Mitochondrial DNA Mutation Enables Growth Of Prostate Cancer In Bone By Activating Specific Signaling Pathways

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Genetics;  Clinical Trials / Drug Trials
Article Date: 09 Jun 2008 - 2:00 PDT

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ORLANDO, FL (UroToday.com) - While many tumors (including prostate cancer) have been found to harbor mitochondrial DNA (mtDNA) mutations, little is known about their functionality according to a group of researchers from Atlanta, Seattle and Charlottesville. Specifically, there have been few analyses of whether the introduction of mtDNA mutations in prostate cancer increases the cancer's ability to grow and metastasize. The study sought to introduce a well defined mtDNA mutation into human prostate cancer cells and study the growth of these cells in the bone microenvironment. A further objective was to determine the molecular mechanisms of any observed growth enhancement by studying alterations of gene and protein expression.

To do this work, cytoplasmic hybrids (cybrids) that contain human prostate cancer with well defined mtDNA mutation (T8993G) were created along with their wild type (T8993T) controls. These pairs of cells were then grown as xenografts in nude mice with bone stromal cells or as intratibial injections to simulate bone metastasis. Resultant tumors were assayed for gene expression using high throughput chip technology and results confirmed by both RT-PCR and immunohistochemistry.

They found that the T8993G missense mtDNA mutation substantially increased tumor growth in the bone environment. There was a unique and reproducible pattern of gene expression that was induced only when both the mtDNA mutation was present and cells were in the bone microenvironment. Especially prominent were changes in the expression of FGF-1 and focal adhesion kinase (FAK), both of which are known mediators of human prostate malignancy. These alterations were observed in chip, RT-PCR and IHC analyses.

They conclude that mtDNA mutation, so commonly observed in prostate cancers, can enhance the growth of cancer in the bone microenvironment. This effect may be mediated by alterations in the FGF-1 signaling pathway and the overexpression of FAK. These data support the concept that mtDNA mutations enhance the growth and survival of prostate cancer bone metastasis.

Presented by Rebecca S Arnold, MD, Carrie Qi Sun, MD, Jendai Richards, MD, Ilse Coleman, MD, Peter Nelson, MD, Harsha Ramaraju, MD, Leland W K Chung, MD, Jae Lee, MD, Fray F Marshall, MD, John A Petros, MD at the Annual Meeting of the American Urological Association (AUA) - May 17 - 22, 2008. Orange County Convention Center - Orlando, Florida, USA.

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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