By Rihard Raza | February 21, 2012
ScienceDaily (Feb. 20, 2012) ? Genomic instability brought on by an erosion of the protective caps on chromosomes, followed by activation of an enzyme that reinforces those caps, enables malignant cells to evade destruction and acquire much more deadly characteristics, researchers report in an On the web Now write-up at the journal Cell.
In a strain of mice engineered to develop prostate cancer, all mice that went by means of this two-step method developed lethal cancer and 25 percent had the disease spread to the spine. Two groups of mice that avoided this cycle developed only precancerous lesions or localized prostate cancer.
A comparative evaluation of genetic modifications in the metastatic mouse tumors and those identified in metastatic human prostate cancer identified the Smad4 gene as a driver in bone metastasis. Fourteen other genes had been found to be related with human prostate cancer prognosis.
The study focused on telomeres ? repeat nucleotide sequences at the guidelines of chromosomes that stop genomic damage during cell division. Telomeres shorten with every single cell division, sooner or later permitting genomic instability in the cells that normally causes these abnormal cells to die.
In cancer the enzyme telomerase becomes activated and lengthens telomeres, preserving damaged cells to survive and reproduce. Telomerase is inactive in standard cells.
Telomerase activation confers new strengths on tumors
?These in vivo mouse scientific studies, together with human and mouse prostate cancer genomic information, supply evidence that telomere dysfunction plays a essential function in prostate cancer initiation and progression,? mentioned co-senior author Lynda Chin, M.D., professor and chair of The University of Texas MD Anderson Cancer Center?s Department of Genomic Medicine.
?Our research also show that telomerase activation right after genomic instability triggered by telomere dysfunction enables evolving cancers to progress and acquire new biological properties, including central features of advanced human prostate cancer,? Chin mentioned.
Chin, co-senior author and MD Anderson President Ronald DePinho, M.D., and colleagues conducted this research although at Dana-Farber Cancer Institute in Boston.
Telomere dysfunction, fired-up telomerase, result in bone metastasis
The team took a strain of mice with both the p53 and pten tumor-suppressing genes knocked out that normally develop nonmetastatic prostate cancer and engineered some to express telomerase. They had been cross-bred for several generations.
- Control mice with intact telomeres (either wild-kind mice or those with telomerase expressed) avoided the genomic instability triggered by telomere shortening. All of these mice created locally invasive, nonmetastatic prostate cancer.
- Mice with out telomerase were subject to telomere dysfunction and genetic modifications and created precancerous high-grade prostate intraepithelial neoplasia (HPIN) but 60 percent of them did not progress to prostate cancer. Signs of programmed cell death triggered by genetic abnormalities abounded in this group.
- Mice topic to telomere dysfunction, genomic instability and telomerase activation also developed HPIN but then progressed to lethal bulky tumors, with 5 of 20 producing spinal metastases that were not noticed in the genome-stable mice.
?Not only did telomerase reactivation bypass the cancer progression block that arises with telomere dysfunction, it also conferred a new property ? bone metastasis ? that was not observed in tumors that did not go via telomere dysfunction followed by telomerase reactivation,? mentioned first author Zhihu Ding, Ph.D., formerly of Dana-Farber and now with Sanofi-Aventis, Inc.
?This provides the first genetic evidence that telomerase reactivation and genome stabilization are required to drive complete malignant progression in epithelial cancers,? Ding said.
Aligning genetic alterations in mice and humans
Chin, Ding and colleagues analyzed gene copy quantity aberrations ? genes deleted or amplified ? in 18 advanced tumors from the mice and 194 human prostate tumors.
They identified 22 of the 94 copy quantity alterations involving deletion or amplification of 741 genes identified in mice were comparable to those discovered in humans. A series of analyses of alterations located in bone metastases pointed to deletions of the Smad4 tumor-suppressor gene, which regulates the transforming growth aspect beta (TGF-?) pathway.
The team took this finding back to the mouse model with tumor suppressors p53 and pten knocked out. These mice don?t create bone metastasis, but when the researchers also knocked out Smad4, far more aggressive tumors created, which includes bone metastasis in 3 of 24 mice.
Genes prognostic for human prostate cancer
Subsequent, they looked at 14 genes in nine molecular pathways located to be enriched in bone metastasis to see if they had been prognostic for recurrence (as measured by PSA levels right after surgery) among 140 prostate cancer patients.
The 14-gene set was significantly prognostic of biochemical recurrence, providing evidence of their biological relevance to human prostate cancer, but the researchers noted that their individual contributions and mechanisms of action will require additional analysis.
?General, our findings validate the integrative approach of employing genotype-phenotype correlations identified in the mouse model with the power of genomic and bioinformatic analyses to discover and explain molecular mechanisms that drive prostate cancer,? mentioned co-very first author Chang-Jiun Wu, Ph.D., a postdoctoral fellow in MD Anderson?s Department of Genomic Medicine.
This study was funded by grants from the National Cancer Institute, the Prostate Cancer Foundation, the U.S. Department of Defense, the Damon Runyon Cancer Research Foundation, the Several Myeloma Study Foundation, an American Cancer Society and the Robert A. and Renee E. Belfer Foundation.
Recommend this story on Facebook, Twitter,
and Google +1:
Other bookmarking and sharing tools:
Story Source:
The above story is reprinted from supplies supplied by University of Texas M. D. Anderson Cancer Center, through Newswise.
Note: Supplies may be edited for content material and length. For further information, please contact the source cited above.
Journal Reference:
- 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, 2012 DOI: 10.1016/j.cell.2012.01.039
Note: If no author is given, the source is cited rather.
Disclaimer: This article is not intended to give medical advice, diagnosis or treatment. Views expressed right here do not necessarily reflect those of ScienceDaily or its staff.
ScienceDaily: Newest Science News
Topics: Science News | No Comments ?
Comments
? 300-million-year-old forest discovered preserved in volanic ash | Home | Blocking telomerase kills cancer cells but provokes resistance, progression ?
iphone update iphone update blackberry outage blackberry outage seal beach ca seal beach seal beach
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.