Table 2.

Benefits and disadvantages of different mouse model types

Type	Models early stage	Late stage	Used for drug response	Immune status	Benefits	Disadvantages
GEMMS
Null	Yes	No	Yes	Normal	Can identify phenotype of single genetic alteration on congenic backgrounds.	Phenotypes may differ between mice and humans.
					Can identify genes involved in tumor initiation and progression.	Tumor genotypes may differ between mice and humans.
					Can assess tumor response to drugs.	Drug response not to human tumor.
					Can identify developmental genes and haploinsufficient phenotypes.	Embryonic lethality may prevent identification of function in adult tissues.
					Technology adapted to knockout by CRISPR-Cas9.	Technology considered expensive and time consuming.
Conditional	Yes	Potentially	Yes	Normal unless by design	Bypasses embryonic lethality phenotype.	Optimally, Cre recombinase should be expressed solely in the desired tissue; promoters driving Cre recombinase in the colon almost all have some extraintestinal activity.
					Can relocate Apc-initiated tumor from small intestine to colon.
Laparotomy	Yes	No	Yes	Altered inflammation	Can relocate Apc-initiated tumor from small intestine to colon.	Procedure creates atopic inflammation.
Metastatic	Yes	Yes	Yes	Altered through TGF-β	Can reproduce metastasis by changing immune response (APC, KRAS, TP53, TGFBR2).	No model gives both liver and lung metastasis routinely.
TRANSGENIC
Random	No	No	No	Normal	Can observe phenotype when gene is overexpressed.	Random insertion affects genes other than gene of interest.
Site specific	No	Potentially	No	Normal	RNA guide can eliminate random insertion.
CHEMICAL INDUCTION	Yes	No	Yes	Altered inflammation	Tumor progression from adenoma to adenocarcinoma similar with human histology.	Tumors rarely proceed to metastasis.
					Tumors have high KRAS/CTNNB1 and low APC/TP53 mutation frequency.	Human tumors have high APC/TP53 and lower KRAS mutation frequency.
					AOS/DSS good model for inflammatory bowel disease.	Not applicable for the study of the normal immune response, requires chemical injury to colon.
					Technically simple, inexpensive.	Low tumor burden, tumors take a long time to develop.
PERITONEUM	No	Potentially	Yes	Normal	Technically simple.	Dependent on syngeneic, xenografted, or transgenic mice to model.
						Spontaneous GEMMs models do not yet exist
SYNGENEIC	Yes	No	Yes	Normal	No tumor rejection.	Cannot use human tumor material.
						Cell lines often used for grafts are not an original tumor genotype.
XENOGRAFT
Subcutaneous	No	No	Yes	Altered deficient	Tests human cancer directly.	Immuno-deficient.
					Technically simple, rapid tumor formation.	Tumors are not present in the correct microenvironment.
					Can assess tumor response to drugs.	Not always easy to identify antitumoral drug response.
						Mouse stroma replaces human.
						No insight into tumor initiation events.
						Mostly non-metastatic, rarely models late-stage disease.
Orthotopic	No	Potentially	Yes	Altered deficient	Tests human cancer directly.	Immuno-deficient.
					Histology similar.	Mouse stroma replaces human.
					Potential to generate liver metastasis.	Tumor burden is lower than subcutaneous xenografts.
					Genetically engineered mice are not necessary.	No insight into tumor initiation events.
					Can assess tumor response to drugs.	Not always easy to identify antitumoral drug response.
ORGANOID
Subcutaneous	No	No	Yes	Altered deficient	Technically simple, rapid tumor formation.	Tumors are not present in the correct microenvironment.
						Immuno-deficient.
						No insight into tumor initiation events.
						Mostly non-metastatic, rarely models late-stage disease.
Orthotopic Transplantation and in situ gene editing	Yes	Yes	Yes	Potentially altered deficient	Mouse and human organoids are both transplantable into the colon.	Requires colonoscopy system and special equipment.
					Can obtain metastasis.	If using human tissue for transplantation, mice must be immuno-deficient.
					It is not necessary to generate genetically engineered mice.
Use of CRISPR-Cas9					Can get tumor formation in selected sites in distal colon.
					Tumors monitored with colonoscopy.