carcinogenesis Flashcards by Robinson Raymundo

Initial damages or mutations may be caused by

environmental exposure (acquired from exogenous agents e.g., viruses or environmental chemicals, or by endogenous products of cellular metabolism

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why DNA repair is very important in determining if a mutation will develop?

If there is DNA repair, the damage will come back to normal and if the DNA repair mechanism is defective, there will be mutations.

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tumor-specific mutations are often identified by:

DNA sequencing

Chromosomal analyses

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4 classes of genes are the principal targets of cancer-causing mutations:

Proto-oncogenes
Tumor suppressor genes
Genes that regulate apoptosis
Genes involved in DNA repair

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Transforming genes that promote autonomous cell growth and cause cancer

ONCOGENES

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friendly” versions of oncogenes present in normal cells

Proto-oncogenes (p-onc)

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Mechanism of oncogene activation

mutation
chromosomal translocation
gene amplification

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Mechanism of oncogene action

Growth factors
Cell surface receptors
Intracellular transduction pathways
Transcription factors
Cell cycle proteins
Inhibition of apoptosis

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Negative regulators of cell growth

• Anti-oncogenes

TUMOR SUPPRESSOR GENES

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Describe a RB (retinoblastoma) protein

Governor of proliferation
• Regulator of cell cycle
• Inhibitor of G1/S transition during cell cycle progression

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Function of P53

Acts as a transcription factor
Prevents propagation of genetically damaged cells
• Blocks cell cycle progression
• Encodes for the protein p53

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Most frequently mutated gene in human cancers

P53

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Gatekeeper of colonic neoplasia

APC (Adenomatous Polyposis Coli)/β-catenin

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Function of APC (Adenomatous Polyposis Coli)/β-catenin

Decreases growth promoting signals

• Has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development

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Mutation in genes that regulate apoptosis result in

less cell death and enhanced survival of cells

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Mutations in DNA repair genes impair the ability of

cell to recognize and repair nonlethal genetic damage in other genes

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Cancer arises from nonlethal genetic damage which can be transmitted to

cell progeny

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Promotes cell growth and requires the alteration of only 1 allele to create an out of control cellular growth (dominant gene

PROTO-ONCOGENES

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3 KINDS OF GENES THAT ARE TARGETS FOR CARCINOGENIC TRANSFORMATION

PROTO-ONCOGENES
TUMOR SUPPRESSOR GENES
GENES THAT REGULATE APOPTOSIS

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Function of tumor suppressor genes

Inhibits cell growth and requires the alteration of both alleles to affect cell growth (recessive oncogenes

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Ability of transformed cells to acquire further abnormal characteristics over time, independent of tumor size

TUMOR PROGRESSION

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What are the abilitie that a tumor acquires in tumor progression

ability to invade
ability for metastatic spread
ability to develop anaplasia

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Oncogenes are cancer-causing genes derived from proto-oncogenes by:

Mutation
Retroviral transduction
Gene amplification or dislocations

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Oncogenic receptors exist in a

prolonged “on” state, even in the absence of bound growth factor

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codes for receptors associated with glial cells

RET proto-oncogene

Point mutations in the RET proto-oncogene (codes for receptors associated with glial cells) are associated with

multiple endocrine neoplasia (MEN) and familial medullary thyroid carcinoma

Exist on the inner plasma membrane and following activation work to phosphorylate cytoplasmic proteins

Signal Transducing Proteins

A GTP-cleaving protein receptor associated transducing protein

RAS

function of MAP (mitogen activated protein

increases nuclear transcription factors

Normally works to activate MAP

RAS

Forms a heterodimer with MAX protein forming the MYC-MAX combination which activates transcription

C-MYC

contribution of MAD in transcription

combine with MAX to turn off transcription and is therefore a tumor-suppressor gene

function of Cyclins

work to activate CDKs

METHODS OF ACTIVATION OF ONCOGENES

Point mutations Chromosomal rearrangements Gene Amplification

Gene emplification is associated with ____ in neuroblastoma and _____ in breast cancer

N-MYC in neuroblastoma and C-ERB 2 in breast cancer

Tumor suppressor genes work through similar mechanisms as proto-oncogenes through

Signal transduction Cell surface receptors Nuclear transcription regulators

A protein exclusive to the nucleus, is the most common transformed gene in human cancer, presenting in over 50% of human tumors

p53

action of p53 in the nucleus

it stops replication of damaged cells

function of p53 after cell damage

p53 gets rapidly up regulated and its accumulation triggers increased transcription of DNA repair proteins and those that stop the cell cycle

Other tumor suppressor genes include

NF-1, NF-2, VHL, and WT-1

Function of BCL-2

inhibits apoptosis and is transformed in most B cell lymphomas

why defective DNA repair genes implicated in development of cancers

they may allow cell division despite mutated DNA

illustrates a cancer associated with defects in DNA repair

HNPCC (hereditary nonpolyposis colon cancer)

2 categories of initiators

Direct-acting agents | Indirect-acting agents

Induction of certain irreversible changes (mutations) in the genome

Initiation

carcinogenic product of metabolism is called

ultimate carcinogen

Process of tumor induction in previously initiated cells

Promotion

how does ionizing radiation induce DNA mutations

generation of free radicals from water or oxygen

mechanism of ionizing radiation

Ionization of macromolecules Free radical formation Activation of latent oncogenic viruses Regenerative replication

Epstein - Barr virus (EBV)

Burkitt lymphoma | o Nasopharyngeal CA

Hepatitis B virus (HBV)

Hepatocarcinoma

Human Herpesvirus 8 (HHV 8)

Kaposi’s sarcoma

Human Papillomavirus – 16 (HPV-16)

Cervical CA

General effects of UV rays

Inhibition of cell division Inactivation of enzymes Killing of cells

Damagae to DNA by UV rays occurs through

formation of pyrimidine dimers

H pylori causes

adenocarcinoma and gastric lymphomas

Bacterial cause of gastric malignancies

H. pylori

First bacterium classified as a carcinogen

H. pylori

Oncogenic RNA viruses example:

Human T-cell lymphotropic virus type I (HTLV-1)

Types of Chemical carcinogeneis

Direct acting Procarcinogenesis Aromatic amines/azo dyes Naturally-occurring