Cancer Model Organisms Flashcards
(39 cards)
Need animal models b/c
- can’t go from cell culture to human might kill human imediatley
- animal models allow us to do preclinical testing of diagnostic, preventative, and treatment approaches
- allow us to understand gene fx in context of whole organism
- understand dx etiology and pathogenesis by accurate recapitulation in model animal
Classification of animal models
- spontaneous models
- induced dx models
- Negative dx models
- Orphan dx models
spontaneous dx modeles
conditions occur naturally (not too many of these)
induced dx models
conditions are experimentally induced (can induce these with good specificity)
negative dx models
conditions never occur in particular species as compared to other species (some species just won’t get certain caners)
orphan dx models
conditions never occur in humans (like neoplasia on a mouse tail)
Animal models of cancer spontaneous causes
- chemical
- viral
- irradiation-induced
- hormonal
- transpolantaiton-based
- genetic
induced models
have more of these available to us know b/c CRISPR/ cas9
Advantages of modeling caner I mouse
- mouse biology well characterized
- genetic homology btwn mice and other mammals like humans is high
- commonly used for pharmacological, toxicological, carcinogenic testing
- genetic tools well estabilished (genome sequenced, many strains inbred/ knockout/ transgenic mice available)
- short lived species
- fast expansion mouse colony possible
- relavitly inexpesinve
Main approaches for cancer modeling
- Patient derived xenograph
2. Genetically engineered mouse
genetically engineered mouse
put in genetically engineered embryonic stem cells in make tumor bearing genetically engineered mouse can do GEM derived allograph and can transplant tumors to diff types of mice (immunocompetent mice so can test things involving immune response like drug treatment and metastasis)
Patient derived xenograph
- Xenograph models require immunocompromised host**
- isolate cancer cells and inject into immunocompromised mouse or can isolate genes with mutations to put into immuniocompromised mouse
- may inject along with humanized stroma to make microenviorment in mouse more like human microenvionrment (“patient in mouse transplantation model”)
- absence of immune response makes many drugs that work in xenogrpahs fail in clinical trails
- this is good for studying early stages of carcinogenesis and this is well suitable for studies of cancer propagating cells
cancer stem cell targeting
cancer stem cells have ability to propagate and these typically are hardest to kill and if they stay will lead to cancer recurrence; trying to make specific drugs against cancer propagating cells
Guides for validation of animal models of cancer
- Common molecular mechanisms
- Pathology mimics patient cancer
- Neoplastic progression includes metastasis recapitulates patient cancer
- Therapeutic and host immune response resemble pateint
- Involvement of specific organ or cell linage resembles patient
- can be difficult to get all of these in one model system but it is good guidline
Common molecular mechanisms
ideally model of cancer should have similar molecular mechanisms to those that have been studied genomically
Target pathays in molecular circuitry of cancer
p53 and Rb
- both TSGs
- defects in these pathways in over 80% human cancers
- both play critical roles in cell cycle differentiation and apoptosis
- p53 and Rb gene replacement is clinically beneficial
- trying to develop diff drugs to work on the but they were tested on xenograph animal systems so not getting great results
Mouse heterozygous for Rb
they end up with pituitary tumor instead of eye tumor
- great model for studying carcinogenesis bc can make many sections of pitiuatory glands
- loss of reaming WT copy Rb is initiating/ early event in carcinogenesis in these mice
- takes time for enough mutations to form to get tumors (progression tumors from early to late stages requires significant time)
synergistic mutations
need combination of mutations ie synergiestic mutations to -> tumor and in some cases metastasis
(in Rb heterozygous mice synergistic mutations = p27, p21, p53, and Arf)
p53 and Rb heterozygous mice
shorter lived than if just knockout one of the two b/c accelerates cancer formation
adenovirus-mediated Rb gene therapy
arrests tumor growth (make injection of adenovirus expressing Rb gene and inject into tumor and see tumor growth arrest and start to resorb)
importance of Rb heterozygous mouse model
- shows loss of reamingn WT Rb copy is initating/ early event in carcinogenesis in these mice
- indicates other genes cooperate in tumor supression
- suggests Rb gene replacement = clinically beneficial
- shows not all mouse tumors similar to humans (pititiary, thyroid, parathyroid, and adrenal gland tumors instead of retinoblastoma)
Brca1 gene heterozygous mice
die while in humans get breast and ovarian cancer
Why do mice w/ hereditary targeted gene mutations have different dxs than humans
- negative model (diff genetic mechanisms in mice and humans, not v often)
- mice die early from something else and human tumor doesn’t have time to develop; need more selective cell type-specific models
- conventional (transgenic and targeted mutant) mice = hereditary cause for caner while in humans most cancer inducing mutations in somatic cells in adult life; need mouse models with better controlled time of mutagenesis to get sporadic cancers instead of familial in mice (human cancer almost entirely sporadic)
systems for conditional regulation of gene expression
- Cre-LoxP system
- Tamoxifen-mediated regulation
- Tet-mediated gene activation or inactivation
