Neoplasia II Flashcards
What do cyclins do?
- start cells into proliferation
- cell going through its cycle is controlled by synthesis, degradation, and state of phosphorylation of these proteins
Cyclins form complexes with what two things to modulate cell division?
- cyclin-dependent kinases (CDKs)
2. cyclin-dependent kinase inhibitors (CDKIs)
Cell cycle
G1 interphase/G1-S transition S interphase G2 interphase G2-M transition M mitosis
Why are there checkpoints in the cell cycle?
designed to stop damaged cells from replicating
The G1 interphase/G1-S transition can only occur when what transcription factor is free in the nucleus?
E2F (regulated by Rb phosphorylation)
What occurs during S interphase?
cells replicate DNA
What regulates G2-M transition?
CDK1-cyclin B complex
What are interphase cells?
those in phases G1, S, and G2 (non-mitosis)
Following Mitosis, phase cells can which two ways?
non-dividing state (G0) or continue to the cell cycle
checkpoints
G1/S restriction point (R) regulated by the state of phosphorylation of Rb
-on phosphorylation of Rb, the E2F transcription factor is liberated allowing progression into S phase
What does the intra S checkpoint monitor?
errors in transcription forks
What does the G2/M checkpoint monitor?
assembly of the mitotic spindle apparatus
If replication errors cannot be corrected by the checkpoints, what happens?
apoptosis or DNA repair mechanisms
DNA damage
abnormal or absent P53
Why is the expression of P53 gene to make p53 protein important?
it increases cyclin dependent kinase inhibitor (CDKI) p21 protein (WAF1) which prevents phosphorylation and arrests cell cycle
What happens when there’s an abnormal or absent p53?
regulatory function impaired
or cells with damaged DNA complete mitosis and thus propagate a mutation
Where do neoplastic transformations come from?
abnormalities in genes that regulate cell proliferation
What are the 4 main genetic mechanisms of neoplastic transformation?
- oncogenes
- tumor supressor genes (anti oncogenes)
- anti-apoptotic genes
- loss of cellular repair gene products
What kind of gene is the p53?
tumor supressor gene
What do oncogenes cause proliferation of?
Abnormal mitotic cells that should not be there
What do anti-apoptotic genes do?
keep cell from being killed
oncogenes
- derived by mutations
- expressed dominantly
- promote growth in absence of normal growth promoting signals
- their products, oncoproteins, are devoid of normal regulatory elements
Where are abnormalities of oncogenes found?
tumors (primary events in malignant transformation)
What do oncogenes do?
- don’t respond to normal growth factors
- increase secretion of growth factor independently of what the body needs
- increase the number of receptors
What are the three kinds of oncogenes originally isolated from tumor forming RNA retroviruses?
- V-oncs (viral oncogenes)
- C-oncs (Cellular oncogenes)
- P-oncs (proto-oncogenes)
V-oncs (Viral oncogenes)
genes within a virus that code for a protein involved in the development of neoplasia
C-oncs (cellular oncogenes)
genes that code for proteins in the development of neoplasia
P-oncs (proto-oncogenes)
genes that code for proteins involved in control of cell growth
two point mutation examples
Rb and P53
tumor supressor genes (anti-oncogenes)
- loss of activity of genes which produce products that inhibit cell growth
- generally act in a recessive manner to produce tumors
- malignant phenotype only develops if both alleles of a gene fail to suppress growth
What does the absence of tumor supressor genes promote?
neoplasia!
- tumor suppressor genes are gatekeepers that normally direct control cellular growth (Rb, P53, APC)
Rb
- first tumor suppressor gene discovered
- on chromosome #13
- found in many other tumors
What is the most common genetic abnormality ?
p53**
APC
Adenomatous polyposis coli
What are the 2 forms of Rb?
familial and sporadic
familial form of Rb
- affected children have one mutant gene(inactive) and one normal gene (active)
- if the second gene undergoes somatic mutation, tumor will develop (both gene alleles must undergo mutation)
When is P53 activated?
- in response to DNA damage–> cell cycle arrest and DNA repair
- if repair not achieved, p53 causes cell to enter apoptotic pathway of cell death
- loss of p53 activity allows proliferation of cells with DNA damage
APC (adenomatous polyposis coli) progression
- inherit a single inactive copy=> multiple benign adenomata of the large bowel
- if cells develop a second mutation of the normal inherited gene on the other allele–> carcinoma of the colon
anti-apoptotic genes
- overexpression of genes for anti-apoptosis protein (bcl-2)
- prevents normal cell death (failure to eliminate genetically damaged cells)**
What does the loss of DNA repair systems activity lead to?
- DNA instability
2. somatic mutations in oncogenes or tumor supressor genes
DNA repair genes
-well developed system of detection and repair of DNA (sometimes called “caretaker” genes)
philadelphia chromosome
translocation between chromosomes 9 and 22; found in leukemia
What are the 4 chemical carcinogens in Neoplasia?
- polycyclic hydrocarbons
- aromatic amines
- nitrosamines
- aklyating agents
polycyclic hydrocarbons
- tar; potent agents in cigarette smoke
- cause lung cancer
aromatic amines
- industrial exposure (rubber, dye) and converted to active agents in the liver; concentrated in the urine
- primarily bladder cancer
nitrosamines
- bacteria in gut converts dietary nitrites and nitrates to nitrosamines
- GI tract tumors
alkylating agents
- bind directly to DNA and are directly mutagenic
- used in cancer chemotherapy (e.g.. cyclophosphamide)
What are the 3 stages of chemical carcinogenesis?
- initiation
- promotion
- progression
inititation (carcinogenesis)
-induction of genetic changes in cells (altered genome)
promotion (carcinogenesis)
- induction of cell proliferation via mitogenic or cytotoxic mechanism
- initially reversible if promoting agent is withdrawn
progression
- persistent cell proliferation–>
- initiated cells acquire secondary genetic abnormalities in oncogenes–> dysregulation
- autonomous cell growth–> invasive neoplasm with subclones
key facts: chemical carcinogens
-most info from animal studies
-following exposure there is a LONG LATENT PERIOD before neoplasm develops
(-altered cells are primed but require second change to bring about molecular genetic changes expressed as neoplasia)
What are 2 main effects of DNA damage through irradiation (neoplasia)
DNA breaks and instability
direct exposure (e.g. x-rays) increases risk of tumors in bone marrow and skin of exposed areas
- environmental exposure more complex issue
- radon increases risk of carcinoma of the lung
- radioactive iodine therapy increases risk of thyroid carcinoma
- incorporation of radioactive metals into bone increases the risk of tumors of bone marrow and bone
ultraviolet light
major cause of neoplasia esp. many types of malignant skin tumors
what is the physical agent of asbestos induced neoplasia?
inhaled asbestos fibers
Preneoplastic conditions
-increased risk of neoplasia
hyperplasia, dysplasia, and chronic immune diseases
hyperplasia in preneoplastic conditions
- endometrial
- epithelial hyperplasia of breast lobules and ducts
dysplasia in preneoplastic conditions
- chronic gastritis predisposes CA of stomach
- chronic colitis predisposes CA of the colon
- hepatic cirrhosis predisposes liver cell CA
chronic immune diseases in preneoplastic conditions
- celiac disease predisposes gut lymphoma
- autoimmune thyroiditis predisposes thyroid lymphoma
immune response in neoplastic disease
tumors display abnormal antigens
- an immune response against tumor may occur
- weak
- not effective in eradicating an established tumor
CA
carcinoma
oncofetal antigens
- normally expressed only during development
- become re-expressed in the less differentiated neoplastic cells
incidence of lung cancer is increasing rapidly in women as a result of
cigarette smoking (>deaths than breast cancer)
Cancer facts
- survival rate for many tumors has greatly increased over past 25 years with advancement in treatment
- cancer prevention strategies depend on elimination of causative factors
- cancer detection strategies depend on screening population for early forms of neoplasia at an early stage of development
tumor markers
tumors liberate products that can be detected in blood samples
- may aid diagnosis
- also use to follow up therapy
- -> blood levels become increased if tumor recurs
- -> often before imaging can detect
tumor marker: AFP= alpha Fetoprotein
hepatocellular carcinoma and
germ cell tumors
tumor marker: human chorionic gonadotropin (hCG)
trophoblastic tumors
tumor marker: Acid phosphasase
prostatic carcinoma
tumor marker CEA =Carcinoembryonic antigen
Gastrointestinal tract neoplasia
tumor marker hormone products
endocrine tumors
novel anti-cancer drugs
-inhibitors of specific proteins in tumor cells (proteins involved in cell cycle entry and progression) or specific second messenger pathways
novel anti-cancer drugs
molecular pathology= can detect the specific target by screening patients prior to treatment
breast cancer drug (screening targe)
Herceptin (trastuzumab) (HER-2)
breast cancer mechanism of action
- herceptin
- binds to HER2, a member of the EGF-receptor family of proteins
- binding of Herceptin reduces the activation of the HER2-linked tyrosine kinase
- induces activation of the cell cycle inhibitors p21 and p27
What is the gastrointestinal stromal tumors (GIST) target?
Glivec
gastrointestinal stromal tumors (GIST)
Glivec is an inhibitor of the receptor tyrosine kinases for PDGF and stem cell factor (SCF) c-kit
- inhibits PDGF and SCF mediated cellular events
- in vitro inhibits proliferation and induces apoptosis in GIST cells, which express and activating c-kit mutation
tumor supressor genes
anti-oncogenes
What chromosome is p53 on?
chromosome 17p13
What does APC degrade?
degrades alpha catenin so if defective then alpha catenin levels rise in the cell and drive cell proliferation
What do mutations in DNA repair allow?
proliferation of cells with DNA mutations, replication error positive (RER+) phenotype
What leads to tumor heterogeneity?
tumors accumulate mutations
What is tumor heterogeneity?
multiple oncogene abnormalities in a single tumor
What is a complete carcinogen?
environmental agent that is both an initiator and promotor
*association with mesothelioma of the pleura is particularly strong
asbestos induced neoplasia
What is RER+ phenotype?
replication error positive
potent cause of neoplasia of lung and pleura
asbestos induced neoplasia
How are DNA repair genes assessed?
looking at tandem repeated DNA sequences in cells which normally remain constant
–> In DNA repair errors, cells develop changes in the repeat length of microsatellite DNA –> microsatellite instability
What is herceptin?
monoclonal antibody relating to breast cancer
2 types of antigens in immune response of neoplastic disease
- tumor specific antigens
2. tumor associated antigens
What is the 2nd most common cause of death in developed countries
cancer
What is the 1st most common cause of death in most developed countries (23% of all mortalities)
ischemic heart disease
What causes incidence of different histological types of cancer to vary greatly b/w different populations?
occupational, social, and geographic factors
What cancer is increasing among caucasians in many countries?
malignant melanoma of the skin
What is a multistage process involving initiation, promotion, and progression?
Carcinogenesis
Where is there a high incidence of stomach cancer compared to other countries (smoked raw fish)?
Japan
How does tumor heterogeneity occur?
- endothelial cells in capillary release protein growth factors
- malignant cells release angiogenic proteins and supress levels of angiogenesis inhibitors
What are genes that promote autonomous growth in cancer cells?
oncogenes
What are two examples of oncofetal antigens?
- alpha fetoprotein (AFP) (hepatocellular carcinoma)
2. carcinoembryonic antigen (CEA) (Gastrointestinal tract malignancies)
