Therapeutic Potential Of Adult Bone Marrow-derived Mesenchymal Stem Cells In Prostate Cancer Bone Metastasis

Main Category: Stem Cell Research
Also Included In: Cancer / Oncology;  Prostate / Prostate Cancer
Article Date: 28 Jan 2010 - 0:00 PDT

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UroToday.com - In the December 1, 2009 issue of Clinical Cancer Research, Dr. Diptiman Chandra and colleagues from the University of Alabama report on the use of bone marrow-derived mesenchymal stem cells to inhibit prostate cancer (CaP) metastasis in bone.

In bone, binding of receptor activator of nuclear factor κB ligand (RNAKL) to RANK on osteoclasts stimulates their maturation and activity. Osteoprotegerin, a soluble decoy receptor for RANKL inhibits this binding and leads to decreased osteoclast activity and bone metastasis. Systemic delivery of osteoprotegerin is under development as a CaP therapeutic strategy. Adult bone marrow derived mesenchymal stem cells home to metastatic sites, differentiate and express osteoprotegerin. These investigators hypothesized that a deficiency in mesenchymal stem cells in the bone metastatic environment contributes to the ability for osteoclast degradation of bone.

This study compared the ability of naïve mesenchymal stem cells and mesenchymal stem cells that overexpress osteoprotegerin to inhibit prostate cancer PC3 cell bone lysis in a mouse intra-tibial injection model. The PC3 cells expressed the reporter luciferase, which permitted bioluminescence imaging quantification of tumor size. PC3 cells were injected into the tibias of SCID mice. One day later adult bone marrow derived mesenchymal stem cells, either unmodified or overexpressing osteoprotegerin were injected into the tumor sites. Bone histomorphometry and immunohistochemistry assessed tumor and osteoclast activity in the bone tumors.

At 4 weeks post-injection, there was 90% inhibition of tumor growth, with no difference between modified and osteoprotegerin overexpression adult bone marrow derived mesenchymal stem cell effect. Adult bone marrow derived mesenchymal stem cells preserved trabecular and cortical bone structures in these mice. In addition, osteoclast proliferation was inhibited. To test the effectiveness of adult bone marrow derived mesenchymal stem cell inhibition in established tumors, they were injected 2 weeks after PC3 cells and in this case they were not effective in inhibiting tumor growth. Further exploration by performing the experiment at one week indicated that PC3 cells stimulate adult bone marrow derived mesenchymal stem cells to produce new, woven bone that surrounds the tumor. Mechanical strength testing of the bone suggested it similar to normal bone. The adult bone marrow derived mesenchymal stem cells differentiation into an osteoblastic lineage was not due to upregulation of osteogenic genes, but more likely was induced by the enhanced osteoclastogenesis.

Chanda D, Isayeva T, Kumar S, Hensel JA, Sawant A, Ramaswamy G, Siegal GP, Beatty MS, Ponnazhagan S

Clin Cancer Res. 2009 Dec 1;15(23):7175-85.
doi:10.1158/1078-0432.CCR-09-1938

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

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