question

What is cancer?

answer

The uncontrolled proliferation of cells.

question

What causes cancer?

answer

Caused by a loss in growth control or apoptosis mechanisms. Cells can become immortal.

question

What is the main reason underlying cancer initiation?

answer

The accumulation of mutations

question

6 hallmarks of cancer

answer

Self-sufficiency of growth signals Insensitivity to anti-growth signals evasion of apoptosis limitless replicative potential sustained angiogenesis tissue invasion and metastasis

question

What is the main cause of cancer

answer

Environmental conditions, including life style factors like exposure to UV radiation, carcinogens and certain viral/bacterial agents.

question

Is there a hereditary predisposition to cancer?

answer

yes-->inheritance of mutant genes.

question

Four factors that can cause mutations

answer

Radiation Chemicals (carcinogenic) Infectious agents Hereditary factors

question

What are two types of mutations that can lead to development of cancer

answer

Oncogenes and inactivated tumor supressor genes

question

What is the correlation between cancer and tobacco use

answer

As incidence of cigarette smoking increased per person per year, the incidence of male lung cancer death rate per 100,000 people also increased. The number of yearly lung cancer deaths shows direct correlation to cigarette consumption per person per year.

question

What types of cancers can cigarette smoking cause?

answer

Lung cancer prostate cancer bladder cancer

question

What does the Ames test do?

answer

The Ames test quantifies the mutagenic capacity of chemicals.

question

How does the Ames test measure mutagenicity?

answer

The Ames test quantifies the ability of a certain chemical element to cause his- mutants to revert and grow on media lacking histidine.

question

What is the relationship between mutagenicity in the Ames test and carcinogenicity in mouse models?

answer

As the amount of substance in micrograms required to produce 100 his revertants per plate decreases, the carcinogenic potency increases. So there does appear to be a correlation between mutagenicity and carcinogenicity.

question

Examples of physical carcinogenic agents (not chemicals)

answer

ionizing radiation: X-rays, gamma rays produce free radicals that cause DNA double-strand breaks UV radiation: causes formation of thymine dimers, which, if not properly repaired or removed, causes mutations (skin cancer).

question

What types of base changes are characteristic of UV damage?

answer

CC-->TT conversions, and thymine dimers

question

What are CC-->TT dipyrimidine mutations correlated with?

answer

Incidence of skin cancer

question

What are C-->T mutations NOT at dipyrimidine site correlated with?

answer

Internal cancers

question

One protein that is mutated in cancers

answer

p53

question

Mutation pattern in skin cancers is indicative of what?

answer

UV-induced damage

question

What are biological carcinogenic agents?

answer

Viruses: by expression virally encoded or host oncogenes; by expressing proteins that inactivate tumor suppressor genes. Bacteria: bacteria and other parasites can facilitate cancer development by producing CHRONIC INFLAMMATION.

question

What are damaging agents in the case of bacteria?

answer

Due to chemicals from chronic inflammation; or due to direct virulence factors, such as CagA, which is from H.pylori. CagA stands for cytotoxin-associate gene A.

question

Link between oncogenesis and chronic inflammation

answer

Chronic inflammation leads to chronic elevation of local levels of inflammatory cytokines, prostaglandins, and reactive oxygen and nitrogen species. These can lead to the neoplastic process.

question

What are oncogenes

answer

Oncogenes are those genes whose activation initiates or facilitates the development fo cancer. They act in an AUTOSOMAL DOMINANT MANNER.

question

Are oncogenes normal?

answer

Oncogenes are usually modified or over-expressed versions of normal or even essential proto-oncogenes.

question

What is src?

answer

Src is a non-receptor tyrosine kinase protein encoded by the SRC gene. It is involved in cancer. Src is short for sarcoma.

question

What are tumor suppressors?

answer

Tumor suprressors are genes that are inactivated during cancer progression. They exhibit and autosomal recessive phenotype.

question

What is the phenotype for oncogenes?

answer

Autosomal dominant

question

What is the phenotype for mutant tumor suppressors?

answer

autosomal recessive

question

Mechanism of oncogene activation

answer

Point mutation, gene amplification, or chromosomal translocation causes changes in expression of proteins from proto-oncogenes. Local DNA rearrangements and viral insertional mutagenesis also occur.

question

What does point mutation in proto-oncogene cause?

answer

Hyperactive protein

question

What does gene amplification in proto-oncogene cause?

answer

excess of normal protein

question

What does chromosomal translocation in proto-oncogene cause?

answer

Excess of normal protein OR abnormal hyperactive protein

question

What do local DNA rearrangements do to proto-oncogene

answer

insertions, deletions, or inversions/transpositions can cause abnormal hyperactive proteins

question

What does insertional mutagenesis do to proto-oncogenes

answer

cause excess normal protein

question

Example of point mutation that can cause cancer

answer

Point mutations can cause proteins to go from inducible to constitutively active. for example, the Ras proteins with defective GTPase activity that constitutively stimulate transcription of genes in response to growth factors.

question

How can gene amplification lead to cancer?

answer

Amplification of growth stimulating genes such as growth factors, growth factor receptors, transcription factors over-activates pathways, leading to excessive proliferation and cancer development.

question

One specific example of gene amplification implicated in cancer

answer

Amplified oncogenes can produce normal growth factor receptors, but in very high quantity. This leads to excessive receptor activity and cancer.

question

Deletion mutation that can cause cancer

answer

Some oncogenes encode for mutant receptors whose tyrosine kinase is permanently activated. Missing growth factor binding site, which makes the receptor constitutively active. It exhibits tyrosine kinase activity in the absence of growth factor.

question

Chromosomal translocation oncogene specifics

answer

Chromosomal translocation can place myc gene in close proximity to IgH enhancers. Since immunoglobulin heavy chain gene is only expressed in B lymphocytes, this translocation can cause solid-state lymphoma. We do know that the myc/max mechanism controls aspects of cell proliferation in a concentration dependent manner, since the expression of myc is tightly regulated. when myc heterodimerizes with myc-associated factor X, it can bind enhancer regions and cause cell proliferation. Excessive quantities of myc protein lead to excessive myc-max heterodimers, meaning excessive enhancer activation, meaning excessive proliferation.

question

Philadelphia chromosome

answer

The Philadelphia chromosome 9:22 translocation produces bcr-abl oncogene fusion. This leads to excessive proliferation and myeloid leukemia.

question

Cell fusion experiments demonstrate what nature of tumor suppressors

answer

Cell fusion experiments demonstrate the recessive nature of tumor suppressors. When a cancer cell is artifically fused with a normal cell, the resulting hybrid cell shows normal growth control. however, when some chromosomes are lost during division, another cancer cell exhibiting uncontrolled growth arises.

question

Link between heriditary and non-hereditary tumor suppressor mutations

answer

If retinoblastom mutant is inherited from gamete, then all somatic cells of progeny will have one defective RB gene. If the second copy of the RB gene undergoes a spontaneous inactivating mutation, then loss of heterozygosity leads to cancer.

question

Mutation rate per gene per cell

answer

10^-6

question

Non-hereditary retinoblastoma

answer

Mutation in one copy of RB occassionally occurs; mutation in the second copy of RB in a cell that has a mutation in the first copy will lead to homozygosity for inactive RB gene, which will lead to nonhereditary retinoblastoma.

question

Cancer cell development and progression key points

answer

cancer is produced by cumulative effects of a dozen mutations These result in failure of growth control, cellular immortalization and invasive properties Mutations in oncogenes and tumor suppressors inactivate cell cycle controls reactivation of telomerase immortalizes cell by subverting chromosomal clock

question

Stages of cancer development

answer

Initiation (mutation) Promotion (cell proliferation) tumor progression, which includes successive stages of mutation or epigenetic change, proliferation and selection, mutation or epigenetic change, proliferation and selection, ad nauseum

question

Progression of colon cancer

answer

involves an initial mutation of APC, and then successive mutations with intermediate periods of cell proliferation and selection.

question

Why does mutation accumulate in cancer cells?

answer

Because of genetic instability, such as defects in DNA repair or chromosome sorting during mitosis

question

Mutations in colon cancer (successive)

answer

APC, KRAS, SMAD4, p53, then others

question

What is a tumor?

answer

An abnormal accumulation of cells

question

Two types of tumors

answer

localized benign invasive, diffuse and malignant

question

Factor besides mutation that can contribute to cancer development

answer

Epigenetic changes

question

Epigenetic processes and miRNAs in cancer development

answer

Epigenetic changes are heritable changes in gene expression that occur without changes in DNA base sequence; involve DNA methylation and chromatin alterations.

question

miRNAs involvement in cancer development

answer

miRNAs bind to mRNA and regulation mRNA stability and translation levels. miRNAs can promote oncogenesis or act as tumor suppressors.

question

What underlies genetic instability?

answer

Genetic instability results from defects in different DNA repair mechanisms

question

Defects in DNA mismatch repair lead to?

answer

colon cancer

question

Defects in nucleotide excision repair lead to?

answer

xeroderma pigmentosum-->inability to repair mutations caused by UV light

question

Defects in homologous recombination enzymes BRCA1/2 lead to?

answer

Breast cancer disposition

question

What allows carcinomas to invade other tissues and penetrate into the body

answer

Cancer cells produce metalloproteases that degrade and modify the extracellular matrix; cancer cells undergo changes in gene expression that alter their adhesion properties.

question

4 steps in cancer metastasis

answer

1) Invasion: movement out of the original primary tumor 2) intravasation and dissemination: entry into the blood stream and circulation around the body. 3) extravasation: exit from blood stream and deposition in tissues (called micrometastasis) 4) Colonization: expansion of one or more micrometastatic clusters to macrometastatic growths (>2mm)

question

What is the hypothesis to explain where and when metastatic disease arises?

answer

Soil and seed hypothesis

question

How do cancer cells promote angiogenesis?

answer

Cancer cells produce angiogenic factors, and these stimulate tumor vascularization.

question

What are three angiogenic factors?

answer

VEGF, FGF, angiopoietin

question

Tumor volume vs. days graph

answer

This graph shows that tumor cells growing on the iris of the eye have access to blood supply, whereas those suspended in the anterior chamber do not. Thus, over days, tumor cells on the iris increase much in volume, whereas tumor cells suspended in the anterior chamber do not show increase in volume

question

How do tumor cells use there vascular network?

answer

They use the vascular network blood supply to grow in size at their primary site and to metastasize.

question

How do we diagnose cancer?

answer

Histology and molecular profiling (immunohistochemistry, transcripome and proteome profiling). Allow clinician to diagnose the type and stage of different cancers and predict outcome.

question

What histologic signs are examined when making cancer diagnosis

answer

large nuclear size high nuclear to cytoplasmic ratio pleomorphic nuclear shape high mitotic index disorganized tissue poorly differentiated poorly defined tumor boundary and rough edges

question

Three traditional approaches to cancer therapy

answer

Surgery radiation chemotherapy

question

Downside of surgery

answer

can leave behind traces of cancer cells or micrometastases that can relapse

question

Downside of radiation and chemo-therapy

answer

destroy healthy neighboring cells and other actively dividing cells

question

Customized cancer therapy?

answer

Antibody and small molecular inhibitor therapies have been developed to interfere with growth/spread of cancer cells or their facilitators.

question

Gleevec

answer

small molecule inhibitor that inhibits Bcr-abl oncogene

question

tamoxifen

answer

specific inhibitor for the ER (activated in breast cancer)

question

avastin

answer

monoclonal antibody that binds and sequesters VEGF (angiogenic factor)

question

Personalized medicine

answer

specific combinations of drugs or other therapies to treat patients as per their specific cancer profile

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