Pathology Flashcards
What initiates a tumor?
Clonal expansion of a single precursor cell that has incurred genetic damage
What does carcinogenesis result from?
the accumulation of complementary mutations in a stepwise fashion over time
What are the four classes of normal regulatory genes that are principle targets of cancer-causing mutations?
- proto-oncogenes
- tumor suppressor genes
- DNA repair genes
- genes regulating cell death
What lies at the heart of carcinogenesis?
Nonlethal genetic damage lies at the heart of carcinogenesis
How does a cell proliferate?
Growth factor signaling pathways
Growth factor binds receptor -> activates signal transduction cascade that activates transcription factors
ALL are protooncogenes that stimulate growth
T/F tumor cells can synthesize their own growth factor to which they are responsive
True
What mutation can lead to constitutive signaling that is independent of the presence of growth factors?
A mutation of the growth factor receptor
What normal protooncogene is activated by receptor tyrosine kinase activity?
RAS
What does RAS do?
encodes for a protein that binds GDP/GTP
inactive ras binds GDP -> surface receptor binding swaps GDP for GTP
What are normal proto-oncogenes in AKT signaling?
Pl3 kinases
What activates Pl3 kinases?
growth factor binding and initiating receptor kinase activity
What does Myc do?
Mechanism poorly understood in tumorigenesis
Activates expression of genes involved in cell growth
Can upregulate expression of telomerase in some contexts
Can reprogram somatic cells to pluripotential stem cells
How does the protein product of Rb function?
It inhibits cell proliferation (nuclear proliferation brakes)
Active Rb binds and inhibits transcription factors -> prevents cells from advancing from G1 to S phase
What is the role of p53 in tumor formation?
p53 is a tumor suppressor that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
GUARDIAN of the genome
Prevents propagation of genetically damaged cells -> normal cells have low levels
What is the role of the intrinsic pathway in the evasion of cell death?
The Bcl-2 protein, which normally inhibits the release of cytochrome c which would otherwise initiate the intrinsic pathway
-> encodes a pro-cell survival gene -> unregulated expression prolongs cell lifespan
What is the role of the extrinsic pathway in the evasion of cell death?
It’s less commonly affected in cancer
FLIP -> anti apoptotic -> pro cell survival
blocks extrinsic pathway by binding procaspase-8 without activating it
Dec Fas expression may also make cells less susceptible to induction by FasL -> pro survival
What must a tumor cell do to become metastatic?
A) invade the extracellular matrix
B) disseminate through the vessels unharmed
C) locate a suitable distant site/tissue to live
D) successfully grow/proliferate there
How do tumor cells tend to act when in the blood stream?
They tend to aggregate with each other and other blood cells (platelets, coag factors
What determines where a tumor cell leaves capillaries?
The anatomic location and vascular drainage of the primary tumor -> also tropisms for tissues
What are the different types of tumor antigens?
1) products of mutated genes (oncoproteins)
2) overexpressed cellular proteins
3) tumor antigens produced by oncogenic viruses
4) oncofetal antigens
5) altered cell surface glycolipids and glycoproteins
6) cell type specific differentiation antigens
What are the three most important cells involved in cell mediated antitumor effector mechanisms?
Cytotoxic T Lymphocytes
Natural Killer Cells
Macrophages (M1)
In what ways can cancer avoid the immune system through cell selection and immunoediting?
They can form antigen negative variants or cause a loss or reduction of MHC expression
They can also be weakly immunogenic until cancer burden becomes too large to control
In what ways can cancer avoid the immune system through immunosuppresion?
1) Tumor cells can secrete TGF beta and IL-10 to suppress the TH1 response and convert effector T cells to Treg
2) They can upregulate T cell suppression through CTLA-4 and PD-1
3) Myeloid derived suppressor cells
What are causes of inflammation that can be tumor promoting?
1) release factors that promote proliferation
2) reactive oxygen species
3) removal of growth suppressors
4) enhanced resistance to cell death
5) inducing angiogenesis
6) activating invasion and metastasis
7) evading immune destruction
What is a carcinogen?
An agent that is able to damage DNA, resulting in a heritable, nonlethal mutation that gives rise to neoplasia
3 types: chemical, radiation, microbes
What is the role of initiators and promotors in chemical carcinogens?
Initiation -> permanent DNA damage, irreversible
Promotion -> promote proliferation of initiated cells, doesn’t affect DNA and is reversible
What is the difference between direct acting and indirect acting in chemical carcinogens?
Direct acting -> require no metabolic conversion to be carcinogenic
Indirect acting -> require metabolic conversion (majority)
What enzyme is typically responsible for metabolizing most carcinogens?
Cytochrome P450
What is the primary target of UV irradiation in DNA?
Pyrimidine molecules -> forms pyrimidine dimers
What viruses are typically oncogenic?
Retroviruses: felv, bovine leukemia virus, avian leukosis virus
DNA viruses: bovine papillomavirus
What are the 3 main outcomes of bovine leukemia virus?
- persistant infection w/ no clinical signs
- persistant lymphocytosis
- lymphoma (adults)
