Pathology: Neoplasia Flashcards
What is the molecular basis of cancer?
a tumor is initiated by the clonal expansion of a single precursor cell that has incurred genetic damage
What does “hallmarks of cancer” mean?
carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time
What are the 4 classes of normal regulatory gene that are the principle targets of cancer causing mutations?
1) Proto-oncogenes
2) DNA repair genes
3) Tumor suppressor genes
4) Genes regulating cell death
How does a cell proliferate?
Using the growth signal pathway GF binds to receptor thus activating that receptor. Production/activation of numerous cytoplasmic signal transducing proteins in the nucleus. This activates transcription factors in the DNA. This leads to transcription of growth promotors & regulators
What is Growth Factor (GF) used for?
Normal cells require GF to proliferate
How does growth factor work?
Most soluble GF are made by a cell to act on a neighboring cell.
True/False: tumor cells can synthesize their on GF to which they respond to?
True
What can lead from common mutations in GF receptors?
Constitutive signaling that is independent of the presence of GF
What are examples of constitutive signaling ?
C-kit & HER2
What are the 2 signaling transducing proteins?
RAs and P13 kinase
What is Ras and what does it encode for?
Is a normal protooncogene that is activated by tyrosine kinase receptor activity & it encodes for a protein that binds to GDP & GTP
What does active & inactive Ras bind to?
Inactive Ras binds to GDP and when surface receptor binding facilitates swapping of bond GDP for GTP is active RAs
What are P13 kinase?
Normal proto-oncogenes in AKT signaling (another growth signaling pathway)
How is p13 kinase activated?
like Ras it is activated by GF binding & initiating receptor tyrosine kinase activity
What is transcription factor?
Are the proteins that actually bind to the DNA & turn it on/off
What does Myc do that we know of?
Very broad activities
activates the expression of many genes involved in cell growth
Can upregulate expression of telomerase
Can reprogram somatic cells to pluripotential stem cells
What is the importance of telomerase in neoplasia?
It is an important mechanism of cell aging
“Tumors up regulate this & have “cell replicate immortality”
What do Rb (retinoblastoma proteins) do?
They normally inhibit cell proliferation and lives in an active form that binds to E2F (transcription factor that goes to DNA & says lets grow)
What does the active form of Rb do?
The active form binds to & inhibits transcription factors thus preventing from advancing from G1 phase to S phase in replication.
What is the importance of mutated Rb?
It is inactive and is the brake failure of cell division
What are the examples of mutated Rb neoplasias?
Canine hemangiosarcoma & Osteosarcoma & retinoblastoma
What is P53?
It is a tumor suppressor that regulates cell cycle progression, DNA, repair, cellular senescence & apoptosis. It is also the “guardian of the genome”. It also prevents propagation of genetically damaged cells
What level of P53 is normal in normal cells?
Normal cells have low levels of P53
What holds P53 in check?
MDM2
What are the normal biochemical pathways that lead to intrinsic apoptosis?
Bcl-2 protein
What is the most commonly affected pathway affected in cancer
Intrinsic apoptosis pathway
What does Bcl-2 protein normally do?
Normally inhibits release of cytochrome C which would otherwise inhibit the intrinsic pathway & encodes a protein that inhibits apoptosis
What does failure of Bcl-2 protein cause?
Prolongs cell lifespan by preventing apoptosis
What does failure of Bcl-2 protein cause?
Prolongs cell lifespan by preventing apoptosis
What are the normal biochemical pathways that lead to extrinsic apoptosis?
FLIP
What does FLIP normally do
blocks the extrinsic pathway by binding procaspase-8 without activating it
What does failure of FLIP do?
Prolongs cell life span and prevents apoptosis
What must tumor cells successfully do to produce a metastatic leasion?
invade the extracellular matrix
disseminate through the vessel unharmed
locate a suitable distant site/tissue to live
successfully grow/proliferate there
What do tumor cells tend to aggregate with?
Each other and Platelets and coagulation factors
What is important to keep in mind about tumor metastasis?
Where the tumor leaves capillaries is related to anatomic location & vascular drainage of the primary rumor
What places are “good” for matastisis and why?
Lungs and liver because they have high blood circulating
What are the tumor antigens?
products of mutated genes-oncoproteins
overexpressed or aberrantly expressed cellular proteins
tumor antigens produced by oncogenic viruses
oncofetal antigens
altered cell surface glycolipids & glycoproteins
cell type specific differentiation antigens
Why are cytotoxic T lymphocytes important?
Can respond to new antigens
many tumors produce proteins to decrease T cell response
their presence can be marker for better prognosis
Why are NK cells important?
recognize absence of MHC1 or stress-induced proteins expressed on cell surface
Why are M1 and M2 important.
M1 are pro-inflammatory which is important anti-tumor effector mechanism
M2 is associated with wound healing anti-inflammatory
True/False: Immunodeficiency is not skewed toward infectious agents?
False
How does cancer evade an intact immune system?
Antigen negative variants
loss or reduction of MHC expression
weakly immunogenic until tumor burden is to large to control
Immunosuppression
TH1 suppression
convert T-cell to Treg
upregulation of T cell suppresion
Myeloid derived suppressor cells
What does TGFB & IL-10 do?
suppress Th1 response
convert effector T cells to Treg- immunosupressive
What upregulates T cell suppression?
CTLA-4
PD-1
What promotes tumor inflammation?
release of factors that promote proliferation
reactive oxygen species production
removal of growth supressors
enhanced resistance to cell death
inducing angiogenesis
activating invasion & metastasis
evading immune destruction
What helps tumor cells evade the immune system?
TAMs
MDSCs
