Chapter 7 pt 3 Flashcards
What is NF1
a tumor suppressor that encodes neurofibromin 1, a GTPase that inhibits RAS signaling
NF1
Germline mutuation
Sporadic mutation
cant make inhibiting GTPase => increase in RAS signaling
- germline LOF => many benign neurofibromas, optic nerve gliomas and malignant peripheral nerve sheath tumors
- sporadic mutation: neublastoma, juvenile myeloid leukemia
What is NF2
encodes neurofibromin 2 (merlin), a cytoskeleton like protein in cell to cell junctions
NF2
Germline mutuation
Sporadic mutation
- germline LOF => neurofibromitosis type 2 => high risk for benign bilateral acoustic schwannomas
- Sporadic=> schwannoma and mengiomas
What is PTCH1
PTCH 1 is a tumor supressor then encodes PATCH receptor
SHH ligand binds to PATCH receptor.
When SHH is bound => stops supresses cell prolferation
When SHH is not bound => supressing proliferation
thus, mutation in PTCH1 => Patch receptor cannot bind SHH
PTCH1
Germline mutuation
Sporadic mutation
Germline mutation: LOF => gorlin syndrome => high risk for basal cell carcinoma and medulloblastoma
Sporadic: basal cell carcinoma and medulloblastoma
In what cancers do you often see a mutated PTCH1 gene?
- Basal cell carcinoma
2. Medulloblastom
What is VHL?
VHL is a tumor supressor that encodes a part of the ubiquitin ligase that breaks down HIF (hypoxia induced factor)
increased VHL => low HIF
VHL
Germline mutuation
Sporadic mutation
- Germline mutation: LOF => high HIF => increase nuclear translocations => increase cell growth and proliferation => Von Hippel Lindau syndrome => increase chance of getting [renal cell carcinoma, pheochromacytoma, hemangioblastomas, retinal angiomas]
- Sporadic => renal cell carcinomas
What is von-Lippau syndrome
Occurs when we have a mutation in VHL => increase in HIF => increase in translocation => increase in cell growth and proliferation =>
increase risk for
- renal cell carcinoma
- pheochromacytoma
- retinal angioma
- hemangioblastomas
What mutations do we often see in sporadic renal cell carcinomas?
aquired biallelic VHL LOF mutations
CDH1 is what
a tumor supressor that encodes E-cadherin
CDH1 encodes E-cadherin.
What does E-cadherin do?
- inhibits growth of epithelial cells via contact
2. Bind and sequesters B-catenin => prevent invasion and metastasis
How does E-cadherin contribute to malignancy
Loss of E-cadherin=>
- promote growth of epithelial cells
- will not bind and sequester B-catenin => bind to TCF TF in the nucleus => invasion and metastasis
CDH1
germline muation
sporadic mutation
G: LOF => famial gastric cancer
Sporadic: gastric carcinoma and lobular breast cancer
BRCA 1 and BRCA 2
tumor supressor that encode Breast Cancer 1 and Breast Cancer 2 => repair dsDNA breaks
BRCA1 and BRCA2
Germline mutuation
Sporadic mutation
G:
- familial breast and ovarian carcinoma
- carcinoma of male breasts
- chronic lymphocytic leukemia (BRCA2 only)
Sporadic mutations are RARE
mutation of BRCA 2 will cause what that a mutation in BRCA 1 will not cause
chronic lymphocytic leukemia
What is MSH
MSH 2 and 6 are tumor supressor genes that code for proteins that REPAIR MISMATCHED DNA
MSH
Germline mutuation
Sporadic mutation
G: hereditary nonpolyposis colon carcinoma
S: colonic and endometrial carcinoma.
What is WNT1
WHT1 is a tumor supressor then is needed for normal development of
- kidneys
- gonads
What gene is WNT1 on
Chr11q13
WNT1
Germline mutuation
Sporadic mutation
G: LOF Familial Wilms tumor (pediatric kidney cancer)
S: Wilms tumor and leukemias
What are characteristsics of familial tumors
bilateral
multicentric
In VHL, what is the mostly likely reason for increased red cell count?
paraneoplastic syndrome
What cancer has VERY good prognosis in children, which is contradictory to a general rule of thumb.
Children do not do well with sarcomas.
However, FIBROSARCOMAS have a VERY good prognosis in kids.
APC
Germline mutuation
Sporadic mutation
- FAP: familial adenomatous polypsosis: individuals will develop thousands of adenomatous polyps in thei colon during teens or 20s
- Colon, stomach and pancreatic carcinomas; melaomas
what percentage of cancers have a p53 mutation
> 50%
inheritance of MSH is what?
all others are what
AR
AD
What is immunotherapy?
Immunotherapy is when we artificually stimulate our immune system to treat cancer, so that we can improve our bodies natural ability to treat.
how does our immune system identify forein or native cells?
Uses checkpoints: molecules that are on our immune cells that need to be + or inactivated to cause a immune response response.
How do cancer cells avoid being attacked by the immune system
They manipulate the checkpoints
In immunotherapy, __________ holds a great deal of promise as cancer treatment
immune checkpoint inhibitors
What are our immune checkpoint inhibitors we are looking at in immunothereapy
- PD1/PDL1 inhibitors
- CTLA4 inhibitors
- PDE4 inhibitos
What are PD1 and PDL1
What cells are they located on
How does cancer utilize these to avoid immune system
Programmed cell death protein :
PD1 is a immune checkpoint located on Tcells;
PDL1 is located on wild cells.
Defection of good cell: PD1 on T-cells bind to PDL1 on wild cells => passes the inspection=> T cell is NOT activated,
Bad cell: do not bind: T cell is activated => immune response is initiated to kill!
Cancers have started to increase the expression of PD1 and PDL1 to try to trick our immune system.
What is the tx to PD1 and PDL1?
What is the downside?
PD1/PDL1 inhibitors; monoclonal AB that will prevent PD1 and PDL1 from binding. However, this always prevents binding of our normal, healthy cells => activate immune response to normal cells.
Thus, our immune system system attacks normal cells => causes fatigue, cough, skin rash/itching/ N, loss of apetitie
Why do normal chemo therapys often cause the sx they do?
PD1/PDL1 inhibitors activate immune responses to even our normal cells, causing severe symptoms like
Fatigue, N, skin rash/itching, cough and no appetaite
_______ binds to CD80/86 on APC to activate T-cells
_______ binds to CD80/86 and does NOT activate T-cells
CD28 on T-cells binds to CD80/86 => activate T cells
CTLA4 on T cells binds to CD80/86 => prevent activation of T-cells because CD28 cannot bind
CTLA4 is a checkpoint protein receptor that _______ our immune response
downregulates
What cancer drugs have been used to CTLA4?
How is this drug?
CTLA4 inhibitors (ipilimubab)
This drug is worse that PD1/LD => more serious, life threatening SI
CTLA 4 inhibitors are often used to treat what?
Skin melanoma
PDE4 (phosphodiesterase): what does it do
PDE4 inactivates cAMP => immune response => psoriatic lesions
What happens when cAMP is inactivated
- release of proinflammatory mediators from MO, neutrophils, T-cells and monocytes
- infiltration of immune cells and proliferation of keratinocytes => psoriatic lesions
Why is cAMP important
- Prevents the release of pro-inflammatory mediators (TGFa, IL17, IFN-y)
- Promotes the release of anti-inflammatory mediators (IL-10)
- Prevents activation of immune cells
How does PDE relate to cancer
PDE => inactivate cAMP => increase proliferation of kertinocytes and cause psoriatic lesion
ppl with psoriatic lesions are 40% more leikly to develop psoriatic arthiristis and 12% increase risk for non-melanoma skin cancer. Thus, we should focus on PDE inhibtors
Warburg effect
Warburg effect (aeorbic glycolysis)
Warburg effect is a normal alteration in metabolism that occurs in rapidly proliferating cells (in embryo). However, cancerous cells become fixed in this process.
What happens is that rapidly proliferating/cancerous cells increase their uptake in glucose, use this glucose => lactate (fermentation via glycolysis), INSTEAD OF METABOLIZING
why do cancer cells undergo a change in metabolism that is less NRG effiicient?
- Aerobic glycolysis produced metabolic intermediates that are used to make cellular components of rapdily dividing cells. Meanwhile, mtoxphos does NOT.
- In rapidly dividing cells, mT swictches from needing to make more ATP to needing to produce metabolic precurors (lipids, proteins, NT)
In aerobic glycolysis, are we metabolising glucose?
NO. It is undergoing fermentation via glycolyis
What 3 metabolic reprogramming occurs to accomplish Warburg effect?
- P13K/AKT signaling: increases transport and glycolysis of glucose & makes lipids and proteins
- Activation of tyrosine kinases: phosphorylate M2 isoform of pyruvate kinase, inhibit PEP=> pyruvate => build up of glycolytic intermdiates to make DNA. RNA, proteins
- MYC is upregulated => increase glycolytic enzymes and glutaminase, which the mT needs to make glu
How do cancer cells evade apoptosis?
- defects in intrinsic ** and extrinsic patterns of apoptosis
- Increase expression of BCL2 and MCL1, both antiapoptotic proteins
Overexpression of BL2 and MCL1 in cancer cells is linked to what
cancel cell survial
drug resistance
In more than 85% of follicular B-cell lymphomas, the ______________ is
overexpressed d/t a _____ translocation
antiapoptotic protein, BCL2
14:18
All cancers have cells that are stem-cell like: immortal and can replicate and unlimited amount of
times.
Cancer stem cells arise how?
- Transformation of normal stem cells => cancer stem cell.
2. Acquired genetic lesion that causes a more mature cell => have stem cell like properties
The changes to become a cancer stem cells causes what to happen
- inactivate senescence
- reactivate telomerases
=> allow the cancer cell to replicated unlimed times
Vascularization of tumors is necessary to them to grow.
It is controlled by balancing angiogenic and
anti-angiogenic facts made by tumor and stromal cells.
what regulates angiogenesis?
- Hypoxia => increase HIF => + VEGF (pro-angiogenic factor) => angiogenesis
- p53 => anti-angiogenic thrombospondin 1
- RAS, MAPK, MYC => upregulate VEGF => increase angiogensesis
Invasion and metastasis are the results of complex interactions between what 2 cells?
cancer cells
normal stroma cells
Is saying “metastic leukemia” correct?
NOOOO.
lymphomas and leukemias DO NOT METASTASIZE!
Instead, we say “systemic leukemias
Steps of invasion of EcM
- Loosen up tumor cell-tumor cell interaction by loosing adhesion molecules (E-cadherin)
- Degrade ECM: tumor cells or stromal cells (fibroblasts/inflammatory cells) make proteolytic enzymes to get through BM and interstitial CT: type 4 collagenase
- Attach to the novel ECM components: tumor cells must have adhesion molecules that will attach to proteins in the ECM (fibronectin)
- Migration and invasion through BM via:
A. cytokines released from the tumor, B. chemotactic/GF released from breaking through ECM
What in the next step in invasion and metastasis
vascular dissemination
once tumor cells invade and go into our vasculature, what do they have to be cautoius of?
They are going to be prone to destruction by
- stress
- apoptosis caused by loss of adhesion, and 3. attack of the immune system
once in vasculature, how to our tumor cells prevent being destroyed?
AGGREGATE.
- with one another
- with platelets: increase survival and implantability
- coagulation factors, forming emboli.
they then circulate to the area they want to metastasize to
Where a circulating tumor cells leaves the capillaries to deposit depends on what factors
- anatomic location
- vascular, lympahtic spread: will often metasize to first capillary bed. however some cancers (organ tropism cancers) prove this false. thus, there are other ways
- Some cancers have adhesion moleculands whos ligands are preferentially expressed on some endothelium
- Some cytokines prefer to bind to receptors in certain areas
- microenvironemt: does not occur in spleen or skeletal muscle often
What 3 cancers show organ tropism?
- Prostatic carcinoma: bone
- Bronchiogenic carcinomas: brain and adrenals
- Neuroblastomas: bone and liver
Some cytokines prefer to bind to receptors in certain areas. what are these receptors in breast cancer
CXCR4
CCR7
what is dormancy?
micrometases that have stopped metastaszing
What 3 cancers most often go into dormancy?
- Melanoma
- Breast
- Prostate
Our immune system CAN actually recognize tumor cells as non-self and destroy. How are they presented to our immune system?
On MHC Class I on CD8+ CTLs
Tumor antigens include mutated protooncogenes, tumor supressor genes, overexpressed/iregularly expressed proteins, tumor antigens made by oncogenic viruses
and what 2 other things
- oncofetal antigens
2. altered glycolipids and proteins
Immunosuppressed pts have increased risk for cancer, particularly, what kind?
oncogenic DNA viruses
How can immunocompetent pts escape immunity?
- Not present MHC Class 1
- outgrowth of antigen-negative varients
- Upregulate factors (TGF-B and PD-L1) from MO and stromal cells and down regulate co-stimulators, to create a immunosupressive env
If we inherit mutations in genes that repair DNA, this can increase our risk for cancer.
Defects can occur in which 3 repair mechanism?
- Nucleotide excision repair
- DNA recombination
- Mismatch repair
Which condition has a defect in nucleotide excision repair?
What can this increase our risk for?
Xeroderma pigmentosa
increased risk for skin cancer exposed to UV light, because we cannot repair pyrimidine dimers
Which gene can we damage that will impair mismatch repair
What disease does this increase our risk for?
MSH
Hereditary nonpolyposis colon cancer syndrome
Which diseases do we have defects in recombination repair?
What does this increase our risk for?
- Blood syndrome
- Ataxia-telangiectasia
- Fanconi anemia
DNA damaging events, like ionizing radiation
Which gene can we damage that will impair DNA recombination?
Normal function?
What disease does this increase our risk for?
BRCA1 and 2
Normally, this fix dsDNA breaks by homologous recombination
Famial breast cancers
Lymphoid neoplasms are d/t mutations in lymphoid cells caused by the expression of which genes that cause genomic instability?
RAG1 and RAG2
Infiltrating cancers cause chronic inflammation that not only causes systemic responses (anemia, fatigue and cachexia), but also benefit the tumor by
- Release of GF and proteases that free GF from the ECM
- Damage the ECM => increase risk of invasion and mestasisis
- Tumor cells feed off of normal stroma cells to promote growth and survival
- Promote angiogenesis => + VEGF
- Suppress growth inhibitors
- Avoid being discovered by the immune system by:
- M2 MO, which will suppress immune response and promote angiogenesis, fibroblast proliferation and deposit collagen
- Upregulate factors (TGF-B and PD1) that create a immunosupressive env
How does cancer cause systemic symotoms, such as anemia?
Cancer => chronic inflammation => sequester iron and downregulate EPO
What is cachexia
How does cancer cause systemic symotoms, such as cachexia?
equal loss of fat and muscle, accompanied with fatigue, weakness, anemia & anorexia. At the same time, our BMR increases
Proteolysis-induced factor released from the tumor => equal loss of fat and muscle
TNF-alpha produced the systemic inflammation
TNF-alpha causes what in cancer?
systemic inflammation
Tumor cells can get several types of oncogenic mutations like point mutations and nonrandom chromosomal abnormalities such as translocations, deletions and gene amplifications.
Balanced translocations cause =>
Deletions cause=>
Gene amplification=>
Balanced translocations => overexpress oncogenes and make fusion proteins that alter signalig
Deletion => LOF of tumor supressor genes and can sometimes + protooncogenes
Gene amplification => overexpression and increase fx of oncogenes
Chromothrypsis: is what
a single catastrophic event that causes dozens => hundreds of DNA breaks. DNA repair mechanisms repair them haphazardly and produces dramatic rearrangements => thus, we lose segments of chromosome
is chromothyrpsis seen in alot of caners?
YES
Epigenetics: post-translational modifications of histones (Acetylation) and DNA hypermethylation
without a change in primary DNA sequence can do what?
silence tumor supressor genes
In epigenetics, what is altered: code or structure of DNA?
structure
what are microRNA?
miRNA are non-coding regions of RNA that INHIBIT translation.
Decrease expression of tumor suppressive microRNA can do what?
=> increase translation of oncogenic mRNA
Increased expression of onco-miRIs can do what?
=> decrease expression of tumor supressors => increase tumor development
What are long-intervening noncoding RNA (linc-RNA)
linc-RNA modifies the activity of chromatin writes => modifies histones, which control gene expression
Can a single genetic alteration cause cancer?
NO. You must also lose control of oncogenes, tumor suppressor genes
A classic example of incremental acquisition of the malignant phenotype is found in colon carcinoma.
Many of
these cancers evolve through a series of morphologically identifiable stages: what are they?
colon epithelial hyperplasia => form adenomas => enlarge => undergo malignant transformation
Each step of aquiring maligancy requires more mutations. What are the steps?
- First hit: familial of acquired mutation of cancer suppressor gene
- of RAS
- Loss of tumor supressor gene on 18q or TP53
Neoplastic changes caused by chemicals occur in 2 steps: what are they?
Initiation: Highly electrolophilic chemical will cause damage to nucleophillic DNA that is irreverersible
Promotor: induce tumors in a initiated clel by proliferiferation
What are characteristics of initiation damage?
rapid
irreversible and has memory: thus, promoter can attack later
does NOT cause cancer by itself: needs promoter
Are promoters tumorgenic?
NO. they are not
We can have 2 types of initaters. what are they?
- Direct-acting carcinogen: do not require metabolic conversion: often times they are weak but used for chemo therapy (alkaline substances). Often times, they work but then patients will get a SECOND type of cancer
- Indirect acting carincinogen: require metabolic conversion, often times through CYP P450 mono-oxidase
Which are most common: indirect or direct acting carcinogen?
Indirect
What is an example of an indirect acting carcinogen?
Polyhydrocarbons that are + when we broil or grill meats
Discuss the key features of metabolic activation and molecular targets in chemical carcinogenesis
Metabolic activation: often through CYPP450 dependent monooxidase, which are polymorphic
Molecular target: primary sequences of DNA
Somoking is an indirect-acting carcinogen. Smokers with what metabolic activator will have a 7 FOLD higher can of acquiring lung cancer
CYP1A1
What is the UV spectrum
200-280: UVC
280-320: UVB
320-400: UVA
200-280: UVC
280-320: UVB
320-400: UVA
Which are mutagenic, but blocked by ozone?
Which are responsible for causing skin cancer by forming pyrimidine dimers?
C
B
UV damage causes what?
- Squamous cell carcinoma
2. Melanomas
What is the difference between non-melanoma and melanoma skin cancer?
Non-melanoma skin cancer is caused by total cumulative sun: low and slow exposure over life
Melanoma skin cancer is caused by intermittant sudden exposure: (sub bathing): high and fast exposure
What is the first thing affected by EXTERNAL radiation?
skin
How does ionizing radiation cause damage?
make free radicals from H20 or O2 => break chromosomes, translocation, point mutations
Do all tissues have the same amount of vulnerability to ionizing radiation?
No.
Skin, GI and bone are resistant
Suzi encountered high amounts of ionizing radiation. What cancers should she be cautious of?
Thus, the most common.
- Myeloid tumors
- thyroid cancers in young children
- Breast, lung and salivary gland cancers
oncogenic RNA viruses
Attacks:
Causes:
- HTLV-1
Attacks: CD4+ T-cells
Causes: Adult T-cell lymphoma/leukemia (ATLL) => causes polyclonal expansion of T-cells
Which virus is endemic to Japan, carribean, SA and Africa?
HLVA-1
What protein is responsible for the transforming activity and transcription of viral RNA replication in HTLV-1?
Tax
How does Tax contribute to increased pro-growth signaling and cell survival of HTLV1
- cyclin D1 and repress CDK inhibitors => progress through cell cycle
- P13/AKT and NF-kB survival path: increase growth and survival
HPV (16 and 18)
Tropism:
Causes what cancers?
Squamous cells
Squamous cell carcinoma of the cervix, anogenital region and head and neck
How does E6
E7 cause caner?
- E6 degrades TP53 => stimulate TERM
2. E7 binds to E2F bs on RB, inactivate CDK inhibitors p21/27 and activates cyclin A and E
can HPV cause carcinogenesis along?
NOOOOO. RAS MUST ALSO BE MUTATED
EBV
Tropism:
Causes:
Tropism: CD21/CD4+ B cells
Causes: Burkitt cell lymphoma and nasopharyngeal carcinoma in PATIENTS THAT ARE IMMUNOSUPRESSED
How does EBV target B+cells?
Uses its CD21 receptor to + Bcell pathways
Benny is not immunocompromised and has good T-cell immunity, how will EBV affect him?
Sally has HIV (immunocompromised) and does not have good T-cell immunity, how will EBV affect her?
only a small fraction will become tumors
EBV infected B cells will rapidly become B-cell tumors
HepB
Tropism
Causes
Tropism: hepatocytes
Causes: hepotocellular carcinoma
What percentage of people with hepatocellular carcinoma have HEP B
70-85%
While the oncogenic effects of HBV and HCV are multifactorial, what is the dominant effect in the development of hepatocellular carcinomas?
Immunologically mediated chronic inflammation and hepatocyte death leading to regeneration and, over time, genomic damage
Which key molecular step within hepatocytes blocks apoptosis, allowing the dividing hepatocytes undergo genotoxic stress and to accumulate mutations that cause HBV induced hepatocellular carcinoma?
activation of NF-kB pathway
How is HepB and HepC different?
HepB=> onocgenic DNA virus
HepC=> RNA
What are the oncogenic DNA viruses?
- HepB
- EBV
- HPV
What are the bacterial viruses that cause cancer?
H. Pylor
H.pylori causes what cancers?
What associated gene is present?
Gastric carcinomas and if chronic, MALT lymphomas.
CagA => proliferation of epithelial cells
Chronic H.pylori infection leads to POLYCLONAL B-cell proliferations that may give rise to a?
Monoclonal B-cell tumor (MALT lymphoma) of the stomach
What is characteristic of neoplasms in the gut and urinary tract?
melana (blood in stool)
hematuria
What is the KEY to determine how malignant or benign tumors will affect us clincally?
location
What are paraneoplastic syndromes?
Tumor associated syndromes that produce symptoms NOT associated with the tumor.
What are the EARLIEST clinical manifestation of a neoplasm and can trick us, to make us think that the tumor has spread?
Paraneoplastic syndromes
What is the most common endocrinopathy?
Cushing syndrome
1What are the major forms of underlying cancer associated with Cushing Syndrome?
Small-cell carcinoma of lung
Pancreatic adenoma
Neural tumors
What are the 2 general processes involved in cancer-associated hypercalcemia?
Which of the 2 is considered to be paraneoplastic?
- Osteolysis caused by cancer
2. production of calcemic-humoral substances (PTH-related protein)
What is the most common paraneoplastic condition
Hypercalcemia
Lung cancer patients with Cushing syndrome have elevated serum levels of?
POMC
Corticotropin
What are the 2 major forms of underlying cancer seen in Myasthenia?
- Bronchiogenic carcinoma
2. thymic neolasms
What is important to note when a patient comes in with aganothis nigricans?
50% of them will get cancer in 40 years
What are the 2 major forms of underlying cancer seen in patients with Hypertrophic osteoarthropathy and clubbing of the fingers?
1) Bronchogenic carcinoma
2) Thymic neoplasms
* Also seen in Myasthenia syndromes
Big Ten Hype
Grading of tumors is based on what?
Cytologic appearance: differentiation, architecture and number of mitosis
based on the idea the differentiation and behavior are related
Poorly differentiated cancers =>
more aggressive
Who grades
pathologists
how to stage cancers
TNM
- Size of primary lesion (0-4); 0= insitu lesion
2 number of LN spread to (0-3)
- metastasis (0-2)
how do we determine staging?
who grades it?
surgical exploration and imaging
oncologist
Which has more clinical value: staging or grading?
staging
______: (15:17) => associated with DIC
AML
can tumor markers be used to detect cancer?
no.
they can be used to see if recurred or to track therapy
which markers have [low sensitivity and specificty] and thus cannot be used for early cancer detection
alpha -fetoprotein
CEA
PSA
