1. Mice Carcinogenesis
Misagh Fathi –Medical Nanotechnology MSc student | Dr.khosravani | School of Advanced Technologies in Medicine-TUMS
2. Carcinogens
Substances that increase the risk of NEOPLASMS in humans or
animals. Both genotoxic chemicals, which affect DNA directly, and
non-genotoxic chemicals, which induce neoplasms by other
mechanism, are included.
3. Mice as a laboratory model system
• The mouse was used as a laboratory animal as early as 1664, by
Robert Hooke
• Around 1902, the era of modern mouse genetics began when a Harvard
researcher, William Castle, began studying inheritance in mice
• The laboratory mice used by Castle and Lathrop (generating colonies for mouse
hobbyists and later for researchers)are the ancestors of most of the strains that
are routinely used by researchers
4. Advantages of mice
• Small
• require little food or housing space
• have good-sized litters of offspring
• easy to handle
• can be readily shipped from breeding facilities to research
locations
• similarity of mouse and human genetics (75%)
5. Different methods of carcinogenesis in mice
radiation
• Ionizing
radiation (IR)
chemicals
• Natural
Carcinogens
• Chemical
carcinogens
Genetically
Altered
• Transplantation
Mouse Models
• Genetically
Engineered
Oncogenic
Viruses
• Oncogenic
DNA Viruses
• Oncogenic
RNA Viruses
7. ultraviolet radiation carcinogenesis
• Ultra violet's position on the electromagnetic spectrum is on the boundary
between ionizing and non-ionizing radiation. Exposure to ionizing radiation is
known to increase the future incidence of cancer, particularly leukemia
• UV radiation is a potent DNA damaging agent and a known inducer of skin
cancer in experimental animals
• UVR exposure elicits numerous cellular and molecular events which include
the generation of inflammatory mediators, DNA damage, epigenetic
modifications, and oxidative damages mediated activation of signaling
pathways
8. Chemical carcinogens
• Digestive system cancer in mice, induced by polycyclic aromatic
hydrocarbons, has been studied since the 1940s.
• Some chemical agents may have broad-spectrum effects in mouse
models. For example, cadmium has been shown to induce a range of
cancers in animals
9. Naturally Occurring Carcinogens
MYCOTOXINS
Aflatoxins
-mycotoxins are toxic secondary products resulting from the
metabolism of molds
-most common aflatoxin B1. Much more is known about the
occurrence and toxicity of the aflatoxins than about any
other mycotoxin and, probably, most other natural
contaminants. humans are exposed to aflatoxin mostly from
corn and peanuts
10. HYDRAZINES IN
MUSHROOMS
PLANT
CONSTITUENTS
AND
METABOLITES
-Agaricus bisporus: a commonly eaten cultivated
mushroom in Europe & North America
-Gyromitra esculenta: approximately 500 out of 1 million
people are poisoned resulting from the ingestion of this
mushroom
-Pyrrolizidine alkaloids: are very potent toxins in the liver
and lung and are carcinogenic when administered to rats
orally or parenterally under conditions that permit long-term
survivals
-Allylic and Propenylic Benzene Derivatives:
induced hepatic tumors and subcutaneous angiosarcomas
within 18 months
Naturally Occurring Carcinogens
11. Naturally Occurring Carcinogens
• Cycasin:
one of the most potent carcinogens found in plantsWhen administered orally,
cycasin is highly carcinogenic in the liver, kidney, and colon of rats, and also
induces tumors in other species
• Thiourea:
has been shown to cause thyroid tumors, hepatic adenomas, and epidermoid
when administered to rats as 0.2% of the drinking water or diet for as long as
2 years
• Coumarin:
is present in a number of plants and has induced bile duct carcinomas in rats
fed 0.35% to 0.5% of the compound in the diet for approximately 18 months.
12. Chemical Carcinogens
• Benzidines:
Very toxic industrial chemicals- They are absorbed through the skin, causing
lethal blood, bladder, liver, and kidney damage and are potent, broad-
spectrum carcinogens in most species.
Hydrocarbons, Aromatic- Benzene Derivatives
• Chromium:
A trace element that plays a role in glucose metabolism. chromium and some
of its compounds have been listed as known carcinogens.
Metals, Heavy
• Arsenic:
A shiny gray element , mostly in the form of metallic arsenides and certain
arsenic compounds have been listed as known carcinogens
13. Chemical Carcinogens
• Peroxisome Proliferators:
A class of nongenotoxic CARCINOGENS that induce the production of
hepatic PEROXISOMES and induce hepatic neoplasms after long-term
administration
• Trichloroepoxypropane:
A potent epoxide hydrase and aryl hydrocarbon hydroxylase inhibitor. It
enhances the tumor-initiating ability of certain carcinogens
Epoxy Compounds- Hydrocarbons, Chlorinated
• Nitrosoguanidines:
Nitrosylated derivatives of guanidine. They are used as MUTAGENS in
MOLECULAR BIOLOGY research
14. Chemical Carcinogens
• Dioxins:
A family of compounds that contain the 1,4-dioxin structure. Many specific
dioxin derivatives are listed as CARCINOGENS; TERATOGENS; or
MUTAGENS
• Diethylstilbestrol:
A synthetic nonsteroidal estrogen used in the treatment of menopausal and
postmenopausal disorders. It was also used formerly as a growth promoter in
animals and has been listed as a known carcinogen.
• p-Dimethylaminoazobenzene:
A reagent used mainly to induce experimental liver cancer, this compound
"may reasonably be anticipated to be a carcinogen."
15. Genetically Altered Mice
• Mice are desirable as cancer models because of the discovery in 1981 that the
mouse germline can be changed to accept the delivery and consistent expression of
foreign genes. This followed the demonstration in 1976 that normal cells have
proto-oncogenes that are defective in tumor cells; these defective genes are called
oncogenes, and many have now been associated with the development of human
tumors. The first publications about transgenic cancer models appeared in 1984.
• tumor suppressor gene
• proto-oncogenes
• - homologous recombination in mouse embryonic stem cells, or ES cells, allows
researchers to remove a gene (knock out), or replace it (knock in), or perform a
variety of other alterations of mouse DNA segments that replicate the different types
of genetic aberrations or mutations that the research community has found to be
associated with human tumors.
16. Genetically Engineered Mouse Models in
Cancer Research
• A. Studying Loss of Gene Function in Mouse Models
• 1. MOUSE GENE KNOCKOUTS
“knockout” strategies are used to remove the gene of interest by engineering
constitutive or conditional deletions in the gene. For genes that span large
genomic regions, deletion of the first few exons encoding the start codon is
often sufficient to block transcription or translation into a functional protein
product.
17. Genetically Engineered Mouse Models in
Cancer Research
• 2. MOUSE MODELS OF RNA INTERFERENCE
RNA interference (RNAi) can be used to specifically knock-down the expression of
target genes post-transcriptionally before the mRNA can be translated into protein-
Target sequence-specific small interfering RNAs (siRNAs) are short antisense
peptides 21–28 nucleotides long. The RNA-induced silencing complex (RISC)
recognizes the double-stranded siRNA fragments and cleaves the endogenous
complementary messenger RNA (mRNA) that is then rapidly degraded. Though
siRNA has been widely used to knockdown expression of target genes, it is limited to
transient transfection in vitro.
Short hairpin RNA (shRNA) can be used to cause long-term gene knockdown, both in
vitro and in vivo. The shRNAs are much longer, generally between 50 and 70
nucleotides in length, allowing them to be transcribed as stable messages in vivo.
They are made as a single-strand molecule that then forms a short hairpin tertiary
structure, folding in on itself to form a stem–loop structure in vivo. After transcription
and folding, the enzyme Dicer cleaves off the loop leaving behind a double-stranded
siRNA molecule that can then be recognized by RISC. The shRNA sequences can be
cloned into viral vectors to be stably incorporated into the genome for sustained
knockdown of target genes.
18. B. Studying Gain of Gene Function in Mouse Models
• MOUSE CONSTITUTIVE TRANSGENIC MODELS
• Gain-of-function studies are often used to study oncogenes in mouse models.
Transgenic or knock-in animals constitutively overexpressing an oncogene
can be used to study how the oncogene drives tumorigenesis in vivo
Transgenic animals are created by the pronuclear injection of transgenes
directly into fertilized oocytes, followed by implantation into pseudo-pregnant
females
19. C. Modeling Chromosomal Translocations in Mice
• . TRANSLOCATOR MICE
• Human cancers, such as leukemia, often involve chromosomal translocations
that lead to fusion proteins with new functions that play a role in
tumorigenesis.
20. Transplantation Mouse Models
• 1. Allograft transplantation models
also known as syngeneic models, consist of tumor tissues derived from the same
genetic background as a given mouse strain. Cancerous cells or solid tumors are
transplanted into a host mouse. An advantage of syngeneic models is that the host
immune system is normal, A disadvantage is that the transplanted mouse tissue may
not fully represent the complexity of human tumors in clinical situations
• 2. Xenograft transplantation models (Humanized mice (HM) )
This method involves actual human cancer cells or solid tumors which are
transplanted into a host mouse. The host mice are special, though-they have
impaired immune systems and the foreign cells will not be rejected by the host.
These transplants may be orthotopic, meaning that the tumor is placed in the site it
would be expected to arise naturally in the host Or they may be subcutaneous, or
placed just beneath the host's skin. An advantage of xenografting is that the studies
of the cancerous tissue employ real human cancers. On the other hand, because of
the changes to the host immune system, it may not mimic the situation in actual
patients.
21. Oncogenic Viruses
cancerRNA VirusesCancerDNA Viruses
Adult T-cell leukemia
Lymphoma
Human T-cell leukemia
virus (HTLV-1; HTLV-
2)
Uterine (cervical)
cancer
Papovaviridae
Sarcomas (cancer of
connective tissues)
Sarcoma viruses of
cats, chickens,
rodents
Burkitt's lymphoma
Nasopharyngeal
carcinoma
Herpesviridae
Mammary gland
tumors
Mammary tumor virus
of mice
Liver cancerHepadnavirus
Feline leukemiaFeline leukemia virus
(FeLV)
Adenocarcinomas
(cancer of glandular
epithelial tissues)
Adenoviridae
