The flashcards below were created by user
on FreezingBlue Flashcards.
cell cycle phases
- Primary: G1, S, G2, M
- Secondary: G0
- preparation for DNA synthesis
- Quiescent cells + external growth factors = new transcription, synthesize proteins for DNA synthesis
- includes regualtory checkpoint, defaults to block continuation/proliferation
- could be between 1 and 20 hours long
- DNA replication
- monitors environment, size, accuracy of DNA. commits to mitosis
- checkpoint at G2/M boundary
- cells damaged by Xrays arrest here
- resting, post-mitosis
- can synthesize up to 20% of proteins produced by active cells, to keep cells alive. Also, regulatory proteins specific to quiescent cells
- occurs when gowth factors are limited or negative regulators block cycle transit
cell cycle checkpoints
- transition points where monitoring of cell leads to decisions about continuation.
- Used to growth arrest cells with damaged DNA until repairs can be made
- regulatory proteins that drive cell cycle
- expressed and function at specific times in cycle, then ubiquinated/degraded in proteosome
- activate cyclin-dependent kinases (cdks)
- G1: cyclins D and E
- S: Cyclin A
- G2/M: cyclin B (mitotic cyclin)
cyclin-dependent kinases (cdks)
- phosphorylate crucial targets that allow continuation past checkpoints in cell cycle
- require cyclins
- concentration of cdks always constant (cyclins are available as needed)
primary regulatory substrate of G1
- Rb (retinoblastoma)
- hyperphosphorylated first by cyclinD/cdk4 and cyclinE/cdk2 to allow cells past the G1 checkpoint
are most cells in adults proliferating
What enables a quiescent cell to reenter cell cycle and proliferate (injury, etc)?
growth factors activate receptor tyrosine kinases which stimulate signaling pathways leading to transcription and translation of new genes, which initiate a transcriptional cascade
- Tumor suppressor protein, inactivated by cyclin D/ckd4 and cyclin E/ckd2 at the G1 checkpoint (default inhibits E2F and blocks progression)
- Mutated in most cancers
- unphosphorylated and hypophosphorylated are active. Hyperphosphorylated is not.
transcribed at part of G1 transcriptional cascade, blocked by linkage to Rb/HDAC/repressiveCRC until it becomes hyperphosphorylated, all three disassociate and a HAT/activating CRC attach, ER2F causes transcription of genes needed to replicate DNA in S phase.
cyclin-dependent kinase inhibitors (CKI)
- activated by extracellular or intracellular signals
- inhibit or slow proliferation by blocking hyperphosphorylation of Rb
- block activation of cdk4/cdk2
- CKI p21 (cyclin E/cdk2) transcribed in response to DNA damage (by p53)
- CKI, transcribed by p53 in response to DNA damage to block cyclin E/cdk2 from phosphorylating Rb, blocks proliferation of (damaged) cells
- KEEPS Rb ACTIVE
why is cancer associated with age?
it takes time to accumulate enough mutations (long latency)
how many mutations are necessary to cause cancer?
- 2-8, caused by cellular stresses (metabolic, proteotoxic, mitotic, oxidative, and DNA damage)
- A SINGLE ONCOGENE IS NOT SUFFICENT TO TRANSFORM PRIMARY CELLS
- abnormal accumulation of mutations
- elevated mutation RATE
- either caused by or causes cancer, but is required either way (but not TOO much)
tumors are made up of
- multiple sub-populations of cells (heterogeneous) with distinct characteristics
- arises from gradual accumulation of mutations and epigenic changes, confer a selective advantage in many environments for metastasis
cancer stem cells (CSC)
- long-term self-renewal, increased proliferative potential, capacity to differentiate, telomerase expression, multi-drug resistance, enchanced DNA repair and ability to remain quiescent
- enables tumors to propagate indefinitely, regrow after chemo (often resistant to chemo), be heterogenous
- aka cancer propagating cells
Cellular response to stress
- quiescence, senescence or apoptosis
- Includes metabolic, proteotoxic, mitotic, oxidative, and DNA damage stresses
initiation (tumor progression)
- exposure to a mutagen (initiator) results in a permanent change to DNA (mutation), usually activates a gene related to cell proliferation (direct carcinogens)
Promotion (tumor progression)
- when initiated cells are stimulated to proliferate (like with growth factors)
- classified as indirect carcinogens or co-carcinogens
- reversible process
- mutagenizes cells and stimulates proliferation, therefore associated with cancer risk
- inflammatory neutrophils and macrophages secrete growth factors and cytokines (promoters) and produce reactive oxygen species (initiators) to mutagenize DNA.
genetic risk factors for cancer
- inherited mutation in cancer suppressor gene
- polymorphisms in carcinogen activating enzymes, carcinogen detoxifying enzymes, DNA repair proteins - could increase or decrease risk
hallmarks of cancer (8)
- 1. sustaining proliferative signal
- 2. evading growth suppressors
- 3. resisting cell death
- 4. inducing angiogenesis
- 5. activating invasion and metastasis
- 6. enabling replicative immortality
- 7. deregulating cellular energetics
- 8. avoiding immune destruction
- altered gene whose product can act in a dominant fashion to help make a cell cancerous
- Dominant (only takes 1 copy), gain of function mutations, no longer tightly regulated
- usually positive regulator of proliferation
normal gene usually involved with regulating cell proliferation that can be converted/mutated into a cancer-promoting oncogene
hallmarks of viruses that cause oncogenesis
- DNA viruses, NON-LYTIC, replicate in the nucleus
- can be direct or indirect carcinogens
a permanent, heritable change (DNA mutation)
a temporary alteration in the expression of a protein that causes cell proliferation, like cytokines or growth factors
what the parts of a retrovirus gene do (LTR, gag, pol, env)
- LTR: long terminal repeat (at beginning and end), make THOUSANDS of copies. Promoter.
- gag: makes the matrix, capsid, nucleocapsid. Group antigen
- pol: integrase, reverse transcriptase. Required for replicative competences
- env: envelope (surface glycoproteins, transmembrane proteins)
sinple vs complex retrovirus
simple contains just the bare minimum of genes. Complex contain accessory genes
integration in viruses
- retroviral DNA enters into the host genome. Essential for viral replication
- Enters randomly, but in tumors it's in a very specific site (clonal integration)
- This site is necessary for oncogenic transformation
transduction in viruses
recombination events with viruses, can steal oncogenes from host (random insertion). Can lose integral genes of own and become replication incompetent without a "helper" virus that is still replication competent.
efficiency of tumor formation in transducing vs non-tranducing vs non-tranducing, long-latency
- transducing: extremely high, 100%
- non-transducing: high to intermediate
- long-latency: very low (<5%)
tumor latency in transducing vs non-transducing (vs long latency non-transducing)
- transducing: short (days)
- non-transducing: intermediate (weeks, months)
- long-latency, non-transducing: long (months to years)
Where do oncogenes come from?
oncogenes originate from normal cellular genes that have been transcriptionally altered, activated or mutated.
how do retroviruses lead to cancer? (2)
- 1. can occasionally activate or tranduce (promoter insertion) cellular genes that lead to cancer (like a tumor initiator)
- 2. trans-activate cellular genes that are proliferative in function and increase the susceptibility of this infected cell to secondary mutations that lead to cancer (like a tumor promoter)
oncogenes can encode (2)
- proteins (Ras, KIT, etc.)
- regulatory non-coding RNAs (miRNA)
categories of oncogenes (2)
- growth factor signaling components: growth factors, growth factor receptors, signaling intermediates, transcription factors
- cell cycle related: cell cycle regulators, differentiation regulators, apoptosis regulators
"normal" cells in culture with oncogenes expressed
properties of transformed cells (5)
- 1. loss of contact inhibition (form foci/piles)
- 2. anchorage independence (soft agarose okay)
- 3. reduced growth factor requirement (sometimes autocrine)
- 4. morphological changes (round, few attachments)
- 5. limitless replicative lifespan
cancer cells proliferate ___________ as regular cells (rate)
can be faster, slower or the same.
- confer a selective grwoth or survival advantage.
- Need 2-8 of THESE to make a tumor.
- Activate a proto- to an oncogene or inactivate a tumor suppressor
- do not specifically provide a growth or selective advantage.
- Most of mutations in cancer.
- Can become driver mutations as microenvironment changes
- arise in normal cells.
- Pediatric cancers have the fewest
cancer signaling pathways
a set of 12 pathways that make up the driver mutations, new treatment tries to target multiple of these pathways so that cancer doesn't have time to adapt
proto-oncogene conversion (aka proto-oncogene activation) (2)
activated by mutations that either 1. modify coding region (produce oncogenic protein) or 2. deregulate expression (allow overexpression or expression when it shouldn't)
chromosomal mechanisms of proto-oncogene conversion (3)
- gene amplification: increased proto-oncogene DNA copy number = increased protein
- translocation: joins one part of a chromosome to another (like crossing over) to deregulate or make fusion protein
- simple mutation: SNP or indel in coding or non-coding regions.
cells that block cell cycle exit (bc12 inhibits apoptosis, myc prevents differentiation) could be a potential ____________
Retinoblastoma (disease) 2 forms and how they occur
- Tumor suppressor gene
- inherited: inherits inactivated copy, so only has one. Then any mutation = tumor. Multiple tumors in both eyes
- sporadic: must have two mutations in same cell to inactivate both cells. Rare, equals a single tumor in one eye.
Loss of heterozygosity (in tumor suppressor genes)
indicates the change in chromosome banding when a chromosome that already has one deleted tumor suppressor loses the other one
- "guardian of the genome", tumor suppressor gene.
- mutated in 50% of cancers
- transcription factor (short half-life, but stress stabilizes it so it can function).
- stimulates p21 (CKI that keeps Rb active) and Bax (pro-apoptotic)
pro-apoptotic gene, transcribed by p53
steps of metastasis (6)
additional mutations to 1. breech basement membrane. 2. recruit new blood vessels 3. invade surrounding tissue 4. intravasation 5. extravasation 6. colonization
what increases with tumor size?
- risk of metastasis.
- greater than 2cm are at risk, but sometimes even this is too late
how do tumors effect their microinvironment?
- recruit inflammatory cells and activate stroma (fibroblasts - secrete ECM to promote motility and survival).
- Recruited inflammatory secrete growth factors, cytokines, and angiongenic factors.
- Also secrete proteases to degrade ECM so cells can move.
invasion strategies of lymphoid tumors or sarcomas
- migrate as individual cells (ameboid or mesenchymal)
- lack cadherins, low integrins and proteases
invasion strategies of epithelial cancers
move as clusters/sheets, held together by cadherins, gap junctions. Lots of integrin receptors and proteases.
epithelial-mesenchymal transition in cancer
Carcinomas are induced to change (TGF-beta from neighbors), migrate and turn back into epithelial cells. Transient process, only a few cells do this (unlike sarcomas). Act like stem cells.
pathways of metastatic spread (4)
- seeding: (carcinomatosis, as in ovarian cancer)
- transplantation: contaminated organ donor or instrument
- hematogenous spread: through blood, often sarcomas
- lymphatic spread: carcinomas
major inducer of tumor angiongenesis
- transcription factor (hypoxia inducible factor) brought on by hypoxia and/or growth factors, causes expression of angiogenic factor VEGF (Vascular endothelial growth factor)
- normally ubiquinated by prolyl hydoxylase (inactive in hypoxia)
- vascular endothelial growth factor
- causes angiogenesis
- stimulated by HIF-1alpha
how tumors cause angiogenesis
- secrete VEGF, bFGF, attach to ECM so inactive.
- Tumor recruits macrophages and mast cells to chew up ECM, cause inflammation
- No more ECM activates bFGF, VEGF, cause capillary to grow towards tumor
- SIGNIFICANT angiogenic increase from non to invasive tumors (not entirely sure why)
- likely caused by breach of basement membrane, recruitment of inflammatory cells
vasculator of tumors
- extensive, but abnormal. Vessels are leaky, stopping drugs from getting in there properly.
- increased vasculature is a poor prognosis
- targets VEGF and EC receptors.
- Do not live up to expectations
2 types of circulating tumor arrest
- 1. mechanical entrapment: passive, trapped in first capillary bed
- 2. site-specific mechanism: active, preferentially metastasize. Most tumors use this
Endothelial cell adhesion molecules (CAMs)
- molecules on the surface that interact with tumor cells (like leukocytes rolling)
- constitutive (continuously expressed on surface, aka addressins) or inducible (expressed in response to a signal)
- favorable microenvironment for a tumor metastasis, some cells stay dormant (G0) until this is reached and/or angiogenic switch is thrown. Could also wait in micrometastasis.
- contains recruited bone marrow derived cells to provide growth factors, ECM components, chemokines and adhesion molecules.
ploidy alterations and kinds (2)
- changes in number of chromosomes per cell
- aneuploidy: gain or loss of individual chromosomes
- polyploidy: increase in number of complete haploid sets of chromosomes per cell
increased copy number of a gene or chromosomal region
double stranded DNA break repair (2)
- 1. non-homologous end-joining (NHEJ): G1 stage (no sister chromatid), just ligates together. Error-prone.
- 2. homologous recombination (HR): S and G2 stages (sister chromatid). make free 3' ends, new DNA synthesized to fill in, Holliday junction resolved.
nucleotide excision repair (NER) (2)
- bulky DNA lesions distort helix
- 1. global genome pathway monitors entire genome
- 2. transcription-coupled repair pathway watches blockage of RNA polymerases druing transcription.
- Endonucleases cut out the damaged section on single strand, re-synthesize
Base Excision repair (BER) (2)
- Small chemical changes (methylation, abasic, etc)
- flip out and cleave
- abasic recognized by endonuclease, cleaved
- 1. Short patch repair: one-nucleotide gap-filling reaction
- 2. long-patch repair: re-synthesize 2-10 nucleotides, flap removed.
- not implicated in disease (excessive redundency)
mismatch repair (MMR)
- replication errors.
- ID'd by Msh2/Msh6 (small) or Msh2/Msh3 (larger), determine which strand is right, excise defective and re-synthesize
- lots of colon cancers
- responds to double-stranded break in DNA
- phosphorylates proteins including p53, which upregulates P21 and Bax, cause cell arrest and apoptosis
Chemotherapy traditionally attacks ________
S phase, or DNA replication
chemo drug, targets DHFR, blocks folic acid metabolism to prevent DNA synthesis (cell-cycle specific chemo agent)
how non-cell-cycle-specific chemo works
induce apoptosis by targeting faster metabolism of tumors
depend on hormone to grow (breast cancer needs estrogen, can use anti-estrogens)
Tumors are proliferative but not differentiated, tries to convert tumor to differentiated normal cell, relieving tumor burden, restoring differential cell function
antibody drug therapy
use antibody to traget a tumor-specific antigen (molecule tumor needs for growth)
bone marrow transplant treatment
- used to treat hematological neoplasias and some solid tumors like lymphoma.
- destroy and replace
gene expression arrays
- type tumors for sensitivity
- monitor tumor and host response
3 modalities of cancer therapy, and local vs systemic
- surgery (local)
- chemotherapy (systemic)
- radiation (local)
- (multimodal--any two)
- systemic: oral, IV
- localized: intralesional with vehicle to slowly release, intracavitary, implantable beads
types of radiation therapy
- brachytherapy (short): radioactive seeds or needles inserted
- plesiotherapy (surface): limited depth of radiation
- teletherapy (distance): linear accelerator
pathologic conditions occur naturally
induced disease models
pathologic conditions are experimentally induced
negative disease models
conditions never occur in a particular species, as opposed to another species
orphan disease models
conditions never occur in humans
locus of crossing over in bacteriophage (Lox) and protein that catalyzes recombination (cre) allow us to regulate gene function.
absolute cancer risk
- chance of getting cancer for a large group of animals. GROUP AVERAGE
- CAN'T DETERMINE INDIVIDUAL RISK
- if 13% of a population gets it, absolute risk is 0.13
relative cancer risk
- assesses potential factors/individual characteristics that may be linked to cancer.
- Absolute risk of people WITH the characteristic divided by absolute risk of people WITHOUT the characteristic, otherwise identical.
limitations of relative risk studies
- only apply to those similar to study
- does not always apply to intermediates
- probability--average, not individual