6. Cancer III Flashcards
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 \_\_\_\_
1-2
nutrients
growth
metastasis
angiogenic
VEGF
thombospondin1
oxygen
p53
indirectly
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 > \_\_\_\_
tumor
inflammatory
proangiogenic
HIF1a
chemokines
cleavage
VHL
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
tumor suppressor
renal cell
HIF1a
notch
approved
downstream
surgery
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
ECM
tissue
ECM
lymphocytes
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
E-cadherin
b-catenin
repressors
twist
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
basement membrane
stromal
matrix metalloproteases MMP9 urokinase cathepsin collagen IV
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
integrins actin growth basal stroma
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
adrenal muscle adhesion chemokine colonization
foreign
receptors
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
late early markers snail twist metaplastic
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
aerobic warburg ATP glucose PET
pyruvate
O2
pyruvate
18-F-deoxyglucose
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
p53
PTEN
AKT
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
tumor antigens
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)
YAY
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
sunlight
chemicals
mismatch
recombination
syndromes
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
MSH2/6
PMS2/MLH1
PARP
together
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
LOH early microsatellite 1-6 expand contract
enabler
uniform
HNPCC
• Looks similar to ____ phenotype
APC
• 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
stalk
border
tumor islands
• Left: normal rectal mucosa ○ Glandular and \_\_\_\_ architecture • Right: adenomatous mucosa ○ \_\_\_\_, and increased number of cells § An \_\_\_\_ change during carcinogenesis
ordered
hyperchromatism
early
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
UV light adducts thymidine dimers undamaged global genome repair (GGR) transcription-coupled repair (TCR)
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
recognition pathway xeroderma pigmentosum cockayne's syndrome DNA synthesis
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
7 2 photosensitivity blister bloodshot late skin
Cockayne's syndrome \_\_\_\_ growth Premature aging (\_\_\_\_) \_\_\_\_ skin Loss of \_\_\_\_ fat Photosensitivity \_\_\_\_ deficits in some forms
• NER is defective
stunted pregeroid wrinkled subcutaneous neurologic
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
ds sister chromatid AR ataxiatelangectasia fanconi anemia sporadic
neurologic
BRCA1
sporadic
• 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
phosphorylate
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
RAG1
RAG2
activation induced cytosine deaminase (AID)
antigen receptor
neoplasms
antibodies
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
tumor barrett's esophagitis hepatitis B and C leukocytes proliferation free radicals
chronic inflammatory
enabler
• NER defects can be targeted by using ____ inhibitors
PARP
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)
APC methylation RAS 18 p53
