Week 6 Flashcards
What regulates cell proliferation?
- Nutrient status; ENTOR highly associated w/ nutrient status
- Epigenetics can control whether or not genes will be expressed: Proto-onco genes normal genes that when acquire mutation become onco gene
- Status of DNA: Protien that monitors this: p53; Transcription factor that can interact w/ p21; Need CDK to go to cell cycle and needs to interact w/ cyclins
- Growth factor signaling thru RTK
- Contact inhibition by other cells or those cells can even proliferate them
- Apoptotic cascade suppressed by BCL2; Pro apoptotic: BAX and BAC trigger cytochrome C
Contact inhibtion
- occurs with E cadherin and the extracellular matrix
Growth factors from ECM
- cell surface integrins interact with cytoskeleton at focal adhesion complexes which can initiate production of intracellular messengers or directly transduce signals to the nucleus
- FAK: focal adhesion kinase;
- SRC: tyrosine kinase
- Activated and inactivated by phosphorylation
- Important because extracellular environment can control what happens in intracellular environment by activating integrins which will activate other cascades down the line
How does extracellular environment signal nucleus to transcribe proteins for growth?
-ligand binds to receptor, auto cross phosphorylation which causes phosphorylation of signaling protein that initiates phosphorylation of other proteins to cause DNA to make proteins that will induce cell growth/replication
TGF beta arresting cell division
- TGF beta binds to TGF beta receptor which activates the receptors intracellular protein kinase domain leading to phosphorylation of SMAD protiens which will then enter nucleus and bind to promoters of genes that control transcription
- key target is p21 gene which will inhibit cyclinE/-cdk2 complex to lead to cell arrest
4 types of receptors
- Ligand gated ion channels
- G protein coupled receptors
- Enzyme linked receptors
- Nuclear receptors
G protein coupled receptors
- activate Heterotrimeric g proteins and Alpha subunit ( either stimulatory or inhibitory or phsophorylates)
- specificity is controlled by controlling which g protein sub-unit is activated
- cell response is determined by extracellular signaling
Enzyme linked receptors
- when activated it turns on other enzymes
- Can be receptors that have tyrosine kinase activity or associated with tyrosine kinase
Nuclear receptors
- steroid receptors
- Located in nucleus or cytoplasm
- Signal diffuses across the membrane b/c they are hydrophobic
JAK/STAT pathway
- cytokine receptor
- cytokine binds to JAK receptor
- JAK auto-phosphorylates
- STAT binds to auto-phosphorylated JAK
- JAK phosphorylates STAT
- STAT dimer forms, travels to nucleus binds DNA and changes gene expression
How do the same pathways lead to different outcomes?
- regulation at different points in the pathways
- different receptors: which depends on what kind of cell it is
- different signaling cascades from the same receptors
- local signaling domains within the cytoplasm
How do heterotrimeric G proteins differ in signaling targets?
Gas: stimulatory; will induce cyclic AMP (second messenger) from adenylyl cyclase which will activate PKA
Gai: inhibitory
Gaq
CFTR
activated by PKA in epithelial cells which induces sodium in cell to bring fluid into lumen
What if both Gas and Gai are activated?
Cells knows which one to choose by which ligand has more concentration; may depend on number of receptors of each type
Family of G protein involved in myocardial hypertrophy
-Gq-G11 included in angiotensin receptor and endothelin receptor to induce hypertrophy via activation of downstream effectors
How are multiple signal integrated?
- multiple phosphorylations of a target
- Phosphorylation can activate a protein but sometimes you need more than one signal to activate the phosphorylation
Neoplasm
unregulated growth of cells, growing faster or more than they should
Tumor
a collection of cells that have mutations making them non-functional, can present in new growth or lump
Leukemia
Cancer of the cells in the blood that help fight infection
Dysplasia
- abnormal formation of cells in body
- Disordered growth, abnormal differentiation or proliferation of cell
- Cell does not differentiate appropriately
Myeloproliferative
increase in production in one of the types of cells from the blood
Myeloid neoplasm
Genetic abnormality that causes problem with proliferation or differentiation
Acute leukemia
Increase only in proliferating, cannot differentiate; predominately an increase in immature cells
Chronic myeloproliferative disorder
Increased proliferation but can differentiate; will have increase in all cells, immature and mature
myelodysplastic syndrome
able to differentiate but do so abnormally
Leukocytosis with neutrophilia causes
- infection (20,000 or less WBC, unless C.diff 50,000)
- leukemia (more than 20,000 WBC)
- others
When is it pertinent to differentiate bands from neutrophils?
NICU
Should you be worried if there is low lymphocytes on WBC differential?
- if it is in percentage then no because absolute number would most likely be normal; would not be considered lymphopenia
Essential Thrombocytosis
- mature platelets that are over produced
- Would see tons of platelets in blood smear
- would see more megakaryoctes in bone marrow, not usually in blood
- confirmatory test: Would look for Jak2 mutation
Myeloproliferative Neoplasms
- Chronic myelogenous leukemia: elevated WBC count
- Polycythemia vera: elevated RBC
- Essential thrombocytosis: Platelet count
- Primary myelofibrosis: increased counts hematopoetic cells early, decreased late
Primary myelofibrosis
- increased counts hematopoetic cells early, decreased late
- marrow will be replaced by collagen because over worked
Jak 2 pathway
- ligand binds
- receptor dimerization activates phosphorylation of receptor
- STAT binds phosphorylated receptor
- JAK phosphorylates STAT
- STAT dimer forms
- STAT dimer travels to nucleus then binds to DNA and changes gene expression
Acute myeloid leukemia
- WBC low, blasts elevated
- PT and PTT elevated
Myeloblast
- Common for acute myeloid leukemia: specifically the auer rods
- Can have tons in marrow and only 1-2 in blood
What are you looking for when you have low WBC and elevated blasts?
acute leukemia
CBC results of acute promyelocytic leukemia
low WBC, low platelets, low RBC, with increased blasts
Auer rods
rods present in the cytoplasm of myeloblasts
-common for AML
Bone marrow procedure
- patient is lying prone or on side
- will get from posterior illiac crest on adult and sternum on child
- numbing will go all the way from skin to soft tissue right before periosteum
- Both biopsy and aspirate will be taken
Bone marrow aspirate
fluid from bone marrow; give cell morphology
Bone marrow core biopsy
actual piece of bone; will look for architecture of bone and bone marrow
Myeloid blast
-have tons of granules and aeru rods
How to confirm acute promyelocytic leukemia
FISH: 15-17 translocation
Treatment for acute promyelocytic leukemia
All trans retinolycitic acid: allows for cells to continue to differentiate and alleviates a lot of problems with acute leukemia
Then would be given chemo to treat leukemia
How are acute myeloid leukemias classified
based on genes
What does a reticulocyte count tell you?
Low: problem making cells in marrow
High: problem with peripheral destruction
What is a pseudo pelger huet cell?
bi-lobed neutrophil
What is a megakaryocyte?
precursor cell
myelodysplastic syndrome
- cell can proliferate but does not differentiate correctly
- cytopenia is commonly seen (specifically in platelets) as abnormal cells are destroyed in bone marrow
- caused by deletions in chromosomes
myelodysplastic syndrome prognosis factors
- number of defects
- types and number of point mutations (P53)
- cerverity of cytopenia and what lineages are affected
- number of blasts present in peripheral blood or marrow
Neoplasia
-a disorder of new growth triggered by a series of acquired mutations affecting a single cell and its clonal progeny
Components of Neoplasia
- Parenchyma
- Stroma
Parenchyma
- what is it?
- components
- actual tumor cells
- functional neoplastic cells that had a mutation occur and a malignant clone developed and a neoplasia presented
- determines classification and bio behavior
Reactive Stroma
- response to a tumore
- connective tissue, blood vessels, immune cells from adaptive and innated response
- determines growth, spread, and gross appearance
How to classify tumors
- Absolute Benign: Defined in a capsule that is formed by surrounding soft tissue; Low malignant potential
- Absolute Malignant: Tumor that has a potential to become metastatic; this requires mutations that have to invade in and out of the blood vessels; it can spread directly on surfaces or in lymphatics
- In -situ - hasn’t broken thru basement membrane
- Metaplasia - one differentiated cell type differentiates into another
- Dysplasia - Precursor to malignancy; cells proliferate abnormally but lack ability to metastasis
Sampling method for lung mass
Fine needle aspiration or Pleural effusion
Sampling method for lung mass
Fine needle aspiration or Pleural effusion
Fine needle Aspiration
take a needle and stick it in –b/w ribs and into the lungs; could lead to a pneumothorax
could do a septum cytology but has low sensitivity and low specificity and low cost and not invasive; this can tell us if its invaded into the bronchial tree
Fine needle Aspiration
take a needle and stick it in –b/w ribs and into the lungs; could lead to a pneumothorax
could do a septum cytology but has low sensitivity and low specificity and low cost and not invasive; this can tell us if its invaded into the bronchial tree
Pleural effusion
-used for tumors that are centrally located
Pleural effusion
-used for tumors that are centrally located
What histo technique is used to examine tissue of cancer cells?
-H&E to show architecture of tumor
What histo technique is used to examine tissue of cancer cells?
-H&E to show architecture of tumor
General rule of sampling tissue
- Least amount of harm done to the patient
- Not invasive for the patient
- Can use guided imaging
General rule of sampling tissue
- Least amount of harm done to the patient
- Not invasive for the patient
- Can use guided imaging
Features of malignant cells
- cells are not all the same size or shape (pleomorphism)
- nuclear atypia: prominent nuclei, clumping of chromatin, and hypochromatic
- abnormal mitosis
- loss of architecture
- loss of polarity of cells
- dis-cohesive
- Tend to grow faster than benign tumors
How to find out origin and cell type of cancer
-immunohistochemistry to look for histological markers
cell of origin: Adenocarcinoma
glandular
cell of origin: squamous cell carcinoma
squamous
After cancer has been diagnosed, what are next steps?
- physical exam: help to emphasize any secondary complications of cancer and help to treat those underlying problems
- would get imaging to get exact size of tumor and look for mets (important for staging)
- stage disease (helps to come up with better treatment and give patient prognosis)
- genetic testing: helps with treatment
What is a high therapeutic index?
-medication that would need to be dosed at high level in order to become toxic or have adverse effects
General categories of therapy
- surgical: biopsy, remove tumor, debulk tumor
- radiation: Destroy cells by disrupting DNA thru the use of free radicals which inhibits DNA or RNA synthesis; not very selective; can use implants to make it more localized
- chemo: alkylating agents, anti-metabolites, mitotic inhibitors, DNA active drugs
What do malignant cells present to APC to avoid being destroyed?
CTLA-4
Anti-CTLA 4
prevents cancer cells from presenting CTLA 4 which causes the cancer to present their foreign tissue and allows for T cells to autoregulate by producing co-stimulatory molecules that will inhibit proliferation and differentiation of molecules
Anti-CTLA 4 meds
-potential side effects
- Ipilimumab
- Tremelimumab
- Immuno suppression or auto-immunity
