Tumors follow stem cells to bone

Researchers have identified a molecular mechanism that may explain why so many cancers spread to patients' bones -- they piggyback on signaling pathways that hematopoietic stem cells use to home to the bone marrow for self-renewal.

Representative histology of femurs with tumor indicated by arrows. (Scale bar equal to 500 micrometers.)
Image: Dunn et al., PLoS ONE 4(9), 2009, e6896.

The mechanism, discovered in prostate cancer cells and published online last week in the Journal of Clinical Investigation, may hold implications for a variety of cancers, including breast, lung and colon, which also tend to metastasize to bone tissue, and may have implications for the development of therapies to thwart cancer spread."This paper represents an important addition to our understanding of the bone metastatic process," linkurl:David Roodman,;http://www.dept-med.pitt.edu/hemaonc/faculty_info.aspx?fp=4993 director of the Center for Bone Biology at the University of Pittsburg Medical Center who was not involved in the study, said in an email. "The research may provide potential new targets for preventing metastasis." Nearly 70 percent of patients with breast or prostate cancers, and approximately 15 to 30 percent of those with lung, colon, stomach, bladder, uterus, rectum, thyroid and kidney carcinomas, develop tumors on their bones. Scientists have previously linked this pattern to blood flow, which can carry cancer cells to the bone marrow, and the close proximity of many primary tumors with underlying bones, but many believed anatomy alone couldn't fully explain why these cancers were so much more likely to spread to the bones than other tissues in the body. Five years ago, researchers discovered how stem cells home to the bone marrow for renewal and dormancy -- a mechanism involving the protein stromal-derived factor-1 (SDF1), and its receptor CXCR4. Upon learning of these findings, bone biologist linkurl:Russell Taichman;http://www.dent.umich.edu/pom/faculty/links/rtbio of the University of Michigan wondered if cancer cells used the same signal. It turns out they do, he told The Scientist.Taichman and his colleagues implanted human prostate cancer cells into mice and tracked the cells, and found that they target the same niche within bone marrow as human hematopoietic stem cells. The cancer cells appear to directly compete with the stem cells for the limited space in the niche, where they become dormant until unknown factors later trigger new tumor growth.The researchers then tested the effects of AMD3100, a compound commonly used to antagonize SDF1, forcing stem cells to leave the bone and enter the blood stream. Sure enough, the team found that AMD3100 does the same to prostate cancer cells -- ejecting them from the bone and dumping them into circulation -- suggesting that like stem cells, prostate tumors use SDF1 to home to the bone marrow. The scientists also observed that mice with prostate cancer have lower expression levels of niche adhesion molecules and transcription factors known to regulate stem cell self-renewal and proliferation in bone marrow. The finding indicates the cancer cells may be able to reduce stem cell numbers in bone marrow by altering their proliferation patterns, providing more niche space for themselves, Taichman said.The results could hold implications for treating cancers that spread to bone, wrote Laura G. Schuettpelz, a pediatrician in St. Louis, Missouri, and Daniel C. Link, a researcher at Washington University in St. Louis, in an accompanying commentary. Because cancer cells are resistant to chemotherapy when they lie dormant in bone marrow, using activating agents, such as AMD3100, to force cancer cells into the blood stream may make them susceptible to the treatment, wrote Schuettpelz and Link. This could help prevent recurrent tumors that appear in bones after the primary tumors have been eradicated by chemotherapy."These are carefully done, technically challenging studies using a variety of innovative approaches to address an important and relevant clinical problem," said Roodman. Correction: This article has been updated from its original version to correctly list the authors of the accompanying commentary in the Journal of Clinical Investigation as Laura G. Schuettpelz and Daniel C. Link. The Scientist regrets the error.Y. Shiozawa, et al., "Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow," linkurl:J Clin Invest,;http://www.jci.org/articles/view/43414/pdf doi:10.1172/JCI43414, 2011.
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[1st February 2011]*linkurl:New metastasis mechanism revealed;http://www.the-scientist.com/blog/display/54521/
[3rd April 2008]*linkurl:Cancer stem cells drive metastasis;http://www.the-scientist.com/news/display/53583/
[12th September 2007]

**__Related F1000 Evaluations:__***linkurl:A novel 3-D mineralized tumor model to study breast cancer bone metastasis;http://f1000.com/2630960?key=rgttfgg415w8bhl
S.P. Pathi, et al., PLoS One, 5(1):e8849, 2010. Evaluated by Dietmar Werner Hutmacher, Queensland University of Technology.*linkurl:Whole-body magnetic resonance imaging for detecting bone metastases: comparison with bone scintigraphy;http://f1000.com/2082972?key=wbptqb4hpm53mm9
G. Cascini et al., Radiol Med, 113:1157-70, 2008. Evaluated by: Emilio Quaia and Maria Cova, University of Trieste.