Pathology

Question 1

What initiates a tumor?

Answer 1

Clonal expansion of a single precursor cell that has incurred genetic damage

Question 2

What does carcinogenesis result from?

Answer 2

the accumulation of complementary mutations in a stepwise fashion over time

Question 3

What are the four classes of normal regulatory genes that are principle targets of cancer-causing mutations?

Answer 3

1. proto-oncogenes
2. tumor suppressor genes
3. DNA repair genes
4. genes regulating cell death

Question 4

What lies at the heart of carcinogenesis?

Answer 4

Nonlethal genetic damage lies at the heart of carcinogenesis

Question 5

How does a cell proliferate?

Answer 5

Growth factor signaling pathways
Growth factor binds receptor -> activates signal transduction cascade that activates transcription factors

ALL are protooncogenes that stimulate growth

Question 6

T/F tumor cells can synthesize their own growth factor to which they are responsive

Answer 6

True

Question 7

What mutation can lead to constitutive signaling that is independent of the presence of growth factors?

Answer 7

A mutation of the growth factor receptor

Question 8

What normal protooncogene is activated by receptor tyrosine kinase activity?

Answer 8

RAS

Question 9

What does RAS do?

Answer 9

encodes for a protein that binds GDP/GTP

inactive ras binds GDP -> surface receptor binding swaps GDP for GTP

Question 10

What are normal proto-oncogenes in AKT signaling?

Answer 10

Pl3 kinases

Question 11

What activates Pl3 kinases?

Answer 11

growth factor binding and initiating receptor kinase activity

Question 12

What does Myc do?

Answer 12

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

Question 13

How does the protein product of Rb function?

Answer 13

It inhibits cell proliferation (nuclear proliferation brakes)

Active Rb binds and inhibits transcription factors -> prevents cells from advancing from G1 to S phase

Question 14

What is the role of p53 in tumor formation?

Answer 14

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

Question 15

What is the role of the intrinsic pathway in the evasion of cell death?

Answer 15

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

Question 16

What is the role of the extrinsic pathway in the evasion of cell death?

Answer 16

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

Question 17

What must a tumor cell do to become metastatic?

Answer 17

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

Question 18

How do tumor cells tend to act when in the blood stream?

Answer 18

They tend to aggregate with each other and other blood cells (platelets, coag factors

Question 19

What determines where a tumor cell leaves capillaries?

Answer 19

The anatomic location and vascular drainage of the primary tumor -> also tropisms for tissues

Question 20

What are the different types of tumor antigens?

Answer 20

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

Question 21

What are the three most important cells involved in cell mediated antitumor effector mechanisms?

Answer 21

Cytotoxic T Lymphocytes
Natural Killer Cells
Macrophages (M1)

Question 22

In what ways can cancer avoid the immune system through cell selection and immunoediting?

Answer 22

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

Question 23

In what ways can cancer avoid the immune system through immunosuppresion?

Answer 23

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

Question 24

What are causes of inflammation that can be tumor promoting?

Answer 24

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

Question 25

What is a carcinogen?

Answer 25

An agent that is able to damage DNA, resulting in a heritable, nonlethal mutation that gives rise to neoplasia

3 types: chemical, radiation, microbes

Question 26

What is the role of initiators and promotors in chemical carcinogens?

Answer 26

Initiation -> permanent DNA damage, irreversible

Promotion -> promote proliferation of initiated cells, doesn’t affect DNA and is reversible

Question 27

What is the difference between direct acting and indirect acting in chemical carcinogens?

Answer 27

Direct acting -> require no metabolic conversion to be carcinogenic

Indirect acting -> require metabolic conversion (majority)

Question 28

What enzyme is typically responsible for metabolizing most carcinogens?

Answer 28

Cytochrome P450

Question 29

What is the primary target of UV irradiation in DNA?

Answer 29

Pyrimidine molecules -> forms pyrimidine dimers

Question 30

What viruses are typically oncogenic?

Answer 30

Retroviruses: felv, bovine leukemia virus, avian leukosis virus

DNA viruses: bovine papillomavirus

Question 31

What are the 3 main outcomes of bovine leukemia virus?

Answer 31

1. persistant infection w/ no clinical signs
2. persistant lymphocytosis
3. lymphoma (adults)