessel wall
then cells migrate through extracellular matrix & can divide



benign tumor



malignant tumor


FAP (familial adenomatous polyposis)

inherited condition from mutation of APC gene, which encodes for tumor suppressor APC - downregulates growth promoting signals that come through WNT pathway
results in thousands of adenomatous polyps in colon
Colorectal adenocarcinoma develops in untreated pts by middle age



Activated by WNT signals (which free it from APC destruction complex)
free beta-catenin translocates into nucleus, where it increases transcription of genes including cyclin D & Myc = upregulated cellular proliferation


APC destruction complex

APC binds to beta-catenin and results in beta-catenin destruction
absence of APC causes constitutive activation of WNT pathway and beta-catenin not destroyed/enter nucleus/ cell proliferation


WNT pathway

WNT signals inhibition of APC/beta-catenin destruction complex and cell proliferation by beta-catenin
Absence of WNT signal prevents beta-catenin from entering nucleus


Mutation in APC gene

leads to FAP
constitutive activation of WNT pathway without APC & beta-catenin upregulation of cell proliferation (mutations in Ras, p53, etc lead to malignant tumors)
part of machinery that attaches microtubules to chromosomes in mitosis - loss of function can cause aneuploidy & genomic mutations
Loss of APC function key to colon cancer development


HNPCC (hereditary nonpolyposis colorectal carcinoma)

defects in pathway of DNA mismatch repair - MSH2 or MLH1
MSH2- identifies DNA containing mismatch errors
MLH1- repairs errors
Inherit one defective copy from parent - other copy lost, DNA mismatch repair defective & mutations accumulate at increased rate
Tend to accumulate mutations in microsatellite repeats - prone to replication errors normally repaired by mismatch repair
Results in mutations of Bax - allow for survival of genetically abnormal cells that would normally be destined for death by apoptosis


Mutations in Bax

Seen in people with HNPCC
mutations in Bax allow for survival of genetically abnormal cells that would usually be destined for death by apoptosis


chronic myeloid leukemia

translocation between chromosomes 9 & 22 - Philadelphia chromosome
fusion of BCR & ABL1 genes results in hybrid Bcr-Abl tyrosine kinase = cell proliferation


Bcr-Abl tyrosine kinase

constitutively active & stimulates cell proliferation


imatinib mesylate (Gleevec)

inhibitor of Bcr-Abl kinase to treat CML (chronic myeloid leukemia)


nilotinib (Tasigna) & dasatinib (Sprycel)

Bcr-Abl kinase inhibitors



interfers with estrogen receptor function
can be used to treat ER+ cancers (breast cancers taht express high levels of estrogen receptor)
deprives cells of estrogen signal that stimultes their cell growth


Trastuzumab (Herceptin)

antibody that binds to the extracellular domain of HER2/Neu and has anti-tumor effects - inhibits HER2/Neu tyrosine kinase activity (cell growth via MAP kinase cascade)
Kills cell



treats non-Hodgkin's lymphoma (antibodies interact with antigens on tumor cell surfaces & lead to cell death)



treats colon and lung cancer (antibodies interact with antigens on tumor cell surfaces & lead to cell death)


cetuximab and panitumumab

treats colorectal cancer and head and neck cancer (antibodies interact with antigens on tumor cell surfaces & lead to cell death)