Table 1.

Dysfunctional telomeres (mTerc^−/−) reduce tumor incidence in mouse models of cancer

Genotype/Treatment	Tumor phenotypes	Effect of dysfunctional telomeres (phenotype in mTerc−/− background)	Ref.
No mutations	Few tumors normally seen	Compared to wild-type and early generation telomerase null mice, aging late generation mice show an increase in the incidence of cancer.	32, 42
DMBA/TPA treatment	Treatment with these carcinogens allow for the monitoring tumor initiation (papillomas) and progression to squamous cell carcinomas of the skin.	Loss of telomerase (G1) resulted in decreased growth rate and size of papillomas, with a slight decrease in numbers. G5 mice with dysfunctional telomeres were almost completely resistant to papilloma formation.	50
Ink4a/Arf	Deletion of this locus results in loss of both p16Ink4a and p19ARF. The resulting mice develop lymphomas and sarcomas.	Late generation double knockouts show decreased incidence of spontaneous and carcinogen-induced tumors, and increased tumor latency.	49, 93
APC min	100% of mice with this mutation develop multiple intestinal neoplasias (MIN) that progress from micro- to macro-adenomas.	Short telomeres led to increase in tumor initiation (microadenomas) but decreased size and number of macroscopic adenomas	51
Alb-uPA transgene or CCl4 or DEN treatment	This transgenic mouse and the carcinogenic treatment are both effective ways of modeling hepatocellular carcinoma (HCC)	Successive breeding of Alb-uPA onto a late generation telomerase null background or treatment of G3/G4 mice with CCl4, or DEN resulted in decreased number and size of liver nodules.	53
PMS2	Deficiency of this mismatch repair genes leads to increased susceptibility for lymphomas, sarcomas, and colon carcinomas	Progressively shortening telomeres reduced the incidence of all three tumors types.	94
Eμ-myc	Transgenic expression of c-myc in B-cells leads to potent formation of lymphoma in this model for Burkitt’s lymphoma.	Formation of lymphoma was almost completely suppressed for two years in mice with dysfunctional telomeres (G5/G6), unlike wildtype and G1 mice that rapidly developed cancer within 6 months.	57
ATM	Thymic lymphoma	Delayed onset and decreased incidence of thymic lymphomas	95, 96
P53	Loss of this important tumor suppressor leads to rapid development of mainly lymphomas and soft tissue sarcomas.	Combined homozygous loss of p53 and dysfunctional telomeres led to increased incidence of lymphomas. In addition, late generation mTerc−/− combined with heterozygous loss of p53 showed a shift in tumor spectrum from lymphomas to epithelial cancers (breast, GI, SCC) with non-reciprocal translocations.	47
P53 R172P	This point mutation commonly found in human tumors abolishes the ability of p53 to induce apoptosis and delays tumor formation for about 6 months.	Mice from an intergenerational cross with mTerc−/− animals (iG1) have dysfunctional telomeres and show almost complete suppression of tumorigenesis.	58
ATM, P53	T-cell lymphoma	Loss of p53 accelerated onset of lymphomas in mTerc−/− ATM−/− mice.	97
K5-Terf2	Specific overexpression of TRF2 in the skin of these mice leads to development of spontaneous SCC on the skin.	Increasing generations of telomerase deficient mice showed accelerated onset of spontaneous and UV-induced skin neoplasms.	98

Note: APC^min, adenomatous polyposis coli min (multiple intestinal neoplasias) allele; ATM, ataxia telangiectasia mutated; Terc, telomerase RNA component; PMS2, postmeiotic segregation increased 2;