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135 Cards in this Set

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What are the three most common tumors in men?
1. prostate cancer
2. lung cancer
3. colorectal cancer
What are the three most common tumors in women?
1. breast cancer
2. lung cancer
3. colorectal cancer
What are the three most frequent cancer death in men?
1. Lung cancer
2. Colorectal cancer
3. Prostate cancer
What are the three most frequent cancer death in women?
1. Lung cancer
2. Breast cancer
3. Colorectal cancer
Which of the following two cancer is antosomal dominant and which has defective DNA repair defect?
A. Familial adenomatous polyposis
B. HNPCC
C. Retinoblastoma
D. Xeroderma pigmentosum
Autosomal dominant: A, B, C
DNA repair defect: B, D
What are some features of familial cancers?
1. early age onset
2. occurs in two or more close relatives
3. not associated with specific marker phenotypes.
Name some chronic inflamation conditions that may cause cancer.
Ulcerative colitis
Crohn's disease
H. pylori gastritis
viral hepatitis
Chronic pancreatitis
Name some precancerous conditions that are associated with cancer.
Chronic atopic gastitis of pernicious anemia
Solar keratosis of skin
Chronic ulcerative colitis
Leukemia of oral cavity, vulva, and penis
What are the two nonhereditary predisposing conditions of cancer?
1. Chronic inflammation
2. Precancerous conditions
Seven fundamental changes in cell physiology that together determine malignant phenotype.
1. self-sufficiency in growth signals
2. insensitivity to growth-inhibitory signals
3. evasion of apoptosis
4. defects in DNA repair
5. limitless replicative potential
6. sustained angiogenesis
7. ability to invade and metastasize
What is the mode of protooncogen activation?
insertional mutagenesis
What type of protooncogene dose RAS belong to?
Proteins involved in signal transduction
What types protooncogenes are involved in self-sufficiency in growth signals of cancers?
1. growth factors: SIS, TGF-α, HGF, HST-1, INT-2
2. growth factor receptors: Her2 (amplified in breast cancer), RET
3. signal transducing proteins: RAS, NF-1
4. Nonreceptor tyrosine kinase: ABL (except cABL)
5. transcription factors: MYC
6. cyclins and CDKs:cyclin D, CDK4
List the sequential interactions between cyclins and CDKs that lead to G1-S progression.
CyclinD:CDK4
E2F/DP1/RB
CyclinE:CDK2
Which cyclin:CDK complex is needed for G2-M progression?
CyclinA:CDK2
Which cyclin:CDK complex is needed for progression through M phase?
CyclinB:CDK1
Where is the site of action of p27?
CyclinE:CDK2 downstream signaling
CyclinE:CDK2 complex is later replaced by _____ in the absence of cyclin E.
CyclinA:CDK1
Where is the site of action of p21?
CyclinD:CDK4 downstream signaling
p21 is induced by ____ where as p27 is induced by ____.
p53
TGF-β
Which two cell cycle inhibitors function at cyclinD:CDK4 complex?
p21
INK4
What is the funciton of MDM2?
MDM2 is induced by successful DNA repair to inhibit p53, thereby resuming cell cycle.
What are the mechanisms of growth factor activation in human tumors?
1. mutation
2. gene rearrangement
3. overexpression
Describe the oncogenic version of the growth factor receptors.
constituitive dimerization and activation without binding to the growth factor.
What is the single most common abnormality of dominant oncogene in human tumors?
Point mutations in Ras family gene.
What is the normal signal pathway of Ras?
Ras(GTP)/RAF/MAP
activation of transcription

Regulators:
GAP(GTPase activating protein): augment GTPase activity of Ras.
NF-1: a GAP
Ras can indirectly regulate levels of cyclins. Explain.
Ras->MAPK->AP-1 transcription factor.
Give an example of nonreceptor tyrosine kinase alteration in tumor cells.
Fusion of BCR-ABL gene-> myeloid leukemia.
Which of the following is the most commonly involved trascription factor in human tumors?
A. MYB
B. JUN
C. MYC
D. FOS
C.
Translocation of MYC and Ig gene results in ___.
Burkitt lymphoma
List some tumor suppressor genes.
RB
p53
APC/β-catenin pathway
INK4,ARF
TGF-β
NF-1,2
VHL,PTEN,WT-1,Cadherins,KLF6,PTCH
What is LOH?
Loss of heterozygosity.
Which is the first tumor supressor gene discovered?
RB
How does TGF-β induces inhibition of cellular proliferation?
TGF-β induces p27 which blocks CyclinE/CDK2 signaling.
What is a possible explaination of the pathogenesis of cervical cancer by HPV?
HPV virus may alter tumor suppressor genes such as RB by E7 protein and p53 by E6 protein.
Name some regulations of p53.
1. incude P21, BAX (proapoptotic proteins which down regulates BCL-2)
2. induce GADD45 when DNA repair is successful.
3. GADD45 induces MDM2 which neutralizes p53 to resume cell cycle.
4. HPV E6 protein inhibit p53
What is the action of cell cycle inhibitor ARF?
Inhibit MDM2
What is the normal APC/β-catenin pathway?
without WNT:
APC causes degradation of β-catenin.

With wnt:
APC inactivated, β-catenin accumulates in cytoplasm, translocate to nucleus, induce transcription.
What is the importance of wnt?
Major role in determining cell fate, adhesion, cell polarity during embryonic development. Also required for self-renewal of hematopoietic stem cells.
Do HNPCC patients have normal levels of APC in the cytoplasms?
Yes. But the β-catenin is altered, thus not susceptible to APC degradation.
How do tumor cells evade apoptosis?
lack of p53-> decrease in p21 and BAX-> lack of inhibition of Bcl2.

MYC collaborate by triggering proliferation while lack of p53 prohibits apoptosis.
How does defect in DNA repair contribute to tumor generation?
Allow mutation to accumulate, leading to genomic instability.
T/F: Microsatellite instability is the hallmark of defective mismatch repair.
T. With errors in mismatch reapair, there are expansions and contractions of tandem repeats.
Compare the defective DNA repair mechanism between HNPCC and Xeroderma Pigmentosum.
HNPCC: defective mismatch repair.
Xeroderma Pigmentosum: defective nuclear excision repair (NER).
Give some examples of cancer associated with defective DNA repair by homologous recombination.
BRCA1
BRCA2
ataxia-telangiectasia: ionization radiation. Defective ATM gene.
Bloom syndrome: ionization radiation.
fanconi anemia: DNA cross-linking agents.
What is the function of ATM gene that is mutated in ataxia-talengiectasia?
ATM encodes a protein kinase that senses dsDNA breaks caused by ionizing radiation and oxygen free radical. The kinase also phosphorylates p53 which lead to cell cycle arrest in G1/S check point or apoptosis.
What is the maximal size of the tumor without additional angiogenesis?
1-2mm: the maximal distance across which O2 and nutrients can diffuse from blood vessels.
How are tumor vessel different from normal blood vessels?
tortous, irregular shaped
leaky due to VEGF
continuous growth
What is angiogenic switch?
the time when some cells in the tumnor change to an angiogenic phenotype.
What are some angiogenic factors and what are some antiangiogenic molecules?
angiogenic factor: VEGF, HIF-1
antiangiogenic molecules: thrombospondin-1(tumor cell), endostatin, tumstatin.
How does tumor cells invade ECM?
1. detachment of tumor cells from each other: down regulation of E-cadherin which is linked to catenin.
2. attachment to ECM: via laminin, fibronectin, integrins receptors.
3. degradation of ECM: stromal cells produce matrix metalloproteinase(MMP2,9).
4. migration of tumor cells: cleave products serve as growth promoting, angiogenic, antiangiogenic(endostatin, tumstatin), and chemotactic activities.
How does tumor cells invade and metastasize?
1. invasion of ECM
2. vascular dissemination and homing of tumor cells
After tumor cells invade ECM, how do they disseminate through blood and extravasate?
1. tumor cells circulate in clumps
2. CD44 adhesion molecule facilitate adhesion to endothelial cells. Then tumor cells return to ECM through the same process it get out from it.
How are protooncogenes activated?
1. translocation: remove protooncogenes from its regulatory elements, may also create fusion genes.
2. inversion
Translocation of cyclin D1 and IgH cause what type of cancer?
Mantel cell lymphoma
What is the genetic causes of chronic myeloid leukemia?
translocation of BCR22 and ABL9 -> Philadelphia chromosome.
How does epigenic changes contribute to carcinogensis?
methylation of tumor-suppressor genes (ARF,INK, VHL...)
What are some gatekeeper genes?
oncogenes
tumor suppressor genes
What are some caretaker genes?
DNA repair genes
Describe tumor progression.
Multiple mutations-> increase # of subclones (monoclone origin)-> more adept clones advances to cancer.
What are the three types of carcinogenic agents?
1. chemical
2. radiant energy
3. oncogenic virus and other microbes.
What is Her2?
Protooncogene that codes for a growth factor receptor.
Becomes concogenic through amplification.
Overexpressed om breast carcinomas.
Which gene is overexpressed in breast carcinoma?
Her2
What is cMYC?
How is it activated and regulated?
1. growth response genes.
2. activated when MYC protein is dimerized with MAX protein. Mad competes for MAX, thus Mad:Max complex repress transcription.
What is the gene translocation in Burkitt lymphoma?
MYC(Chromosome 8) and Ig(chromosome 14)
What are some dysregulations of cMYC?
1. alterations in signal pathway.
2. amplification: in neuroblastoma)
3. translocation: Burkitt lymphpma.
What are some effects of MYC protein?
1. enhance progression into G1 phase.
2. promote angiogenesis
3. inhibit differentiation
4. increase chromosomal instability
5. increased telomerase activity
6. loss of E-cadhein expression.
What is the best combination for cancer progression (in tumor cells perspective)?
MYC/Ras activation and anti-BCL protein expression.
What is the one safeguard action of MYC protein?
When it accumulates under oncogenic stress, it can trigger apoptosis.
Explain the dominant negative mutation of p53 gene.
p53 is a tetramer. Mutation in one subpart renders the tetramer defective.
TGF-β upregulates ___ and favors active Rb protein.
p27
What is the most common site of genetic alteration in human tumors?
p53
What are some effects of acivated p53 protein?
1. triggers p21
2. triggers GADD45: DNA repair
3. Bax: apoptosis
4. activate MDM2: feedback loop.
T/F: Loss of p53 or increased Bcl2 activity results in resistance to chemotherapy.
True.
How is MYC regulated?
p14ARF directly inhibits it.
What are the effects of p14ARF?
1. inhibit MYC
2. activate p53
3. sensitize human cells to apoptosis: creating membrane pores.
4. inhibits proliferation by p53-independent pathway.
Is teratoma benign or malignant?
benign
Is melanoma benign or malignant?
malignant
Is Warth's tumor benign or malignant?
malignant:papillary cystadenoma lymphomatosum.
An ectopic rest of normal tissue is called ____.
choristoma
A disorganized mass of mature cells or tissue indigenous to the site is called ____.
Hamartoma.
Compare and contrast benign and malignant neoplasms.
Benign: well differentiated, slow growing, mostly encapsulated, remain localized.

Malignant: anaplasia, rapid cell proliferation, almost never encapsulated, metastasize.
What are some cytologic changes of anaplasia?
pleomorphism
increase in nucleus size
tumor giant cell
nuclear changes: enlargement, irregular shape, hyperchromatism, clumping of chromatin, increased number of mitoses, abnormal mitoses, large nucleoli.
What are some nuclear changes in anapasia?
nuclear changes: enlargement, irregular shape, hyperchromatism, clumping of chromatin, increased number of mitoses, abnormal mitoses, large nucleoli.
List some pathway of spread of malignant neoplasms.
1. seeds cavities: pseudomyxoma peritonei
2. lymphatics: typical of carcinomas.
3. hematogenous: typical of sarcomas.
Do in situ malignancies metastasize?
No.
Why do people with HNPCC have better prognosis?
DNA repair defect results in mutations in genes important for metastasis.
T/F: Bcl dimers favor survival whereas Bax dimer favor apoptosis.
T.
A 14:18 translocation of Bcl-2 results in _____.
follicular B cell lymphoma.
How many doublings of tumor cells will result in 1gm, the smallest detectable tumor mass?
30
Describe the 4 steps of malignant neoplasm process.
1. transformation
2. growth
3. local invasion
4. metastasis
Describe the process of local invasion.
1. loosen IC junctions: down regulation of E-cadherin, mutations in catenin.
2. Attachment to ECM: increase integrin expression to bind to laminin and fibronectin.
3. degrade basement membrane: MMP2,9,serine, cysteine proteases.
4. migration to stroma: cleavage products have growth promoting, angiogenic, and chemotactic effects. Tumor cells develop receptors for ECM proteins and secrete growth factors with autocrine effects.
What blood cells helps metastasized cells survival and implantability on vascular epithelium?
Platlets
What are the key factor of tumor growth rate?
1. doubling time
2. growth fraction
3. rate of cell death
How does debulking(surgery/radiation) help in tumor therapy?
It shifts the remaining tumor cells from G0 to cell cycle, rendering it more susceptible to chemotherapy.
Chemotherapy is most effective against ____ neoplasms.
fast growing
What happens when neoplasm has inadequate blood supply?
hypoxia->apoptosis via p53
What is the function of angiogenesis? (3)
1. provide nutrients and O2
2. endothrlial cells secrete grwoth factors for tumor cells.
3. promote metastasis cia new vessels.
What are some angiogenic factors and anti-angiogenic factors?
angiogenic factors: VEGF, FGF
anti-angiogenic factors: thrombospondin-1, angiostain(plasminogen cleavage product), tumstatin, endostatin(collagen cleavage product).
How do endostain and antibodies against VEGF fignt against cancer?
by limiting angiogensis, causing lack of O2, nutrients for tumor growth.
What are the most immune cells against tumors?
CTL, NK cells
What type of tumor antigens are there?
1. proteins of mutated genes: p53, ras, CDK4, Bcl-Abl gene.
2. overexpressed antigens: c-erbB2(Her2)
3. viral antigens: E7 of HPV.
4. Oncofetal antigens: AFP, CEA can be used for diagnosis and monitor theapy.
5. differentiation antigen: CD10(B cell leukemia), PSA(prostate cancer)
What's the name of the mouse antibody that is used to target Her2 in breat cancer?
trastuzumab
What are some mechanisms that tumor cells use to escape immune system?
1. outgrowth of antigen-negative variants
2. reduced expression of MHC class I molecules
3. cancer immunoediting: immune system selection of tumor subclones for survival
4. secretion of TGF-B for immune suppression
5. express Fas to induce apoptosis of CTLs
List some tumor effects on human hosts.
1. local effects: ulceration of mucosa, obstruction of lumen, destruction of critical structures.
2. hormonal effects: pituitaty adenoma, islet cell cacinoma of pancreas, gastrinoma, carcinoid tumors.
3. cachexia: TNF-A effects. malaise, anorexia, weakness, wasting.
4. paraneoplastic syndrome
What are some tumor local effects on human hosts?
ulceration of mucosa: adenocarcinoma of esophagus.
obstruction of lumen: colon carcinoma.
destruction of critical structures: pituitary adenoma
What are some hormonal effects of tumor on human hosts?
pituitaty adenoma: make prolactin, ACTH, GH
islet cell cacinoma of pancreas: secrete insulin, glucagon, somatostatin, vasoactive intestinal polypeptide.
gastrinoma: produce gastrin.
carcinoid tumors: neuroendocrine cells secrete serotonin, histamine, bradykinin, kallikrein, prostaglandins.
Which metabolite of serotonin cna be measured in urine, and is secreted in increased amount un carcinoid syndrome?
5-HIAA
What are the four symptoms of cachexia syndrome?
malaise
anorexia
weakness
wasting
What do you suspect when a smoker comes in with Cushing's syndrome?
Lung cancer
Give two examples of paraneoplastic syndromes.
1. Paraneoplastic Cushing syndromes: lung cancer (malignant neuroendocrine neoplasm). Weigh gain, central obeicity, moon facies, buffalo bump.
2. Acanthosis nigricans: gastic cancer. Thickened skin in axilla, oral mucosa involvement.
What is the most common cancer death in children?
1. Acute leukemia
2. CNS malignancy
When should you start screen women for breast cancer?
Start at age 40, annually thereafter.
When should you start screen man for prostate cancer (PSA)?
Start at age 50, annually thereafter.
*for African american or people with positive family history, start at age 40.
When should you start screen for colon cancer?
Start at age 50, then every 5 years.
When should you start pap smear for women?
Annual pap smear at 18 yrs or at onset of sexual activity.
List some autosomal dominant cancer syndromes.
familial retinoblastoma
familial adenomatous polyposis
multiple endocrine neoplasia syndromes.
List some autosomal negative cancer syndromes.
defective DNA repair: HNPCC, xeroderma pigmentosum
List some familial cancer syndromes.
BRCA1
BRCA2
E-cadherin
p16 or INK4a
Which of the following is the most common cancer predisposition syndrome?
A. Familial adenomatous polyposis
B. HNPCC
C. ataxia-telangiectasia
D. BRCA1
B
What is the pathogensis of ataxia-telangiectasia?
Mutated ATM gene-> loss of p53-indcuced delaly in cell cycle.

Symptoms: acute sensitivity to radiation, defective lymphocyte maturation. Lead to increased lymphomas.
What types of carcinogens are there?
1. chemical
2. radiation
3. viral
What is the difference between complete and incomplete carcinogens?
Complete carcinogen: can induce both initiation and promotion.

Incomplete carcinogen: induce initiation only.
What are the two processes involved in carcinogenesis?
1. initiation: irreversible alteration of cell's DNA.
2. promotion: reversible process of proliferation and abnormal differentiation of initiated cells after exposure to promoter.
Can promoter damage DNA?
No.
T/F: Initiation is reversible whereas prmotion is irreversible.
F. The other way around.
Cyclophosphamide may increase risk for _____ cancer.
Bladder
AZA/cyclosporin may increase risk for _____.
lymphoma
Which cells are most vulnerable to radiation carcinogens?
1. hematopoietic cells
2. thyroid epithelial cells in children/adolescents
3. breast, lungs, salivary gland
List some microbial carcinogens.
1. H. pylori
2. HepB, HPV, EBV: DNA
3. HTLV-1: RNA
Explain the pathogenesis of cervical cancer by HPV.
E6 degrades p53
E7 associate with p21->prevents inhibition of cyclinD:CDK4. degrades RB->less cell cycle restriction.
Name a slow-transforming RNA oncogenic virus.
HTLV-1: adult T cell leukemia/lymphoma. Infect CD4 cells, become latent for 40-60 years.
Describe the mechanism of H pylori causing lymphoma and carcinoma.
lympoma: chronic infiltrate->persistent infiltrate of B cells->mutations

carcinomas: chronic inflammation->metaplasia->dysplasia->carcinoma.
What is the single most environmental factor contributing to premature death in the US?
smoking
Surgery is curative in stage ___ tumors.
I