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Flashcards in Misc Deck (7)
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1

Criteria for genetically engineered mouse models of human cancers:

(1) mice must carry the same mutation that occurs in human tumors;
(2) mutations should be engineered within the endogenous locus, and not expressed as a transgene;
(3) mutated genes should be silent during embryogenesis and early postnatal development,
except for in models of inherited pediatric tumors; (4) mutations should be within the specific target tissues in selected cell types; and
(5) mutations must occur in a limited number of cells

2

Advantages of human tumor xenograft models in examining responses to drugs:

(1) one can use the actual human tumor tissue, featuring the complexity of genetic and epigenetic abnormalities that exist in the human tumor
population;
(2) human tumor xenografts can be used to aid in the development of individualized molecular therapeutic approaches;
(3) results can be obtained in a matter of a few weeks from a human tumor biopsy regarding response to therapy, whereas the GEM models often require as long as a year to develop prior to drug therapy;
(4) multiple therapies can be tested from a single tumor biopsy;
(5) data from tissue microarrays and genetic microarrays can be readily obtained from the human biopsy and xenograft tissue, before and after drug therapy, for extensive analysis before the patient is subjected to therapy that may not work;
(6) orthotopic xenografts can be appropriately placed to reproduce the organ environment in which the tumor grows, so that the effect of the
tumor on its microenvironment can be modulated, albeit with the exception of certain T-cell populations;
(7) stroma from the human tumor microenvironment can be included in the xenograft to more completely mimic the human tumor microenvironment; and
(8) xenografts using NOD/SCID mice that have been ‘humanized’ by injection of peripheral blood or bone marrow cells, allow for an almost complete reconstitution of the immune response to the tumor.

3

Disadvantages to using mouse xenograft models:

models are time consuming, expensive and technically challenging. In addition, if athymic nude or SCID mice are used, the lymphocyte-mediated response to the tumor is lost, i.e. nude mice lose certain T-cell responses and SCID mice lose both their Tand B-cell responses. However, these immunological deficits can, in principle, be largely
overcome by grafting human tumors onto ‘humanized’ NOD/SCID mice.

4

Advantages of GEM

(1) the mice are immunocompetent, such that
the tumor microenvironment can be mirrored as much as possible in a murine tumor
model; (2) specific genetic abnormalities that are present in human tumors can be
reproduced, in an inducible manner, at specific ages in the tissue-type of origin; (3) the
stages of tumor progression can be studied over time; and (4) several therapeutic
approaches can be explored at various stages of tumor development. Genetic models
are also useful in humanized mice, where human genes, such as the cytochrome P450
genes or human tumor antigens, are expressed in mice to follow drug metabolism or
immunological responses to the tumor

5

Disadvantages of GEM

first, that the complexity of the human tumor cannot be reliably mimicked and, second, mouse tumors are not human tumors and do not often predict what will happen in the human tumor with regard to therapeutic response

6

BBB is absent in these areas of the CNS:

- subfornical organ
- organ vasculosum, lamina terminalis
- median eminence
- posterior pituitary
- pineal gland
- area postrema

7

The extracellular matrix consists of

1. structural proteins (collagen, elastin)
2. specialized proteins (fibronectin, laminin)
3. proteoglycans