Neoplasia 2 Lecture Flashcards
Cancer
Genetic injury
- May be: acquired in somatic cells by environmental agents or inherited in the germ line
(tumors develop as clonal progeny of a single genetically damaged progenitor cell
Heterogenicity
Take a tumor and it consists of different types of cells, some are evasive
Exposure to carcinogens
Radiation, heavy metals, chemicals, retroviruses, environmental factors or genetic defects
Retrovirus?
RNA virus
- MMTV (mouse mammary tumor virus
- – mimics DNA of the host so it is incorporated (taken up and made into DNA in order to be able to be incorporated into the host)
Four classes of genes
Growth promoting protoncogens Growth inhibiting genes Genes that regulate apoptosis Genes that regulate DNA repair -- All play togehter
Normal cell undergoes some type of damage
Repair mechanisms comes in
- Once the DNA can be fixed it can go back to being a normal cell
- BUT if that fails, the mutation will be inherited
- – In somatic cells, they form a tumor because it is growth-promoting genes, inactivating tumor suppressor genes or apoptotics genes (blocking apoptosis – not removed leading to unregulated cell proliferation)
Clonal expansion
Angiogenesis: new blood supply, supplying oxygen so it can use ATP
Tumors are able to stay how?
Develop and escape system in order to stay
- Additional mutations –> tumor progression
- Invade and metatasize
Define oncogenes
Genes who products are associated with neoplastic transformations (help cancer grow)
Define protoncogenes
Normal cellular genes that affect growth and differentiation
– Become oncogenes when mutated
v-onc
Transduction into retroviruses
Changes in situ that affect their expression, function, or both, thereby converting them into c-onc
DNA contains transforming sequences (c-onc)
transfected fibroblasts acquire the growth characteristics of neoplastic cells
How is a stimuli transmitted in the cell?
External stimuli, ligand
- When bound it sends a signal
- At the membrane there is some type of activation
- Signal transduces cellular mediators
- Activation leads to nuclear activation of factors in the nucleus
- Activation of gene activation (cell proliferation, division, inhibition)
Different types of receptors?
Intrinsic kinase activity: kinase in the domain
Without intrinsic kinase activity
GPCRs: G proteins for activation
Platelet-derived growth factor
Help cells related to the migration (blood cells: growth, proliferation)
- Over expression: uncontrolled cell growth
TUmors that produce growth factors:
Responsive to the growth-promoting effects of the secreted growth factors and hence subject to autocrine stimulation
Growth Factor Receptors
(receptor tyrosine kinase)
- Mutations can lead to constitutive activation without binding to their ligands (uncontrolled cell growth)
Guanosine Triphosphate Binding Proteins (RAS family)
Normal flip back and forth between an active (GTP bound) and an inactive (GDP-bound) form
- Mediated by intrinisic GTPase activity, augmented by GTPase-activating proteins (GAPs)
- MutantsRAS bind GAP but their GTPase activity fails to be augmented and they are trapped in the signal transmitting from
- 10-20% of all human tumors carry mutant ras proteins
c-ABL gene
Normal form exerts a regulated tyrosine-kinase activity
- Luekemia, translocation of c-ABL and its fusion to the BCR gene produce a hybrid gene with potent, unregulated tyrosine-kinase activity
Nuclear Transcription Proteins
Products of MYC, JUN, FOS, MYB
- Highly regulated during proliferation of normal cells
- Regulate transcription of growth-related genes
- Staying on leads to tumor or continuous cell proliferation
MHC expressions
Occurs in Burkitt’s lymphoma, neuroblastomas, and small cell cancer of the lung
Cyclins and cyclin-dependent kinases
Regulate the progression of cells through the cell cycle
- D-type cyclins facilitate the trasition from G1 to S phase via CDK4 and CDK6 –> phosphorylate the retinoblastoma protien, releases E3F transcription factors (allows synthesis of S phase genes)
- – Inhibiting of CDKs via CDK inhibitors inhibit cell division (helps in DNA repair times)
Over expression of what is common in cancers
Cyclin D and CDK4
Oncogenes
Cancer may arise due to failure to repair the damage DNA
Protoncogenes may be converted to oncogenes via?
Point mutations
Chromosomal rearrangements
Gene amplification
Point Mutations
~15% of all human tumors carry mutated H-RAS or K-RAS oncogenes
- – RAS losses the ability of GTPase –> stays in active state
- Exposure to chemicals, etc
Chromosomal Rearrangements activate protooncogenes how?
Placement of the genes next to strong promoter/enhancer elements (c-MYC next to heavy chain gene)
Fusion of the gene with new genetic sequences (c-ABL gene with BCR)
Gene amplification
Reduplication of protooncogenes can lead to increased expression or activity
- Amp of c-ERB B2 in breast cancers
- Trisomy
