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