Tuesday, May 27, 2014

Reactivated Telomerase and Prostate Cancer in Mice

In order to determine the role of telomerase in prostate cancer, researchers used a mouse model that was null for Pten and p53, meaning that these tumor suppressor genes lacked proper function and couldn't produce viable proteins.
Given this predisposition for cancer, the mice were then crossed to have the mTert allele so that telomerase activity could be controlled (turned on and off).  When telomerase was not present, telomeres would shorten and their degradation kept cancer at bay.  However, reactivating telomerase allowed telomeres to indefinitely lengthen and interfere with DNA damage signals within the tumors.  As DNA damage accumulates, genome changes imbue the tumors with novel properties leading to aggressive cancer and metastases. Figure 1 is a pictorial representation of this process.
Figure 1.
The researchers took mice of different genotypes from the crosses and observed their tumor growth.  Figure 2 shows the results from mice of three genotypes: (a) PB-Pten/p53 mice with mTert+/+ or mTert+/−  (functional telomerase), (b) mTert/PB-Pten/p53 (nonfunctional telomerase), and (c) LSL-mTert PB-Pten/p53 (nonfunctional telomerase until sexual maturation).  Figure 2, part A shows an actual photograph of the excised tumors, with genotypes a and c showing noticeably larger tumors than b.  Part B also reinforces this observation by quantifying tumor weight.  Part D indicates that the proportion of mice with locally invasive tumors is twice as high for genotypes a and c than it is for genotype b.   This could be attributed to the high genomic instability of genotype b which confers a dysfunctional telomerase.  Thus, while lack of a normal telomerase does aid in the initial development of cancer, it also hinders the tumor 's growth potential.  Of special interest then is Part F, showing that only genotype c exhibited metastases in the spinal bones, a novel phenotype—this can be understood as indicating the importance of telomerase reactivation in cancer progression.  The take home message is that metastasis appears to only occur when there is a certain degree of stability within the genome, which isn't possible without a normally operating telomerase. 
Figure 2. Telomere Dysfunction and Telomerase Impact Prostate Cancer Progression
(A) Gross anatomy of representative prostates at 24 weeks of age.
(B) Quantification of the prostate tumors of G0 mTert (n = 20), G3/4 mTert−/− (n = 31), and G3/4 LSL-mTert (n = 20) mice. Error bars represent SD.
(C) Representative H&E sections of the prostate tumors from G0 mTert (panel a), G3/4 mTert−/− (panel b), and G3/4 LSL-mTert (panel c) mice at 24 weeks of age.
(D) Quantification of locally invasive prostate tumors of G0 mTert (n = 20), G3/4 mTert−/− (n = 31), and G3/4 LSL-Tert (n = 20) mice at 24 weeks of age.
(E) H&E sections of the prostate tumors of G4 LSL-Tert in spinal bone at 24 weeks of age.
(F) Quantification of prostate tumors with spread lumbar spine in G0 mTert (n = 20), G3/4 mTert−/− (n = 31), and G4 LSL-Tert (n = 20) mice.

On a side note: I am curious as to why the mice used in the experiment had to be predisposed to prostate cancer and could not develop it "spontaneously".  I would think that this would call into question the applicability of any findings or correlations between telomerase and prostate cancer if that type of cancer doesn't naturally occur in mice in the first place.  If mice have some genetic characteristic that is protective against prostate cancer, perhaps this characteristic could also affect the function of telomerase and its relation to cancer progression, limiting the generalizability of the findings from a mouse to human model.

Zhihu Ding, Chang-Jiun Wu, Mariela Jaskelioff, Elena Ivanova, Maria Kost-Alimova, Alexei Protopopov, Gerald C. Chu, Guocan Wang, Xin Lu, Emma S. Labrot, Jian Hu, Wei Wang, Yonghong Xiao, Hailei Zhang, Jianhua Zhang, Jingfang Zhang, Boyi Gan, Samuel R. Perry, Shan Jiang, Liren Li, James W. Horner, Y. Alan Wang, Lynda Chin, Ronald A. DePinho, Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases, Cell, Volume 148, Issue 5, 2 March 2012, Pages 896-907, ISSN 0092-8674, http://dx.doi.org/10.1016/j.cell.2012.01.039.