Robbins Neoplasia Ch 5 Flashcards
1
Q
What are the hallmarks of cancer cells?
A
- self-sufficiency in growth signals
- lack of response to growth inhibitory signals
- evasion of cell death
- limitless replicative potential
- development of angiogenesis to sustain growth
- ability to invade local tissues and spread
- reprogramming of metabolic pathways, specifically a switch to aerobic glycolysis
- ability to evade the immune system
2
Q
What are the two basic componenets of tumors?
A
the parenchyma - transformed neoplastic cells
AND
the stroma - non-neoplastic supporting cells derived from the host (connective tissue, blood vessels, host inflammatory cells)
3
Q
What is a chondroma?
A
benign tumor begininning in cartilage
4
Q
Where do papillomas begin?
A
epithelium. They develop finger-like projections.
5
Q
What are cystadenomas?
A
hollow cystic masses that typically arise in the ovary
6
Q
What are neoplasms arising from mesenchymal tissues called?
A
sarcomas
7
Q
What are leukemias?
A
neoplasms arising from blood
8
Q
What is a fibrosarcoma?
A
a cancer of fibrou stissue that originated in the solid mesenchymal tissues.
9
Q
What is a tumor arising from the endoderm called?
A
carcinoma. All epithelial-derived tumors are carcinomas, regardless or germ cell layer origin.
10
Q
What are carcinomas taht frow in glandular patterns called?
A
adenocarcinomas
11
Q
What is a pleomorphic adenoma?
A
when there is divergent diffentiation in tumors, causing mixed cells of origin in a tumor.
12
Q
What is a teratoma?
A
a special type of mixed tumor that contains recognizable mature or immature cells representative of more than one germ cell layer ,sometimes all three. They originate from totipotential germ cells, like those present in ovaries and testes.
13
Q
What is a hamartoma?
A
a mass of disorganized tissue indigenous to the particular site. May show a mass of mature but disorganized hepaticcells, blood vessels, and possibly bile ducts within the liver or a nodule in the lung containing islands of cartilage, bronchi, and blood vessels. Considered a developmental malformation, but some studies suggest neoplastic origin
14
Q
What are choristomas?
A
congenital anomaly consisting of heterotopic rest of cells. (ex: small nodule of well-develped and normally organized pancreatic tissue found in submucosa of stomach, duodenum or small intestine.)
15
Q
What are the four features that indicate whether benign or malignant?
A
- differentiation and anaplasia
- rate of growth
- local invasion
- metastasis
16
Q
Can differentiation and anaplasia be seen in the parenchyme? The stroma?
A
differentiation and anaplasia can only be seen in the parenchymal cells.
17
Q
What is desmoplasia?
A
when cancers induce a dense abundant fibrous stroma, making them hard, so-called scirrhous tumors.
18
Q
What are malignant neoplasms that are composed of undifferentiated cells called?
A
anaplastic tumors
19
Q
What is dysplasia?
A
loss in the uniformity of individual cells and in their architectural orientation. Dyplastic cells exhibit considerable pleomorphism and often possesss hypercrhomatic nuclei that are abnormally large.
20
Q
If a tumor lacks a capsule, is it malignant?
A
not necessarily.
21
Q
How do malignant neoplasms disseminate?
A
- seeding within body cavities
- lymphatic spread (carcinomas)
- hematogenous spread (sarcomas)
22
Q
What is a sentinal lymph node?
A
first regional lymph node that recieves lymph flow from a primary tumor.
23
Q
How is xeroderma pigmentosum inherited/
A
it is an autosomal recessive syndrome of defective DNA repair
24
Q
What are the 4 primary types of genes that can result in cancer if mutated?
A
- growth-promotoing proto-oncogenes,
- growth-inhibiting tumor suppressor genes
- genes that regulate apoptosis
- genes involved in DNA repair
25
What are the two general groups of tumor suppressor genes?
governors - classic tumor suppressor genes such as RB, where mutation of the gne leads to transformation by removing an important brake on cellular proliferation
Guardians - responsible for sensing genomic damage. Choreograph complex damage control response.
26
What is the most common method of mutation in Burkitt lymphoma?
balanced translocation.
27
What is aneuploidy?
any chromosome number in humans that is not a multiple of 23
28
What are microRNAs and how are they involved in cancer?
noncoding, single-stranded RNAs that function as negative regulators of genes. They can be involved in neoplasm if they upregulate production of certain proteins or fail to downregulate.
29
How do genetic deletions normally cause cancer?
lack of function of tumor suppressor genes
30
How do balanced translocations normally cause cancer?
overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity
31
What will overexpression of miRNAs do in terms of carcinogenesis?
it can reduce the expression of tumor suppressors.
32
What can deletion or loss of miRNAs do to cause cancer?
lead to overexpression of proto-oncogenes
33
What is the RAS genes?
most commonly mutated proto-oncogene in human tumors. Member of a family of small G proteins that bind GTP and GDP. Normally they flip back and forth between excited signal-transmitting state and quiescent state. Active when bound to GTP, inactive when bound to GDP.
34
What mechanism do RAS and ABL commonly play a role in?
they are proteins often involved in downstream signal-transducing. They receive signals from activated growth factor receptors and transmit them to the nucleus through a cascade
35
What is RAS protein?
the most commonly mutated proto-oncogene. (30% of all tumors). member of small G proteins that bind guanosines. Normally it flips back and forth between active and inactive when it binds to GTP or GDP. When mutated, it cannot hydrolyze bound GTP to GDP and is constantly active.
36
What is ABL?
proto-oncogene that normally has tyrosine kinase activity. part of the ABL gene is translocated from its normal spot on chromosome 9 to chromosome 22, where it fuses with the BCR gene. The BCR-ABL hybrid protein has unregulated tyrosine kinase activity.
37
What is the MYC protein?
can either activate or repress transcription of other genes. Is also a key regulator of intermediate metabolism, upregulating genes that promote aerobic glycolysis and increased utilization of glutamine. Mutations in MYC are very common in tumors
38
What do CDK and the cyclins do?
they control progression of the cell cycle from G1->S->G2->M.
39
What is the G1 phase?
presynthetic phase
40
What is the S phase?
DNA synthesis phase
41
What is the G2 phase?
premitotic phase
42
What is the M phase?
Mitotic phase.
43
What stage are quiescent cells in?
G0
44
Where are the majority of controls in the cell cycle?
between G0->G1 phase
AND
between G1->S phases
45
What regulates the G1-S transition?
cyclins and CDKs.
46
What regulates CDK-cyclin complexes?/
CDK inhibitors (CDKIs). They ensure that damaged DNA does not replicate.
47
What does the G1-S checkpoint monitor?
the integrity of DNA before DNA replication occurs
48
What does the G2-M checkpoint monitor?
DNA integrity after DNA replication has occured.
49
Which cyclin is usually overexpressed in tumors?
CDK4 or cyclin D
50
What is the difference between a proto-oncogene and an oncogene?
proto-oncogenes are normal cellular genes whose products promote cel proliferation.
Oncogenes are mutant or overexpressed versions that function without restriction
51
What is the RB gene?
retinoblastoma gene. when mutated twice, neoplastic proliferation of retinal cells occurs. Normally it exerts antiproliferative effects by controlling the G1-S checkpoint. It binds to E2F to prevent transcription of genes like cyclin E and arrests the cell in G1. It is deactivated by cyclin D-CDK4/6 complexes and releases E2F to allow cell cycle to continue.
52
What is the two-hit hypothesis?
two mutations are required to produce a retinoblastoma.
53
How many mutations are required for tumors to come from oncogenes? How many are required in tumor suppressor genes?
usually only one for oncogenes.
| In tumor suppressor genes, both copies of the gene must be deactivated so usually requires 2 mutations
54
What complex must be active for initiation of S phase?
cyclin E - CDK2 complex. These are dependent on E2F family, which is blocked by Rb.
55
What is the TP53 gene?
thwarts neoplastic transformation by activationg temporary cel cycle arrest, inducing permanent cell cycle arrest, or triggering apoptosis.
56
Describe the mechanism by which p53 creates a temporary pause in the cell cycle.
DNA damage will lead to phosphorylation of p53 to activate it. Active p53 drives transcription of CDKN1A (p21), which prevents Rb phosphorylation and a pause at the G1-S checkpoint that is long enough to repair DNA damage.
57
What does TGF-beta do?
potent inhibitor of cell proliferation. binds to TGF-beta receptors to activate cascade that results in activation of CDKIs and inhibition of growth factors MYC, CDK2 and CDK4.
58
What is always 100% of the time mutated in pancreatic cancer?
some part of the TGF-beta pathway
59
What is E-cadherin?
mediates cell-cell contact in epithelial layers to maintain normal contact inhibition. Lost in malignant cells.
60
What are SMAD genes?
genes that transduce TGF-beta in pancreas
61
What does the APC gene do?
antiproliferative actions by regulating destruction of cytoplasmic protein Beta-catenin. If mutated, beta-catenin whill translocate to the nucleus and act as a growth promoting transcription factor. Usually causes colon cancer.
62
Describe the extrinsic apoptosis pathway.
TNF receptor CD59 (Fas), binds to CD95L, which attracts FADD. This then recruits procaspase-8 to form death-inducing complex. Procaspase-8 cleaved to form caspase-8, then caspase-3 (the excutioner caspase that cleaves DNA and other substrates to cause cell death)
63
Describe the intrinsic (mitochondrial) apoptosis pathway.
can be triggered by variety of stimuli, including stress, injury or lack of survival factors. Activation causes increased permeability of mitochondrial outer membrane and release of cytochrome C to initiate apoptosis. BCL2 family proteins (BAX and BAK) promote mitochondrial permeability. (these are inhibited by BCL2 and BCL-X). Cytochrome c that has leaked out of mitochondria binds to APAF-1 and activates caspase-9, which cleaves and activates executioner caspases.
64
What is BH3?
a pro-apoptotic protein that neutralizes the actions of BCL2 family (antiapoptotics)
65
What is autophagy?
when cellular organelles are sequestered from the rest of the cell by a membrane and fused to a lysosome for degradation. Also important in apoptosis.
66
What is usually the main cause of follicular B cell lymphomas?
mutations in BCL2 family (anti-apoptotics)
67
What are VEGF?
primary angiogenesis inducer
68
What is TSP-1?
thrombospondin-1. primary angiogenesis inhibitor. Usually induced by p53. It is produced by stromal fibroblasts in response to signals from tumor cells.
69
What is HIF-1alpha?
hypoxia-inducible factor. It is normally destroyed, but tumors prevent its destruction and it translocates to nucleus to activate transcription of VEGF and other angiogenesis promotors.
70
What is VHL?
an angiogenesis inhibitor that binds to and destroys HIF-1alpha under normal circumstances. Mutations in it can cause a variety of tumors.
71
What are the four steps of ECM invasion?
1. loosening of intercellular junctions
2. degradation and type IV collagen cleavage
3. atatchment (laminin and fibronectin receptors)
4. migration (fibronectin and autocrine motility factor)
72
What are MMPs?
matrix metalloproteinases. they regulate (promote) tumor invasion by remodeling insoluble componenes of the basement membrane and release ECM-sequestered growth factors. Cleave collagen IV and laminin.
73
What is the Warburg effect?
when cancer cells tend to switch their metabolsim to aerobic glycolysis. It is less efficient than oxidative phosphorylation. This is also common in rapidly dividing embryonic cells. It is thought that it helps with lipid assembly and other metabolite production to speed up replication so cells that do this will outcompete cells that don't
74
What are the three types of DNA repair systems?
1. mismatch repair
2. nucleotide excision repair
3. recombination repair.
75
What is BH3?
a pro-apoptotic protein that neutralizes the actions of BCL2 family (antiapoptotics)
76
What is autophagy?
when cellular organelles are sequestered from the rest of the cell by a membrane and fused to a lysosome for degradation. Also important in apoptosis.
77
What is usually the main cause of follicular B cell lymphomas?
mutations in BCL2 family (anti-apoptotics)
78
What are VEGF?
primary angiogenesis inducer
79
What is TSP-1?
thrombospondin-1. primary angiogenesis inhibitor. Usually induced by p53. It is produced by stromal fibroblasts in response to signals from tumor cells.
80
What is HIF-1alpha?
hypoxia-inducible factor. It is normally destroyed, but tumors prevent its destruction and it translocates to nucleus to activate transcription of VEGF and other angiogenesis promotors.
81
What is VHL?
an angiogenesis inhibitor that binds to and destroys HIF-1alpha under normal circumstances.
82
What is the Warburg effect?
when cancer cells tend to switch their metabolsim to aerobic glycolysis. It is less efficient than oxidative phosphorylation. This is also common in rapidly dividing embryonic cells. It is thought that it helps with lipid assembly and other metabolite production to speed up replication so cells that do this will outcompete cells that don't
83
What are the three types of DNA repair systems?
1. mismatch repair
2. nucleotide excision repair
3. recombination repair.
84
What is hereditary nonpolyposis colon cancer syndrome?
HNPCC syndrome. characterized by familial carcinomas of the colon, resulting from defects in genes involved in DNA mismatch repair. Can also be caused by mutations in growth -regulating genes that encode TGF-beta receptors, BAX, and other oncogenes and tumor suppressors.
85
What is microsatellite instability?
MSI are tandem repeats of one to six nucleotides found throughout the genome. In patients with HNPCC, these satellites are unstable and increase or decrease in length.
86
What is xeroderma pigmentosum?
inherited disorder that increases risk for develpment of cancers of sun-exposed skin. Defective DNA repair. UV rays can cause cross-linking of pyrimidines and prevent normal DNA replication. Normally this would be repaired by DNA excise mechanisms, but the inherited mutations prevent it. Have MSI (variable length tandem repeating sequences throughout genome)
87
What are examples of neoplastic diseases caused by defects in DNA repair by homologous recombination?
Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia
88
What do RAG1 and RAG2 do?
they carry out V(D)J segment recombination in B and T cells. Without them you lose ability to assemble functional antigen receptors sites.
89
What does AID (activation-induced cytosine deaminase) do?
released by mature B cells after encountering an antigen, it catalyzes both immunoglobulin ene class switch recombination and somatic hypermutation.
90
What types of cancers will mutations in RAG1, RAG2, or AID cause?
lymphoid neoplasms
91
How could a chronic inflammatory response to damage induce tumor formation?
At sites of chronic inflammation, cells begin dividing rapidly to try to repair the damgage. Neutrophils release reactive oxygen species that can damage DNA. There is also an abundance of growth factors at the site of damage. All these factors increase the risk of DNA damage and tumor formation.
92
How can inflammation in response to tumors actually promote their growth?
tumors often take advantage of the growth factors released by immune cells or manipulate them to provide growth signals.
93
What are the three classes of carcinogenic agents?
1. chemical
2. radiant
3. microbial
94
What are direct-acting carcinogenic agents?
those that require no metabolic conversino to become carcinogenic. They are generally weak carcinogens.
95
What are indirect-acting carcinogenic agents?
those that require metabolic conversion to an ultimate carcinogen. Some of the most potent are polycyclic hydrocarbon in fossil fuels and smoked meat or benzopyrene in tobacco combustion.
96
What is the main mechanism by which chemical carcinogens cause cancer?
They have highly reactive electrophile groups that directly damage DNA, leading to mutations and eventual cancer.
97
What is the most important, damaging type of damage caused by radiation that can lead to cancer?
double stranded DNA breaks.
98
By what mechanism do UV rays cause cancer?
they induce pyrimidine dimers within DNA, which are normally repaired, but the system can get overwhelmed, leading to squamous cell carcinomas or melanomas
99
What is the only retrovirus that has been demonstrated to cause cancer in humans?
HTLV-1 virus. (human T cell lymphotropic virus-1). It is associated with T cell leukemia/lymphoma in US. Sexually transmitted virus with latency period of 20 to 50 years. Uses TAX protein.
100
What is the TAX protein?
a special protein encoded by the HTLV-1 and other RNA viruses that causes cellular transformation by interacting with several transcription factors. It can also drive cell cycle progression, causing T cell lymphomas or leukemias.
101
How does HPV cause cancer?
two of its early viral genes, E6 and E7, interact with a variety of growth-regulating proteins encoded by proto-oncogenes and tumor suppressor genes. E7 binds to Rb (retinoblastoma) protein, causing unrestrained release of E2F transcription factor. E7 also inactivates CDKIs.
E6 will bind to and destroy p53.
By itself HPV will not cause malignant cancer. A mutation in the RAS gene is still required, but this obviously happens enough to be a problem.
102
How does EBV cause tumors?
Epstein-Barr virus uses complement receptor CD21 to attach to and infect B cells. Using a gene called LMP1 (latent membrane protein), it promotes B cell surface molecule CD40 (making the B cell more likely to proliferate) and activates BCL2 to prevent apoptosis. It also produces IL-10, which helps protect infected cells from monos, macros and T cells.
Normally LMP1 is rapidly recognized by immune system, but if there is immunodeficiency or random translocation activates the MYC oncogene, cancer can develop.
103
What types of cancer is HPV associated with?
benign warts and cervical cancer.
104
What viral infections cause up to 85% of hepatocellular carcinomas?
hepatitis B and C
105
What is the molecular pathway by which hepatitis infections can cause hepatocellular carcinoma?
the infection causes hepatocellular injury, which triggers rapid proliferation of hepatocytes. Immune cells stimulate activation of a nuclear factor called factor-kB (NF-kB), which is an antiapoptotic.
HBV virus can also transcribe a viral protein, HBx which activates a variety of transcription factors and transduction pathways.
106
What types of cancers can helicobacter pylori cause?
gastric adenocarcinomas and gastric lymphomas from MALTs
107
BY what mechanism does H. pylori cause cancer?
it damages epithelium, causing response of rapid proliferation to heal damage. Immune cells release inflammatory milieu and reactive oxygen species which can damage DNA.
It also encodes a gene, CagA, which initiates signaling cascade and causes unregulated growth factor stimulation.
108
If a tumor cell downregulates its MHC I to avoid cytotoxic T cells, what has it made itself vulnerable to?
NK cells because of the low surface MHC expression.
109
What methods do tumors use to escape immune surveillance?
1. selective outgrowth of antigen-negative variants
2. loss or reduction of expression of MHC to avoid CTLs
3. Immunosuppression (Ex: TGF-beta secretion)
4. Antigen masking
5. downregulation of co-stimulatory molecules.
110
What are the 5 common clinical problems tumors cause?
1. impingement on adjacent structures
2. functional activity like hormone secretion
3. bleeding and infections through ulcerations
4. ruptures and infarctions
5. cachexia.
111
What could an adenoma from the pancreatic islets of Langerhans cause?
over-secretion of insulin, causing glucose instability and possibly death.
112
What is one of the main causes of paraneopolastic hypercalcemia?
overproduction of parathyroid hormone-related protein (PTHrP) by tumor cells.
113
What would be a non-paraneoplastic cause of hypercalcemia caused by tumor cells?
widespread skeletal metastases caused by tumors. This is a direct effect though so it is not considered paraneoplastic
114
How does Cushing syndrome arise?
ectopic production of ACTH by cancer cells.
115
What is grading of cancer mainly based off of?
degree of anaplasia. As it increases, the grade goes up. Ranges from I to IV. Is a measure of invasiveness and likelihood to metastasize.
116
What are the stages of cancer based off of?
based on the size of the primary lesion, its extent of spread to regional lymph nodes and the presence or absence of metastases.
117
Which usually is of greater clinical value: grading or staging?
staging. It gives you information about both primary lesion size and metastases
118
What is PSA?
prostate-specific antigen. it is used with immunocytochemistry to detect prostate cancer. One of the most frequently used tumor markers in clinical use.
119
Do high PSA levels mean prostate cancer?
no not necessarily. It could also be caused by prostate hyperplasia. PSA testing has both low sensitivity and low specificity, but still extremely useful.
120
What is CEA?
carcinoembryonic antigen used for detecting carcinomas of the colon, pancreas, stomach, and breast.
