Chapter 6: Neoplasia Flashcards
(122 cards)
1
Q
All of these questions are based on the blue ‘summary’ boxes in the book
A
okki
2
Q
Benign and malignant tumors can be distinguished from one another based on….
A
the degree of differentiation, rate of growth, local invasiveness, and distant spread.
3
Q
Fill in: Benign tumors resemble the tissue of origin and are poorly/well differentiated; malignant tumors are poorly/well or differentiated
A
well and poorly respectively
4
Q
What does anaplastic mean?
A
These are malignant tumors that are completely undifferentiated
5
Q
Do benign tumors grow slower or faster than malignant?
A
Slower
6
Q
True/false: Benign tumors are poorly circumscribed and invade the surrounding normal tissues.
A
False, this explains malignant tumors. Benign tumors are well circumscribed and have a capsule.
7
Q
Fill in: … remain localized to the site of origin, whereas … are locally invasive and metastasize to distant sites.
A
Benign tumors, malignant tumors respectively
8
Q
The incidence of cancer varies… with what?
A
age, geographic factors and genetic background
9
Q
How can geographic factors be explained?
A
It results mostly from different environmental exposures.
10
Q
True/false: cancer only occurs in older adults
A
False, though it is more common
11
Q
What are some environmental factors that implicated in carcinogenesis?
A
These include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to carcinogens.
12
Q
Cancer risk rises in certain tissues in the setting of increased cellular proliferation caused by …
A
chronic inflammation or hormonal stimulation
13
Q
Epithelial cell linings may develop morphologic changes that signify an increased risk for developing cancer; such lesions are referred to as …
A
precursor lesions.
14
Q
True/false: The risk for developing cancer is modified by interactions between environmental exposures and genetic variants.
A
True
15
Q
Mutations in cancer cells fall into two major classes. Which two?
A
driver (pathogenic) mutations and passenger (neutral) mutations.
16
Q
Can driver mutations become passenger mutations?
A
Yes, passenger mutations may become driver mutations if selective pressure on the tumor changes, for example, in the setting of treatment with an effective therapeutic drug.
17
Q
Tumor cells may acquire driver mutations through several means. What are some examples of those?
A
Point mutations and nonrandom chromosomal abnormalities that contribute to malignancy; these include gene rearrangements, deletions, and amplifications.
18
Q
What is the most common gene rearrangement?
A
Translocations
19
Q
How can a gene rearrangement contribute to carcinogenesis?
A
by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity.
20
Q
How do deletions impact carcinogenesis?
A
By affecting tumor suppressor genes
21
Q
How do gene amplifications impact carcinogenesis?
A
By the increasing expression of oncogenes
22
Q
Overexpression of miRNAs can contribute to carcinogenesis. How?
A
By reducing the expression of tumor suppressors
23
Q
Deletion or loss of expression of miRNAs can also contribute to carciongenesis. How?
A
By overexpression of proto-oncogenes
24
Q
Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes, which involve reversible, heritable changes in gene expression that occur not by mutation but by …
A
methylation of the promoter.
25
What are proto-oncogenes?
normal cellular genes whose products promote cell proliferation
26
What are oncogenes?
mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals
27
Oncoproteints promote uncontrolled cell proliferation by several mechanisms. Name some of them
(get familiar with this list, but they'll be discussed in further detail later!)
• Stimulus-independent expression of growth factor and its
receptor, setting up an autocrine loop of cell proliferation
(e.g., PDGF–PDGF receptor in brain tumors)
• Mutations in genes encoding growth factor receptors or
tyrosine kinases leading to constitutive signaling
• Amplification of EGF receptor family genes such as HER2 in
breast cancer
• Fusion of portions of the ABL tyrosine kinase gene and the
BCR protein gene, creating a BCR-ABL fusion gene encoding
a constitutively active tyrosine kinase, in certain leukemias
• Mutations in genes encoding signaling molecules
• RAS commonly is mutated in human cancers and normally
flips between resting GDP-bound state and active GTP- bound state; mutations block hydrolysis of GTP to GDP, leading to unchecked signaling
• Overproduction or unregulated activity of transcription factors
• Translocation of MYC in some lymphomas leads to overexpression and unregulated expression of its target genes controlling cell cycling and survival
• Mutations that activate cyclin genes or inactivate negative regulators of cyclins and cyclin-dependent kinases
28
What do complexes of cyclins with CDKs do?
They drive the cell cycle by phosphorylating various substrates and normally are controlled by CDK inhibitors
29
What happens when there are mutations in the genes encoding cyclins, CDKs, and CDK inhibitors
Uncontrolled cell cycle progression (found in melanomas and brain, lung and pancreatic cancers)
30
What is Rb also called?
The governor of the cell
31
What is P53 also called?
The guardian of the genome
32
Is Rb a tumor suppressor, or a tumor oncogene?
Suppressor
33
What does suppressor mean?
That both copies of Rb need to be dysfunctional for a tumor development to occur
34
Do both copies of Rb need to be dysfunctional for tumor development?
Yes, but the exception is familial retinoblastoma, where one is already defect
35
RB exerts anti-proliferative effects by controlling the G1-to-S transition of the cell cycle. What does it do in it's active and inactive form?
In its active form, RB is hypophosphorylated and binds to E2F transcription factors. This interaction prevents transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in G1.
36
What does growth factor signaling lead to?
Cyclin D expression, activation of cyclin D-CDK4/6 complexes, inactivation of RB by phosphorylation, and thus release of E2F
37
True/false: Almost all cancers have a disabled G1 checkpoint due to mutation of either RB or genes that affect RB function, such as cyclin D, CDK4, and CDKIs.
True
38
How do viruses contemplate to cancer?
Many oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that bind RB and render it nonfunctional.
39
What is the gene of p53?
TP53
40
What does TP53 do?
TP53 encodes p53, the central monitor of stress in the cell, which can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis.
41
What happens (with regard to p53) when DNA is damages (in a normal cell)
DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of CDKN1A (p21), which prevents RB phosphorylation, thereby causing a G1-S block in the cell cycle. This pause allows the cells to repair DNA damage.
42
When happens when DNA damage cannot be repaired?
p53 induces cellular senescence or apoptosis.
43
How many % of the human tumors demonstrate biallelic mutations in TP53 (both need to be mutated)? What is an exception to this rule?
70%. Patients with the rare Li-Fraumeni syndrome inherit one defective copy of TP53 in the germ line, such that only one additional mutation is required to lose normal p53 function. Li-Fraumeni syndrome patients are prone to develop a wide variety of tumors.
44
Can p53 be incapacitated by viruses?
As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV.
45
What does TGF-β do?
TGF-β inhibits proliferation of many cell types by activation of growth-inhibiting genes such as CDKIs and suppression of growth-promoting genes such as MYC and those encoding cyclins.
46
What parts of TGF-β function are compromised/ mutated in tumors?
TGF-β function is compromised in many tumors by mutations in its receptors (colon, stomach, endometrium) or by mutational inactivation of SMAD genes that transduce TGF-β signaling (pancreas).
47
What does E-cadherin do?
It maintains contact inhibition (that is lost in malignant cells)
48
What does the APC gene do? What happens when it doesn't work?
The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor.
49
The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor. What does this lead to?
One/more of these polyps evolve into colonic cancer
50
How often (in %) is somatic loss of both alleles of the APC gene seen in sporadic colon cancers?
70%
51
What is Warbung metabolism?
Warburg metabolism is a form of pro-growth metabolism favoring glycolysis over oxidative phosphorylation. It is induced in normal cells by exposure to growth factors and becomes fixed in cancer cells due to the action of certain driver mutations.
52
Many ... (RAS, MYC, mutated growth factor receptors) induce or contribute to Warburg metabolism, and many .... (PTEN, NF1, p53) oppose it.
oncoproteins, suppressors
53
Stress may induce cells to consume their components in a process called ... . Cancer cells may accumulate mutations to avoid ..., or may corrupt the process to provide nutrients for continued growth and survival.
autophagy, autophagy
54
Some oncoproteins such as mutated IDH act by causing the formation of high levels of ... that alter the epigenome, thereby leading to changes in gene expression that are oncogenic.
“oncometabolites”
55
Evasion of cell death by cancers mainly involves acquired abnormalities that interfere with the intrinsic (mitochondrial) pathway of .... .
apoptosis
56
How is apoptosis evaded?
By loss / mutation of p53 or overexpression of inhibitor MDM2
by overexpressing anti-apoptotic members of the BCL2 family, such as BCL2, BCL-XL, and MCL1, which protect cells from the action of BAX and BAK, the pro-apoptotic members of the BCL2 family.
57
In a large majority of follicular B-cell lymphomas, BCL2 levels are high because of a (14;18) ... that fuses the BCL2 gene with regulatory elements of the immunoglobulin heavy chain gene.
translocation
58
Fill in: Inhibitors of MDM2 (which activate p53) and inhibitors of BCL2 family members induce the death of cancer cells by *stimulating/unstimulating* the intrinsic pathway of apoptosis and are being developed as therapeutic agents.
Stimulating
59
Explain how normal cells have limited cell divisions
In normal cells, which lack expression of telomerase, the shortened telomeres generated by cell division eventually activate cell cycle checkpoints, leading to senescence and placing a limit on the number of divisions a cell may undergo.
60
What happens in cells that have disabled checkpoints?
DNA repair pathways are inappropriately activated by shortened telomeres, leading to massive chromosomal instability and mitotic crisis.
61
How do tumor cells achieve immortality?
By reactivating telomerase (thus staving off mitotic castrophe)
62
..... of tumors is essential for their growth and is controlled by the balance between angiogenic and anti- angiogenic factors that are produced by tumor and stromal cells.
Vascularization
63
What triggers angiogenesis and how?
Hypoxia triggers angiogenesis through the actions of HIF-1α on the transcription of the proangiogenic factor VEGF.
64
Many other factors regulate angiogenesis. Name some examples
p53 induces synthesis of the angiogenesis inhibitor thombospondin-1, while RAS, MYC, and MAPK signaling all upregulate VEGF expression and stimulate angiogenesis.
65
Is the ability to invade tissues a hallmark of malignancy?
Yes
66
What are the four steps of invasion?
loosening of cell–cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells.
67
How is cell-cell contact lost?
by the inactivation of E-cadherin through a variety of pathways.
68
How is basement membrane and interstitial matrix degradation mediated?
by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs and cathepsins.
69
True/false: Proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic fragments from cleavage of ECM glycoproteins.
True
70
How can the metstatic site of tumors be predicted?
By the location of the primary tumor. Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly)
71
Some tumors show organ tropism. Why?
Probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastic site
72
How can tumor cells be recognized by the immune system?
Non-self and destroyed
73
What is anti-tumor activity mediated by?
predominantly cell-mediated mechanisms. Tumor antigens are presented on the cell surface by MHC class I
74
Which type of cell recognizes MHC class i?
CD8+ CTLs
75
The different classes of tumor antigens include...
products of mutated genes, overexpressed or aberrantly expressed proteins, and tumor antigens produced by oncogenic viruses.
76
Why have an increased risk of development of cancer?
Immunosuppressed, especially ones caused by oncogenic DNA viruses
77
In immunocompetent patients, tumors may avoid the immune system by several mechanisms, which mechanisms are they?
Selective outgrowth of antigen-negative variants, loss or reduced expression of histocompatibility molecules, and immunosuppression mediated by expression of certain factors (e.g., TGF-β, PD-1 ligands) by the tumor cells.
78
How are antibodies used for treatment for advanced forms of cancer?
Because they cane overcome some of the immune system evasions
79
True/false: Individuals with inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer.
True
80
How do patients with HNPCC syndrome have an increased risk for cancer?
Patients with HNPCC syndrome have defects in the mismatch repair system, leading to development of carcinomas of the colon. These patients’ genomes show microsatellite instability (MSI), characterized by changes in length of short tandem repeating sequences throughout the genome.
81
How do patients with xeroderma pigmentosum have an increased risk for cancer?
Patients with have a defect in the nucleotide excision repair pathway. They are at increased risk for the development of skin cancers in sites exposed to sunlight because of an inability to repair pyrimidine dimers induced by UV light.
82
Syndromes involving defects in the ... constitute a group of disorders—Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia—that are characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation.
homologous recombination DNA repair system
83
What is a common example of a mutated homologous recombination DNA system?
BRCA1 and BRCA2 (familial breast cancer)
84
True/false: Mutations incurred in lymphocytes expressing gene products that induce genomic instability (RAG1, RAG2, AID) are important in the pathogenesis of lymphoid neoplasms.
True
85
I beg you to study figure 6.31
OK
86
Chemical carcinogens have highly reactive ... that directly damage DNA, leading to mutations and eventually cancer
electrophile groups
87
True/false: Direct-acting agents require metabolic conversion to become carcinogenic
False, they do not require metabolic conversion (but indirect-acting agents do
88
How are indirect-acting agents activated?
By converting to an ultimate carcinogen by endogenous metabolic pathways.
(hence, polymorphisms of endogenous enzymes such as cytochrome P-450 may influence carcinogenesis by altering the conversion of indirect-acting agents to active carcinogens)
89
After exposure of a cell to a mutagen or an initiator, tumorigenesis can be enhanced by ...
exposure to promoters, which stimulate proliferation of the mutated cells.
90
What are some examples of human carcinogens?
direct-acting agents (e.g., alkylating agents used for chemotherapy), indirect-acting agents (e.g., benzo(a)pyrene, azo dyes, aflatoxin), and tumor promoters.
91
Tumor promoters act by stimulating cell proliferation. How may this occur?
- direct effects of tumor promotors on target cells
| - secondary to tissue injury and regenerative repair
92
True/false: Ionizing radiation often causes chromosome breakage, chromosome rearrangements, point mutations, any of which may affect cancer genes and thereby drive carcinogenesis.
False, point mutations are less common
93
UV rays in sunlight induce the formation of ... within DNA,
pyrimidine dimers
94
Where do pyrimidine dimers lead to?
Mutations that can give rise to squamous cell carcinomas and melanomas of the skin.
95
What does HTLV-I cause?
A T cell leukemia that is endemic in Japan and the Carribean
96
Where does the HTLV-I genome encode for, and what might it lead to?
The HTLV-1 genome encodes a viral protein called Tax, which stimulates proliferation, enhances cell survival, and interferes with cell cycle controls. Although this proliferation initially is polyclonal, the proliferating T cells are at increased risk for secondary mutations that may lead to the outgrowth of a monoclonal leukemia.
97
What may HPV cause?
Benign warts, but also cervical cancer
98
The oncogenicity of HPV is related to the expression of two viral oncoproteins, E6 and E7. Where do these bind to and what does this cause?
the p53 and RB
| tumor suppressors, respectively, neutralizing their function.
99
What do E6 and E7 from high-risk strains of HPV give rise to and why?(which give rise to cancers) have higher affinity for their targets than do E6 and E7 from low-risk strains of HPV (which give rise to benign
warts).
GIve rise to cancer because they have higher affinity (than low-risk strains)
100
What do E6 and E7 from low-risk strains give rise to?
Benign warts (because they have lower affinity)
101
In which diseases is EBV implicated in the pathogenesis?
Burkitt lymphomas,
lymphomas in immunosuppressed patients, Hodgkin lymphoma, uncommon T-cell and NK-cell tumors, nasopharyngeal carcinoma, a subset of gastric carcinoma, and rarely sarcomas.
102
Certain EBV gene products contribute to oncogenesis by stimulating normal B-cell proliferation pathways. Concomitant compromise of immune competence allows sustained B-cell proliferation, leading eventually to development of .....
lymphoma
103
Where does HBV and HCV stand for
Hepatitis B virus and Hepatitis C virus
104
How many of hepatocellular carcinomas worldwide are due to infection with HBV or HCV?
70-80%
105
The oncogenic effects of HBV and HCV are multifactorial, but what is the dominant effect ?
It seems to be immunologically mediated chronic inflammation, with hepatocellular injury, stimulation of hepatocyte proliferation, and production of reactive oxygen species that can damage DNA.
106
How does Hbx protein (of HBV and HCV core protein) contribute to carcinogenesis?
By activating a variety of signal transduction pathways
107
In what type of tumors has H. pylori infection been implicated?
Gastric adenocarcinoma and MALT lymphoma
108
The mechanism of H. pylori-induced gastric cancers is multifactoral. What are some examples of these mechansisms?
Immunologically mediated chronic inflammation, stimulation of gastric cell proliferation, and production of reactive oxygen species that damage DNA
(H. pylori patho- genicity genes, such as CagA, also may contribute by stimulating growth factor pathways.)
109
True/false: H. pylori infection leads to polyclonal B-cell proliferations and that eventually a monoclonal B-cell tumor (MALT lymphoma) emerges as a result of accumulation of mutations.
Yes (it is thought)
110
What is cachexia?
A progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia
111
How is cachexia caused?
By cytokines of the tumor or host?
112
Paraneoplastic syndromes, defined as systemic symptoms that cannot be explained by tumor spread or by hormones appropriate to the tissue, are caused by ...
the ectopic production and secretion of bioactive substances such as ACTH, PTHrP, or TGF-α.
113
How are tumors graded?
by cytologic appearance and is based on the idea that behavior and differentiation are related, with poorly differentiated tumors having more aggres- sive behavior.
114
What is staging?
Extent of tumor
115
How is the staging of a tumor determined?
by surgical exploration or imaging, is based on size, local and regional lymph node spread, and distant metastases.
116
What is of greater clinical value, grading or staging?
staging
117
Several sampling approaches exist for the diagnosis of tumors. What are they?
excision, biopsy, fine-needle aspiration, and cytologic smears.
118
Immunohistochemistry and flow cytometry studies help in the diagnosis and classification of tumors, because ...
distinct protein expression patterns define different entities.
119
How are proteins that are released by tumors into the serum (such as PSA) used in the clinic?
To screen populations for cancer and to monitor for recurrence after treatment
120
How are molecular analyses used in the clinic?
to determine diagnosis and prognosis, to detect minimal residual disease, and to diagnose patients with a hereditary predisposition to cancer.
121
Molecular profiling of tumors by ... are useful in molecular stratification of otherwise identical tumors or those of distinct histogenesis that share a mutation for the purpose of targeted treatment and prognostication.
RNA expression profiling, DNA sequencing, and DNA copy number arrays
122
True/false: Assays of circulating tumor cells and of DNA shed into blood, stool, sputum, and urine are under development.
True
