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20 Cards in this Set

  • Front
  • Back
Terms for development of cancer =

These deal with what?

common theme of cancer development =

etiology of neoplasia including internal causes and cellular mechanisms

agents cause DNA damage resulting in mutations, gene rearrangements, gene amplification, gene deletion, or altered expression of genes that control normal cell growth, survival and differentiation
what was the hypothesis of genetically determined cancer based on?

what are three documented causes of neoplasms?
many neoplasms have abnormal mitoses and other nuclear abnormalities

many cancers are aneuploid, have abnormal karyotypes

chemicals, viruses, radiation
Chemical carcinogens


what were conclusions of mouse skin carcinogenesis model?

how do most chemical carcinogens act to cause neoplasia?
exposure to some chemicals causes cancer
discover via epidemiologic observations (cancer in chimney sweeps) and lab studies in animals

2 stage carcinogenesis: initiation via DMBA and promotion via croton oil
Evolved to multistage/multistep model (which also pertains to other tissues)
most are mutagens
determine via Ames test
Ames Test:
Based on mutant bacteria (Salmonella) that have lost the capacity to synthesize histidine

Bacteria will grow in histidine-containing medium

Bacterial growth is restricted on histidine-free medium
UNLESS, ability to make histidine is restored by a
mutation (reversion to wild type)

Assay is based on counting revertant colonies growing on histidine-free media after exposure to test chemical
Types of DNA damage by chemical carcinogens:
1) Alkylation: causes mismatches in base pairing
2) damage leading to depurination/depyrimidination
3) bulky DNA adducts that may interfere with base pairing
4) double strand breaks
Direct mutagens =

Indirect mutagens =

How is the target of the carcinogen determined?
require no metabolic activation to be reactive with DNA

metabolic activation is required, they are metabolized to become electrophilic species that can react with cellular DNA

target = type of cell affected
Determined by route of contact, distribution of carcinogen in the body, ability of cell or organ to activate or detoxify the carcinogen
Causes of neoplasms

DNA from viruses can be integrated into the host genome leading to the expression of viral proteins

Reverse transcriptase allows RNA viruses to be transcribed into DNA and integrated into host
exposure increases risk by causing DNA damage, chromosomal breakage, cytogenetic abnormalities
Stochastic events leading to cancer =
how and at what point do they happen?
genetic accidents leading to a mutation, mutation results from aberrant intracellular event that doesn't require an external agent such as chemicals, viruses, radiation

happen at a low rate during DNA replication

oxidative damage to DNA
DNA repair

important for -
Accuracy depends on -
important defenses against mutation, may be defective

high accuracy = pre replicative DNA repair
high and low accuracy = post replicative DNA repair
Evidence for role of DNA damage/repair in carcinogenesis

Xeroderma pigmentosum:

Hereditary nonpolyposis colon cancer:

Bloom's syndrome:
rare, recessive, hereditary disease with predisposition to develop skin cancer after exposure to sunlight, patients with XP are markedly deficient in the excision repair of pyrimidine dimers - Ultraviolet light causes formation of pyrimidine dimers
a) cells are deficient in replicative repair
b) decreased cell survival and increased mutation following DNA damage

associated with DNA mismatch repair defect linked to hMSH2 and related genes

rare human recessive hereditary disease
chromosomal instability with predisposition to develop leukemia, lymphoma and carcinoma
Modifiers of carcinogenesis

1) Enzyme induction:
2) Detoxification:
3) Genetic polymorphisms:
4) Diet:
5) Cell Cycle:
CYP (cytochrome P450) induction, CYP usually activates indirect carcinogens

via protective enzymes and molecules (e.g. antioxidants like GSH)

we are not all the same due to variations in:
Activating enzymes
Protective enzymes and pathways including DNA repair

Antioxidants, Vit A for cell differentiation, caloric intake (high=increased risk)

labile cell populations are vulnerable when in cell cycle, dividing cells are more at risk for mutation than stable cells
Steps of carcinogenesis:
1) Initiation and promotion:
Initiation = *First genetic event* initial exposure to carcinogen
Promotion = * epigenetic factors that promote carcinogenesis* subsequent events to accelerate development of neoplasms (also used to refer to epigenetic events that favor tumor development

2) Progression:
*subsequent genetics events* required to cause malignancy
Concept of Two Stage Carcinogenesis:

Steps =

Promotor =

Latent period =
has progressed to a multistage process

Step 1: results from a mutation
Later steps: reflect additional mutation

Promoting agents = stimulants of growth of initiated cells that substitute for subsequent mutations until they occur

Promoters are no longer needed when fully autonomous growth potential is established

Latent period = time between initiation and clinical detection of tumor
How was clonal origin of tumors established?

Suggests that:
using various X-linked markers, chromosomal markers and molecular genetic techniques

most neoplasms originate as progeny of a single initiated cell
reason for inflammatory diseases in carcinogenesis:

types of diseases:
promutagenic reactive oxygen species are generated, there is also increased cell turnover

Ulcerative colitis (hereditary and other)
Hepatitis (viral) B and C
Chronic Pancreatitis (hereditary and other)
Helicobacter pylori/peptic ulcer disease - 1% progress to malignancy
Human Papilloma Virus:
describe relationship to carcinoma

how does it cause cancer?
HPV types 16 and 18 (and some less common types) found in 85% invasive squamous cell carcinomas of the cervix

E7 protein binds Rb, E6 protein binds p53 -> these complexes are degraded rapisdly -> mimics a mutation in Rb and p53 genes
Hep C increases risk for:

what type of virus is it?
How does it cause cancer?
hepatocellular carcinoma

an RNA virus without reverse transcriptase

Nonspecifically -> inflammation/repair
Specifically -> proteins trascribed from viral RNA inactivates protein products of cell's tumor suppressor genes -> deregulates control of cell division
PaniN grades

what for?
what are they?
Pancreatic Intraepithelial Neoplasia

PanIN-1 = mild
PanIN-2 = moderate
PanIN-3 = severe
Evidence supporting immune role in rejecting transformed cells (3):
1) cancer risk in increased in immunosuppressed transplant patients
2) HIV patients develop Kaposi's sarcoma, Non-hodgkins lymphoma and Hodgkins disease
3) Many cancers are prevalent in older populations and immune response is muted in some aged individuals