Chemical Carcinogenesis Flashcards
When mutation occurs what two groups can it be subdivided into?
Reproductive cells and Somatic Cells.
What occurs when there is alteration in somatic cells?
cell death, cancer, aging, heart disease, and other diseases. (Most important is cancer)
What occurs in the alteration of Reproductive cells?
birth defects and genetic diseases.
What is cancer?
disease of cellular mutation, proliferation, and aberrant cell growth.
What are multiple causes of cancer?
infectious agents, radiation, and chemicals.
What percent of human cancers are linked to environmental, dietary, and behavioral factors?
70-90%
Estimated 70-90% of human cancers are linked to what?
environmental, dietary, and behavioral factors.
What is unknown about cancers?
aspects of causes, prevention, and treatment.
in 1775 what did Percival Pott discover?
linkage between increased occurrence of scrotal and nasal cancer among chimney sweeps.
In 1875 What did Karl Thiersch discover?
sunlight exposure and skin cancer.
In 1879 what did Harting and Hesse discover?
Lung cancer and uranium mining.
What was discovered in the early 1900s?
role of chemical mixtures and individual chemicals in mixtures in animal models.
What is neoplasia?
new growth or autonomous growth of tissue.
What is neoplasm?
lesion resulting from neoplasia.
What is benign?
expansive growth, frequently exhibiting slow rates of proliferation that do not invade surrounding tissues.
What is malignant?
Lesion with invasive growth, capable of metastasis to other tissues and organs.
What is Metastasis?
secondary growths derived from a primary malignant neoplasm.
What is a tumor?
Lesion characterized by swelling or increase in size that may or may not be neoplastic.
What is the mechanism for cancer?
- Cells grow as a benign tumor in epithelium —> 2. Break through basal lamina —>3. Invade capillary —> 4. Travel through bloodstream (less than 1 in 1000 cells will survive to form metastases) —>5. Adhere to blood vessel wall in liver. —>6. Escape from blood vessel (extravasation) —>7. Proliferate to form metastasis in liver.
What is cancer?
Malignant neoplasm
What is a carcinogen?
a physical or chemical agent that causes or induces neoplasia.
What does genotoxic mean?
Carcinogens that interact with DNA resulting in mutation.
What is non-genotoxic?
carcinogens that modify gene expression but do not alter DNA sequence.
What are epigenetic modifications?
non genotoxic.
What are the 3 stages of Carcinogensis?
Initiation, promotion and Progression
What is initiation in the first stage of cancer?
Stable DNA change
What is promotion in the stages of carcinogenesis?
Selective clonal expansion of initiated cells to produce a preneoplastic lesion.
What is progression in the 3rd stage of carcinogensis?
conversion of benign preneoplastic lesion into neoplastic cancer.
What are multiple outcomes of “Initiation”? (3)
Remain in static non-dividing state, cell deleted through apoptosis, undergo cell division resulting in the growth and the proliferation of the initiated cell.
In “initiation” what is needed to lock in a mutation?
on cell division.
What are intiators for the “initiation” of Carcinogensis?
Chemical and physical agents.
What is the detailed definition of carcinogenesis initiation?
Rapid, irreversible process resulting in carcinogen-induced mutation or epigenetic alteration (DNA change).
What is the detailed definition of the promotion of carcinogenesis?
selective clonal expansion of initiated cells to produce a preneoplastic lesion.
What are agents are tumor promoters?
exogenous and endogenous agents.
What are tumor promoters?
Not mutagenic and not able to induce tumors by themselves but act through gene expression changes to sustain cell proliferation.
What does it mean to not be mutagenic?
no DNA sequence alteration.
What does it mean to be clinically cancer free?
5 years w/o reoccurance.
Why was scrotal cancer big in 1775?
chimney sweeps worked naked so clothes wouldn’t get caught.
In promotion of carcinogenesis what is required?
multiple cell division and non genotoxic carcinogens.
What is progression in carcinogenesis?
conversion of benign preneoplastic lesion into neoplastic cancer.
In progression additional modifications may occur when?
with increased cell proliferation.
What are hallmarks of progression in carcinogenesis?
accumulation of nonrandom chromosomal aberrations and karyotypic instability.
What are clastogenic agents?
hallmarks.
Is progression irreversible?
NO!
What is important to know about chemical agents and all the stages of carcinogenesis?
chemical agents can act at all stages.
What are the anti-initiation strategies?
normal –> initiated –> Preneoplastic –> neoplastic
What are two mechanisms of action of chemical carcinogens?
Genotoxic and non genotoxic.
What does genotoxic mean??
DNA sequence alteration (Mutagents and DNA repair)
What does non-genotoxic mean?
Non-DNA sequence alteration (epigentic alteration).
What does non-genotoxic consists of?
Receptor mediated, altered methylation, and altered miRNA expression.
What is generally clonal in nature?
Tumors
Many carcinogens are or can be metabolized to what?
electrophilic intermediates.
What happens when carcinogens are/can be metablized to electrophilic intermediates?
can covalently bind to DNA
What can be mutagens?
Many carcinogens
Autosomal dominant inherited cancers provide what?
direct evidence for a genetic component in the origin of cancer.
Autosomal recessive-inherited cancers are associated with what?
chromosomal fragility or decreased DNA repair.
What predisposes affected individuals to cancer?
Autosomal recessive inherited cancers.
What displays chromosomal abnormalities?
cancers
What is MAJOR supporting genetic mechanism of carcinogensis?
the transformed phenotype can be transferred from a tumor cell to non-tumor cells by DNA transfection.
What can cells be transformed by?
oncogenes
Proto-Oncogenes are what?
activated by mutation in cancer cells.
Tumor suppresser genes are what?
inactivated by mutation in cancer cells.
When do oncogenes originate?
when proto-oncogenes involved in normal cellular growth and development are altered.
What is an example of an oncogene?
when growth factors, PDGF (platelet derived growth factor)
Tumor suppressor genes inhibit what?
cellular proliferation
What is an example of Tumor suppressor genes?
P53- Checkpoint control and arrests the cell cycle in G1
What occurs when tumor suppressor genes are altered?
deletion of tumor suppressor occurs
What occurs to oncogenes?
upregulation of proto-oncogene.
What occurs in the cell cycle checkpoint for P53?
no more stop sign in between G1 phase and S phase.
Direct acting carcinogens have no what?
metabolic activation or chemical modification.
Direct- Acting carcinogens are highly reactive electrophiles that do what?
can interact with and bind to nucleophiles such as cellular macromolecules including DNA.
What are examples of Direct-Acting Carcinogens?
Free radicals and Epoxides
Direct Acting Carcinogens form what at the site of chemical exposure?
tumor formation.
Direct acting carcinogens are positive in what assay?
in Ames assay WITHOUT bioactivation (S9)
What is S9?
in vitro liver function, is the factor metabolizing mixture added to Ames Assay to account for bioactivation.
What did Millers discover in 1970s?
Indirect Acting Carcinogens.
What do indirect-Acting carcinogens require?
metabolic activation to be carcinogenic.
What are examples of Indirect-Acting Carcinogens?
Benzyo(a)pyrene two step epoxidation.
Where does tumor formation occur in Indirect-Acting carcinogens?
not generally at site of exposure but at target tissue.
What is Benzoyo(a)pyrene?
it is an indirect acting carcinogen
Indirect acting carcinogens yield what in the ames assay?
positive in ames assay ONLY with biocativation (s9)
Mutagens are what?
Carcinogens
What was introduced by Theodor Boveri in 1914?
Somatic Mutation Theory
What does the Somatic mutation theory suggest?
Cancer was related to chromosome abnormalities in somatic cells.
What did Bruce Ames and Colleagues say in first papers in mid 1790s?
demonstrating that 90% of carcinogens known at that time were mutagens.
Major mutagenic changes in somatic cells lead to what?
a total disruption in DNA- directed cellular organization.
Major mutagenic changes in somatic cells yield what?
may lead to cell death and also lead to inability to grow and divide.
What type of interactions do mutagens have?
Direct or indirect interaction with DNA to form adduct or damage.
What are two mechanisms for mutagens?
- Base pair substitutions and modifications.
2. Frameshift mutations (deletion or insertion)
How DOES DNA repair or the lack of cause cancer?
persistence of mutation or adduct is major determinant of outcome and whether cell is able to repair damage.
What are DNA repair mechanisms?
- Direct reversal of DNA damage
- Excision Repair Systems
- Post-Replication Repair (recombination repair)
- Non-homologous-end joining
What is non-homologous -end joining?
double strand break repair
What are the excision repair systems?
Base excision repair, nucleotide excision repair, and mismatch repair.
What does DNA repair?
Both spontaneous alterations and chemical induced alterations
What do X-rays yield to as a damaging agent?
oxygen radicals, alkylating agents, and spontaneous reactions.
What does the Base Excision repair in X-ray damages?
uracil, abasic site, and single strand break.
Damaging agent is X-rays and what repair process is used?
Base Excision Repair (BER)
What does UV produce as a damaging agent?
Polycyclic aromatic hydrocarbons.
What is the repair process for UV light?
Nucleotide Excision Repair (NER)
What is the repair mechanisms for X-rays anti-tumor agents?
Recombinational repair.
What is the repair process for replication errors?
Mismatch repair
What are epigenetic carcinogens?
do not involve the mutation of DNA sequence.
What lacks genotoxicity?
Epigenetic Carcinogens
Epigenetic carcinogens involve the alteration in the expression of genes that do what?
function in important cellular processes such as proliferation, differentiation and apoptosis.
What is cancer associated with?
Altered differentiation
The cancerous state of tumors is said to sometimes be what?
reversible
Carcinogenesis is induced by what?
non-mutagenic agents.
Not all carcinogens are what?
mutagens
Carcinogenesis is associated with what?
Chances in DNA methylation
Cell transformation can occur when?
at very high frequencies in vitro.
What is receptor mediated?
Epigenetic Carcinogens
What is PPAR alpha?
Peroxisome Proliferator Activated Receptor Alpha
What are PPAR alpha?
Chemicals that increase number and volume of peroxisomes in cell cytoplasm.
What are examples of PPAR alpha?
Herbicides and plasticizers (phthalates).
What are indications of PPAR alpha occurrence?
Liver enlargement and hepatocellular carcinoma in rodent models.
What is the current MOA?
Agonist binding to PPAR alpha which induces cell proliferation and suppression of apoptosis
Has PPAR alpha been confirmed to effect humans?
no
What is AhR?
Aryl Hydrocarbon Receptor
Receptor mediated cells are what?
Agonsits
What is TCDD and Select PCBs linked to?
Tumor development = increase in gene expression.
AhR is a potential function as what?
a hepatic tumor promoters that is AhR-dependent.
Estrogen receptor is a receptor mediated epigenetic carcinogen that disrupts what?
endocrine chemicals that bind to estrogen receptors.
What is the agonist of the estrogen receptor?
17 Beta- estradiol and BPA (Bisphenol A)
What is an antagonist of Estrogen receptor?
Tamoxifen
Estrogen receptor disruption of hormonal control can result in what?
tumor development.
Altered methylation is an example of what?
epigenetic methylation
What is DNA methylation?
Promoter CpG islands
What are the general assumptions of increased DNA methylation?
Decrease in Gene expression.
What are the general assumptions of decreased DNA methylation?
Increased gene expression.
What is tumorigenesis?
Alteration in normal site
In normal cells what occurs when CpG island TSG promoters are unmethylated?
Transcriptionally active open chromatin structure.
What occurs in normal cells in CpG island TSG promoters methylated?
Transcriptionally silent chromatin state.
What is a tumor risk?
Methylated TSG promoter
Change in MiRNA expression yields to what?
Disrupted gene regulation
Depending on target gene and modulation, disrupted gene regulation will yield to what?
Cancer
what is miRNA?
Short RNA
What is the length of miRNA?
22 Nucleotides in length
What are post transcriptional regulators?
miRNA
What does miRNA bind to??
sequences of mRNA
single miRNA may target multiple mRNA transcripts including what?
oncogenes and TSGs
Indirect gene expression alterations include what? (3)
- Translation repression
- Target Degradation
- Gene silencing.
Which genotoxic assays indicate tumor/cancerous growth?
chronic bioassays: in vivo
What are the genotoxic mutation assays?
Ames assay, in vitro mammalian mutation assays (MLA assay), and in vivo gene mutation assays.
What are the 3 general genotoxic assays?
Mutation assays, chromosomal aberration assays, and chronic bioassays.
What are the 3 epigenetic assays?
Receptor binding assays, DNA methylation assays, and miRNA expressions assays.
What are DNA methylation assays?
targets and genome wide
What are miRNA expression assays?
targeted and genome wide
What is the proposed mechanism for Hormesis and Carcinogenesis?
adaptive responses that overcompensate for damage
What occurs in alteration in DNA?
Mutation occurs
