6. Cancer III Flashcards

1
Q

5 - Development of Sustained Angiogenesis

 Tumors limited to ____ mm without blood supply
Neovasculature supplies:
 ____
 Oxygen,
 New endothelial cells produce ____ factors

 Vasculature serves as a route for \_\_\_\_
Normal balance of 
 pro-\_\_\_\_
 \_\_\_\_ (HIF1a target)
 Anti-angiogenic
 \_\_\_\_ (p53 target)
• Angiogenesis requires a balance between pro and antiangiogenic factors
	○ In cancer > tilted towards proangiogenic factors:
		§ VEGF - target of sensor protein (HIF1a)
			□ Sensing low \_\_\_\_ level in tissue, and activates VEGF
	○ Cancer suppresses antiangiogenic factors
		§ Thrombospondin1
			□ Loss of \_\_\_\_ shuts down this pathway
				® Contributes to sustained angiogenesis \_\_\_\_
A

1-2
nutrients
growth

metastasis
angiogenic
VEGF
thombospondin1

oxygen
p53
indirectly

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2
Q

Development of Sustained Angiogenesis

Acquired angiogenic signaling in
 ____ cells
 Stroma
 ____ cells

 Activation of proteases
– Release ____ proteins in ECM
 Hypoxia induces VEGF by ____

• Stromal cells also play a role in angiogenesis
• Inflammatory cells that are recruited to tumor location
	○ Secrete \_\_\_\_ that can trigger angiogenesis
• Proteases secreted by stromal or inflam cells release proangiogenic proteins in the ECM via \_\_\_\_
• Transcription upregulation
	○ HIF1a senses low O2 pressure in the environment and induces VEGF
		§ Normally, HIF1a is tempered by a TSG > \_\_\_\_
A

tumor
inflammatory

proangiogenic
HIF1a

chemokines
cleavage
VHL

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3
Q

Development of Sustained Angiogenesis

 Von Hippel Lindau (VHL) is a ____
 Syndrome with ____ carcinoma, pheochromocytomas, ____ of the CNS, retinal angiomas, renal cysts, etc
 VHL induces degradation of ____

 VEGF also controls vessel branching and density via ____
 Anti –VEGF is now an ____ therapy

• VHL binds to HIF1a and induces degradation
• The cancers are richer in BV
• VEGF is \_\_\_\_ from HIF1a
• VEGF induces existing vessels to become larger and more elaborate, encouraging further circulation
• If you cut the supply of a tumor, it will decrease in size
	○ Anti-VEGF is used in conjunction with other cancer treatment approaches
	○ Collapse the tumor, then \_\_\_\_/radiotherapy and then follow up with chemotherapy
A

tumor suppressor
renal cell
HIF1a

notch
approved

downstream
surgery

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4
Q

6 - Invasion and Metatasis

 Invasion of ____
 Vascular Dissemination
 Homing of Tumor cells

 Invade \_\_\_\_
 Travel through \_\_\_\_
 Intravasation
 Interact with \_\_\_\_ 
 Extravasate
 Invade tissue
 Grow
* Metastasis using BV or lymphatics, or through the body cavities
* Following local invasion, it will use vascular dissemination and will anchor into the new site
A

ECM
tissue
ECM
lymphocytes

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5
Q

Invasion of ECM 1
Loosen tumor cell interaction
 Reduce intercellular interaction
 ____ is lost in almost all epithelial tumors
– Mutation of E-cadherin gene
– Activation of ____
– Increased expression of e-cadherin transcriptional ____

• B-cat activation results in no binding to E-cadherin
	○ It also increases expression of E-cadherin repressors
		§ \_\_\_\_ and slug
A

E-cadherin
b-catenin
repressors
twist

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6
Q

Invasion of ECM 2
 Degrade ____
 Secrete proteolytic enzymes
 Induce ____ cells to secrete proteases

Protease families implicated in tumors
 \_\_\_\_
-- Also release ECM growth factors
-- \_\_\_\_ implicated in malignant counterparts
 \_\_\_\_ plasminogen 
 \_\_\_\_
* If epithelial tumor, the cells must degrade the BM
* MMP degrade the matrix, and allow for tumor growth as well via release of ECM GF
* The proteases degrade \_\_\_\_ in the ECM
A

basement membrane
stromal

matrix metalloproteases
MMP9
urokinase
cathepsin
collagen IV
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7
Q

Invasion and Metastasis - 3 & 4

 Loss of attachment to ECM
– Reduced level of ____

Locomotion
 Complex, multistep process influenced by:
 \_\_\_\_ motility
 Cleaved matrix products  \_\_\_\_ factors
 Cross talk between these components
• The epithelial cells normally are bound to the basal membrane via the integrins that are located on the \_\_\_\_ part of the epithelial cells
	○ If the integrins are lost - the cells will lose attachment
• GF signals the cells telling them where to go
	○ Secreted by \_\_\_\_ and ECM
A
integrins
actin
growth
basal
stroma
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8
Q

Vascular Dissemination and Homing

 Tumors may move to first capillary bed
 Other tumors may be targeted by immune system
 Others “home to target tissues”
 e.g. Lung tumors often go to ____ gland, but almost never to ____

Depends on:
 Tumor cell ____ preferential for target organ
 ____ expression
 ____ ability (local stroma)

• Some cancer cells are recognized by immune system
	○ May be expressing \_\_\_\_ proteins (mutated GFR, etc.)
• The tumor sheds millions of cells per day, but most of them do not metastasize
• Local stroma at target site should support the new site
• The tumor that has many mutations over time, it has the ability to metastasize easily and survive in hostile environments
• Local environment of muscle may not provide good environment for the lung tumor
• The \_\_\_\_ may not be in the target tissue that the tumor recognizes and binds
	○ No receptor-tumor interaction
A
adrenal
muscle
adhesion
chemokine
colonization

foreign
receptors

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9
Q

Molecular Genetics of Metastasis

Two Hypotheses:
 Acquired Metastatic
Potential as a ____ event
 Acquired metastatic potential is ____ and can be predicted

 Identification of “____” of metastasis would be key for treatment and prognosis
 ____ and ____ as candidates
– Repress e-cadherin and mediate Epithelial-to-mesenchymal transition

• Not all tumors metastasize at the same rate
• Development of metastasis can be due to a chance mutation
	○ Or, perhaps some tumor cells earlier on have a genetic predisposition that increases the chance of it metastasizing
• If you can identify markers, and the tumor is cell, you can throw everything you have at it
	○ Currently, because we cannot tell which is metastasize, the treatment is more conservative
• SNAIL and TWIST
	○ No e-cadherin, the cells are looser
	○ Candidates for metastatic markers
	○ Involved in the \_\_\_\_ change in cells that increases the chance of neoplastic changes
A
late
early
markers
snail
twist
metaplastic
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10
Q

7 - Reprogramming of Energy Metabolism

 \_\_\_\_ Glycolysis
 \_\_\_\_ effect
 Less efficient \_\_\_\_ production
-- 2 vs 36
-- High \_\_\_\_ usage 
-- Underlies \_\_\_\_ scan

 Embryonic cells adopt “Warburg Metabolism”
 Dividing cells must make new DNA, lipids, proteins and Organelles.
 Lipids and nucleotides require Glucose metabolite: ____
 Warburg metabolism provides building blocks for other cell components

• Dividing all the time, the tumor has to make as many building blocks as possible
	○ Tumor has to find alternative ways to uphold the energy requirement - via aerobic glycolysis
		§ Occurs despite sufficient \_\_\_\_
		§ You get 2 ATP, it's not worried about the energy; but it's worried about the lipids and nt's which requires \_\_\_\_, which is produced with aerobic glycolysis
		§ Called the Warburg effect
	○ Can inject a glucose metabolite that's not degraded
		§ \_\_\_\_
			□ Will accumulate in tumor cells and will be visualized with PET by taking advantage of the Warburg effect
• \_\_\_\_ cells use the Warburg effect during embryogenesis, not during adulthood
A
aerobic
warburg
ATP
glucose
PET

pyruvate

O2
pyruvate
18-F-deoxyglucose

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11
Q

Mechanisms of Altered Metabolism

 Pro-cell growth mutations favor this metabolism
Implicated players are: 
 \_\_\_\_
 \_\_\_\_ (inhibits AKT activation)
 \_\_\_\_ (downstream of Ras)
• Mutations in p53, PTEN and AKT that induce glucose production
A

p53
PTEN
AKT

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12
Q

8 - Evasion of Immune System

 For a cell to metastasize it must evade the immune system
 Identification of ____
 Target immune system to destroy tumor cells

• Tumor cells have mutated proteins on cell surface that will be targeted by immune cells that'll eventually kill the cell, they must evade it
A

tumor antigens

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13
Q

Hallmarks of Cancer
• Many treatments that target all these hallmarks
○ Telomerase inhibitors - bring down telomere levels
○ EGFR inhibitors - block GF signaling
○ Aerobic glycolysis inhibitors (targeting Warburg effect)

A

YAY

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14
Q

Genomic Instability: Enabler of Malignancy

 Genetic lesions cause cancer
Caused by mutagenic agents
 \_\_\_\_
 Radiation
 Certain \_\_\_\_
 DNA repair staves off malignancy 
-- \_\_\_\_ repair
-- Nucleotide and Base excision repair 
-- \_\_\_\_ repair
 DNA repair deficiency syndromes

 Defects in DNA repair enzymes lead to genomic instability

• An alteration in any DNA repair system will allow for a damaged cell to become malignant
	○ These are all \_\_\_\_; they themselves may not be a cause of cancer but they allow the tumors to grow
	○ Normal DNA repair mechanisms that may be altered
A

sunlight
chemicals
mismatch
recombination

syndromes

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15
Q

DNA mismatch repair

 Recognize mismatch (\_\_\_\_)
 Signal Exonuclease, Exo1 – (\_\_\_\_)
 Nick – \_\_\_\_ binding to nicked end
 Excision
 DNA pol d - ligation
• Involves a change in the letter (ATCG) to another letter
	○ Proofreading repair
• MSH2/6
	○ Recognizes mismatch, and binds to the exonuclease, Exo1 (PMS2/MLH1)
		§ \_\_\_\_, they cut at the site where the mismatch is (by the PARP protein)
	○ And then an excision from the site, and new AA is created by DNA pol
• If there is a problem with any of these, any mutation will not be corrected
A

MSH2/6
PMS2/MLH1
PARP

together

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16
Q

Hereditary Nonpolyposis Colon Cancer Syndrome (Lynch Syndrome)

 Defect in one copy of mismatch repair
 \_\_\_\_ in colon tissue
 Induce cancer by increasing mutation
in TS and oncogenes
 \_\_\_\_ age of onset colon cancer, stomach, intestine, urinary tract, brain and skin

 Characteristic finding is ____ instability
 Microsatellites are ____-mer repeats
 ____ or ____ in genome of patients with HNPCC

• Individuals have a defect in one copy, and the second loss occurs in the colon
• Defect is not the issue, but the defects accumulate in TSG and protooncogenes which is the issue
	○ An \_\_\_\_, not a hallmark
• \_\_\_\_ age like Li-Fremouny syndrome and Retinoblastoma
• Microsatellites
	○ Very small repetitive sequences
	○ And the lengths are not \_\_\_\_ (too long or too short) in patients
		§ Microsatellite instability
A
LOH
early
microsatellite
1-6
expand
contract

enabler
uniform

17
Q

HNPCC

• Looks similar to ____ phenotype

A

APC

18
Q

• Left: polyp in the colon
○ A ____ is present
○ No metastasis because you can see a ____ and no invasion into the bottom
○ Can be an early lesion in a young person, and can develop into a tumor
• Right: malignant tumor from a polyp
○ No distinction bt the polyp and the mucosa
○ In the middle > mucin filled cavity
○ ____ that are separate from the tumor that used to be a polyp
§ Showing local invasion

A

stalk
border
tumor islands

19
Q
• Left: normal rectal mucosa
		○ Glandular and \_\_\_\_ architecture
	• Right: adenomatous mucosa
		○ \_\_\_\_, and increased number of cells
			§ An \_\_\_\_ change during carcinogenesis
A

ordered
hyperchromatism
early

20
Q

Nucleotide Excision Repair

 Removes damage from ____
 Generates bulky ____ on DNA, mostly ____
 Removes short sequence of DNA and repairs using ____ DNA strand
 Two sub pathways
– ____
– ____
• Thymidine, not thymine
○ It can dimerize in response to UV light, and forms adducts that cannot be separated
• Uses non-damaged counterpart to use as a template

A
UV light
adducts
thymidine dimers
undamaged
global genome repair (GGR)
transcription-coupled repair (TCR)
21
Q

Nulceotide excision repair
GGR vs TCR
 Different ____
 Similar downstream ____

 Defective:
 ____
 ____

• Both pathways lead to \_\_\_\_ to excise the damaged DNA molecule and replace with the undamaged DNA molecule
A
recognition
pathway
xeroderma pigmentosum
cockayne's syndrome
DNA synthesis
22
Q

NER syndromes

 Xeroderma Pigmentosum 
-- \_\_\_\_ subtypes based on mutated gene
 Cockayne’s syndrome
-- \_\_\_\_ subtypes
 Others include
XP
 Severe \_\_\_\_
 Skin - \_\_\_\_, oozing lesions
 Eyes – painful in sun, \_\_\_\_
 Neurologic deficits in \_\_\_\_ childhood
 Prone to \_\_\_\_ cancer
• Severe photosensitivity
	○ NER is triggered by UV damage
	○ Any damage formed by DNA won't be corrected
A
7
2
photosensitivity
blister
bloodshot
late
skin
23
Q
Cockayne's syndrome
 \_\_\_\_ growth
 Premature aging (\_\_\_\_) 
 \_\_\_\_ skin
 Loss of \_\_\_\_ fat
 Photosensitivity
 \_\_\_\_ deficits in some forms
• NER is defective
A
stunted
pregeroid
wrinkled
subcutaneous
neurologic
24
Q

DNA repair by homologous recombination

 Repair ____ breaks
 Uses ____ as template
 Causes ____ disorders
– Differ in presentation/include predisposition to cancer
– ____ (ATM), Bloom’s syndrome, ____
(BRCA2), familial Breast Cancer (BRCA1 and 2)
– Mutations in BRCA1 and 2 are not found in ____ cancer

• Defects in the pathway results in AR disorders
	○ TSG involved with AD disorders…
• Bloom's syndrome - \_\_\_\_ symptoms
• Members of same family with breast cancer
	○ If patient has mutated \_\_\_\_ - the whole family must go to genetic counseling because their risk is increased
• P53 and Rb are found in \_\_\_\_ cancers, but BRCA1/2 are not found in sporadic cancers
A
ds
sister chromatid
AR
ataxiatelangectasia
fanconi anemia
sporadic

neurologic
BRCA1
sporadic

25
Q

• BRCA1
○ Double stranded break > allows for assembly of repair protein
§ Can be fixed using the sister chromatid
• If BRCA1 or ATM is not there, they cannot do this process
• If ATM is defective > will not allow for p53 (???) to ____ and induce changes so that EF2 can turn on genes for DNA repair

A

phosphorylate

26
Q

Lymphoid neoplasm
 V(D)J recombination necessary for formation of antigen receptors - ____ and ____
 ____ necessary for immunoglobulin class switch

 Induce somatic hypermutation.

  • - Necessary for diversification of ____ gene assembly
  • - Responsible for ____• VDJ recombination allows for production of ____ against a diverse number of antigens by the lymphoid cells
    ○ Antigen receptors develop on the immune cells
    • Ig class switch
    ○ These receptors can diversify in response to the antigens we’re exposed to
A

RAG1
RAG2
activation induced cytosine deaminase (AID)

antigen receptor
neoplasms

antibodies

27
Q

Tumor-promoting inflammation: enabler of malignancy

 Can be anti-____
 Chronic inflammation
— E.g. ____, H. Pylori gastritis, ____
 Tumors contain ____
– Adaptive and Innate components
– Release growth factors, cytokines, chemokines inducing ____
– Release____

• Normally inflammation protects the body and can be anti-tumorigenic
	○ Inflam cells at the tumor, historically, thought they were responding to protect the body; may be true to a certain extent, however, it became apparent that chronic inflammatory conditions are associated with increased risk of cancer
		§ Barrett's - constant reflux can result in this condition; the \_\_\_\_ environment can increase the risk of cancer
• The leukocytes release GF that can be used by the tumor (even low levels will induce proliferation via hyperresponse)
	○ An \_\_\_\_ of malignancy
• Also release free radicals, and can induce DNA damage which results in additional mutations
A
tumor
barrett's esophagitis
hepatitis B and C
leukocytes
proliferation
free radicals

chronic inflammatory
enabler

28
Q

• NER defects can be targeted by using ____ inhibitors

A

PARP

29
Q

Multistep Carcinogenesis

 Each cancer results from an accumulation of multiple mutations
 e.g. Evolution of Colorectal Cancer

• There is no specific order of mutations
• The graph is for the colon cancer:
	○ Just an example, but a likely scenario for colon cancer
	○ In order for morphologic appearance to change, certain molecular changes must occur
		§ May start with loss of \_\_\_\_ (prevents cell adhesion)
		§ DNA \_\_\_\_ loss (TF can be turned on more easily)
		§ Mutated \_\_\_\_ (despite low levels of GF, cells are more primed to divide)
		§ TS on chr\_\_\_\_
		§ \_\_\_\_ is not there to prevent unchecked cell division)
A
APC
methylation
RAS
18
p53