Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment

Younghun Jung, Yusuke Shiozawa, Jingcheng Wang, Natalie Mcgregor, Jinlu Dai, Serk In Park, Janice E. Berry, Aaron M. Havens, Jeena Joseph, Jin Koo Kim, Lalit Patel, Peter Carmeliet, Stephanie Daignault, Evan T. Keller, Laurie K. Mccauley, Kenneth J. Pienta, Russell S. Taichman

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Bone is the preferred metastasis site of advanced prostate cancer (PCa). Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb. We therefore speculated whether the environment of the forelimb bones is not permissive for the growth of PCa. Consequently, data on tumor prevalence were normalized to account for the number of PCa cells arriving after intra- vascular injection, marrow cellularity, and number of hematopoietic stem cell niches. None of these factors were able to account for the observed differences in tumor prevalence. An analysis of differential gene and protein levels iden- tified that growth arrest specific-6 (GAS6) levels were significantly greater in the forelimb versus hindlimb bone mar- row. When murine RM1 cells were implanted into subcutaneous spaces in immune competent animals, tumor growth in the GAS6-/- animals was greater than in GAS6+/+ wild-type animals. In an osseous environment, the human PC3 cell line grew significantly better in vertebral body transplants (vossicles) derived from GAS6-/- animals than in vossicles derived from GAS6+/+ animals. Together, these data suggest that the differences in tumor preva- lence after intravascular inoculation are a useful model to study the molecular basis of tumor dormancy. Importantly, these data suggest that therapeutic manipulation of GAS6 levels may prove useful as a therapy for metastatic disease.

Original languageEnglish
Pages (from-to)429-439
Number of pages11
JournalNeoplasia (United States)
Volume14
Issue number5
DOIs
Publication statusPublished - 2012 May
Externally publishedYes

Bibliographical note

Funding Information:
Address all correspondence to: Russell S. Taichman, DMD, DMSc, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 N University Ave, Ann Arbor, MI 48109-1078. E-mail: rtaich@umich.edu 1This work is directly supported by the National Cancer Institute (CA163124, CA093900, L.K.M., E.T.K., K.J.P., and R.S.T.), the Fund for Cancer Research (R.T.), the Department of Defense (L.K.M., E.T.K., K.J.P., Y.S., S.I.P., and R.S.T.), and the Prostate Cancer Foundation (K.J.P. and R.S.T.). K.J.P. receives support as an American Cancer Society Clinical Research Professor, National Institutes of Health SPORE in prostate cancer grant P50 CA69568, and the Cancer Center support grant P30 CA46592. 2These authors contributed equally as first authors. 3These authors contributed equally as senior authors. Received 12 December 2011; Revised 27 February 2012; Accepted 5 April 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1596/neo.111740

ASJC Scopus subject areas

  • Cancer Research

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