fundamental properties of cancer cells
1. PROLIFERATION = unregulated cell growth/division
2. METASTASIS = defects in normal restraints that keep cells from spreading and colonizing other parts of the body
- caused when TUMOR-SUPPRESSORS are SUPPRESSED or PROTO-ONCOGENES are OVEREXPRESSED
tumors
- when cells loses genetic control over cell growth
1. BENIGN = multicellular mass that can often be removed by surgery and may cause no serious harm
2. MALIGNANT = when cells in the tumor have the ability to break loose, enter the bloodstream, invade oth
genomic alterations associated w/ cancer
1. single-nucleotide substitutions
2. large-scale chromosomal rearrangements
3. amplifications
4. deletions
- creates abnormal karyotype due to deletions, translocations, abnormal # of chromosomes
clonal
- all cancer cells in primary/secondary tumors are originated from common ancestral cell that accumulated specific mutations
- evidence:
1. BURKITT'S LYMPHOMA = all lymphoma cells in each patient contain identical translocation breakpoints - all have same
age-related cancer
- demonstrates that cancer develops from accumulation of several mutagenic events in a single cell
- cancer is a MULTISTEP PROCESS REQUIRING MULTIPLE MUTATIONS
- incidence of most cancers rises exponentially with age
- as we age, we accumulate more and mo
tumorigenesis
- development of malignant tumor
- each step appears to be result of one or more generic alterations that progressively release the cell from the normal conditions on cell growth and proliferation
- cells end up escaping regulation of cell cycle and diffe
mutator phenotype
- high level of genomic instability in cancer cells
- cancer cells show higher than normal rates of:
1. mutation
2. chromosomal abnormalities
3. genomic instability
genetic defects associated w/ cancer cells
1. genomic instability & defective DNA repair
2. defect in chromatin modifications
3. mutations in genes regulating cell cycle
4. mutations affecting programmed cell death or apoptosis
5. mutations in genes that are responsible for cell-cell contact --> c
genetic instability defects in cancer cells
1. translocations
2. aneuploidy --> predisposition to cancer
3. chromosome loss
4. DNA amplification
5. chromosomal deletions
chronic myelogenous leukemia (CML)
- cancer of white blood cells
- specific translocation = C-ABL GENE on chromosome 9 is translocated into the BCR GENE on chromosome 22
- creates PHILADELPHIA CHROMOSOME
- this BCR-ABL gene codes for the BCR-ABL FUSION PROTEIN which is an abnormal signal t
defects in genes controlling DNA repair
- causes some inherited cancers:
1. CHRONIC MYELOGENOUS LEUKEMIA (CML) = translocation involving Philadelphia chromosome
2. XERODERMA PIGMENTOSUM = 7 DNA repair genes mutated --> hypersensitivity to UV light & predisposition to skin cancer - impaired abil
epigenetics
- study of factors that cause DNA modifications in a heritable way w/o affecting the nucleotide sequence of DNA (nucleotides chemically modified)
- epigenetic changes like DNA methylation and histone acetylation modify gene expression, potentially leading
genetic defects affecting cell-cycle regulation
- growth/differentiation of cells = strictly regulated
- cancer cells --> genes controlling functions of controlling steps of cell cycle, programmed cell death, and response of cells to external growth signals are often mutated/aberrantly expressed --> CE
signal transduction
- process of transmitting growth signals from external envt to the cell nucelus, initiating program of gene expression that propels cell out of G0 and back into cell cycle
- cancer cells = defects in signal transducation pathways
cell-cycle checkpoints
1. G1/S
2. G2/M
3. M
- progress through cell cycle = tightly regulated
- cell monitors external signals/internal equilibrium at these points before proceeding to next stage
- mutations of genes controlling cell cycle contribute to cancer development
- if
G1/S checkpoint
- cell monitors size and DNA inegrity
- cell not adequate size/has DNA damage --> progress halted and conditions corrected
- CDK4/cyclin D complexes activate proteisn that stimulate transcription of genes whose products (like DNA polymerase and DNA ligase
G2/M checkpoint
- cell monitors DNA synthesis and damage and physiological condition in the cell are monitored prior to mitosis
- DNA replication/repair not complete --> cell cycle arrests until this is complete
- CDK1/cyclin B phopsphorylates proteins that bring about e
M checkpoint
- during mitosis, cell monitors spindle formation and attachment to kinetochores
- if spindles not properly formed/attachment is inadequate, mitosis arrested
cyclins & cyclin-dependent kinases (CDK's)
- mediate regulation cell cycle progress by regulating synthesis and desctruction of cyclin proteins
- complex can activate other proteins
- cyclin present --> binds to specific CDK, triggering activity of cyclin/CDK complex which selectively phosphorylat
apoptosis
- programmed cell death that is initiated if DNA damage is so severe that repair is impossible so that there are not a lot of old/defective cells in organism
- series of proteases, called CASPASES, are responsible for initiating apoptosis and for digestin
BAX/Bcl2 roles in apoptosis
- gene products BCL2 and BAX can trigger/prevent apoptosis
- normal cell = balance of BAX/Bcl2 which form inactive heterodimers
- excess Bcl2 --> formation of Bcl2 homodimers, PREVENTING apoptosis (cancers w/ Bcl2 overexpression are resistant to chemother
proto-oncogenes
- responsible for basic cellular function in normal cells
- when normal cells are not dividing, these are repressed, or their products' activities are monitored
- genes whose products control cell growth/division
- genes encode:
1. TF's that stimulate exp
cancer-causing genes that are mutated/misexpressed in cancer cells
1. proto-oncogenes
2. tumor-suppressor genes
oncogene
- proto-oncogene that is mutated or aberrantly expressed and contributes to development of cancer
- proto-oncogenes that have undergone gain-of-function alteration that may arise from:
1. a mutation in the proto-oncogene that encodes for a protein w/ abno
tumor-suppressor genes
- products normally regulate cell cycle checkpoints (in response to DNA damage or growth-suppression signals from external environment) and initiate process of apoptosis
- suppress tumor formation
- when they're mutated (underexpressed)/inactivated, cells
ras proto-oncogenes
- encode signal transduction molecules associated w/ cell membrane and regulate cell growth and division
- mutated in more than 30% of human tumors
- ras proteins = signal transduction proteins that stimulate cell to divide in response to external growth
cyclins
- form complexes w/ CDKs that are important regulators of each phase of cell cycle
- cyclin D1 & E = proto-oncogenes
- CYCLIN D1 = overexpressed in breast, lung & esophagus cancer
- CYCLIN E = overexpressed in breast & colon cancer, & leukemia
p53 tumor-suppressor gene
- encodes nuclear protein (p53) that acts as a TF that represses or stimulates transcription of more than 50 different genes
- can arrest cell cycle at several phases
- cells lacking it are unable to arrest at cell cycle checkpoints or enter apoptosis in
p53 regulation by MDM2
- p53 protein normally bound to protein MDM2
- presence of MDM2 on p53:
1. tags p53 for degradation
2. sequesters the transcriptional activation domain of p53
3. PREVENTS phosphorylations/acetylations that convert p53 from INACTIVE to ACTIVE form
- ACTIVA
increasing p53 expression
1. chemical damage to DNA
2. double-stranded DNA breaks induced by ionizing radiation
3. presence of DNA-REPAIR INTERMEDIATES (when one strand has been repaired, & other still has problems - happens if repair enzymes aren't working) generated by exposure
p53 responses to DNA damage
1. cell-cycle arrest @ G1/S or G2/M checkpoint
2. stalls process so DNA has more time to be repaired
3. DNA damage = irreparable --> apoptosis
how p53 protein regulates cell cycle
1. activated p53 protein stimulates transcription of gene encoding p21 protein which INHIBITS CDK4/cyclin D1 complex to halt cell cycle at G1/s
2. regulates expression of genes that retard progress of DNA replication --> allows time for DNA damage to be r
RB1 Tumor-suppressor gene
- located on chromosome 13
- encodes for pRB protein = tumor suppressor protein that controls G1/S cell cycle checkpoint
- cells progress through G1/S transition when pRB is phosphorylated and CDK4 binds to cyclin D
- if pRB NOT phosphorylated --> remains
familial retinoblastoma
- inherited disorder in which tumors develop in eyes of young children due to inheriting 1 mutated RB1 allele
- more prone to mutation in other allele quite soon
- increased chance of developing other cancers
sporadic retinoblastoma
- requires 2 independent mutational events of RB1 w/in same cell
- mutations of BOTH alleles happens after birth & at a later age
- much less common
metastisize
- to leave site of primary tumor & invade other tissues, cancer cells must dissociate from primary tumor, and secreate proteases that digest components of EXTRACELLULAR MATRIX & BASAL LAMINA that normally INHIBIT migration of cells by surrounding and sepa
proteolytic enzymes
- break the long chainlike molecules of proteins into shorter fragments
- these (ie: METALLOPROTEINASES) are present at HIGHER than normal levels in highly malignant TUMORS & aren't susceptible to normal controls conferred by regulatory molecules like TIS
inherited cancer
- most inherited cancer-susceptibility genes aren't sufficient themselves to trigger cancer development
- at least 1 other SOMATIC MUTATION in other copy of the gene must occur to drive a cell towards tumorigenesis
- mutations in other genes also usually
familial adenomatous polyposis (FAP)
- shows how inherited mutations in one allele of gene = only 1 step in pathway to malignancy
1. individuals inherit 1 mutant copy of APC (ADENOMATOUS POLYPOSIS) GENE (on long arm of chrom. 5) whose gene product's normal function = tumor suppressor control
viruses causing cancer
- can transform normal cells into malignant cells
- most animal viruses that cause cancer are RETROVIRUSES = RNA genetic element
- humans = DNA viruses which require host cell to reproduce themselves (require host cell to be in actively growing state)
-->
carcinogenic
- a cancer-causing substance/agent
- any substance or event that DAMAGES DNA has potential to be CARCINOGENIC if it causes mutations to occur in PROTO-ONCOGENES or TUMOR-SUPPRESSOR GENES
- carcinogens = chemicals, radiation, some viruses, & chronic infect