A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone

Xin Li, Robert Loberg, Jinhui Liao, Chi Ying, Linda A. Snyder, Kenneth J. Pienta, Laurie K. McCauley

Research output: Contribution to journalArticle

Abstract

Monocyte chemoattractant protein 1 (CCL2) is a recently identified prominent regulator of prostate cancer growth and metastasis. The purpose of this study was to investigate the mechanistic role of CCL2 in prostate cancer growth in bone. The present study found that CCL2 was up-regulated in osteoblasts (3-fold by PC-3 and 2-fold by VCaP conditioned medium) and endothelial cells (2-fold by PC-3and VCaP conditioned medium). Parathyroid hormone-related protein (PTHrP) treatment of osteoblastic cells up-regulated CCL2 and was blocked by a PTHrP antagonist, suggesting that prostate cancer-derived PTHrP plays an important role in elevation of osteoblast-derived CCL2. CCL2 indirectly increased blood vessel formation in endothelial cells through vascular endothelial growth factor-A, which was up-regulated 2-fold with administration of CCL2 in prostate cancer cells. In vivo, anti-CCL2 treatment suppressed tumor growth in bone. The decreased tumor burden was associated with decreased bone resorption (serum TRAP5b levels were decreased by 50-60% in anti-CCL2-treated animals from VCaP or PC-3cell osseous lesions) and microvessel density was decreased by 70% in anti-CCL2-treated animals with bone lesions from VCaP cells. These data suggest that a destructive cascade is driven by tumor cell-derived, PTHrP-mediated induction of CCL2, which facilitates tumor growth via enhanced osteoclastic and endothelial cell activity in bone marrow. Taken together, CCL2 mediates the interaction between tumor-derived factors and host-derived chemokines acting in cooperation to promote skeletal metastasis.

Original languageEnglish (US)
Pages (from-to)1685-1692
Number of pages8
JournalCancer Research
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, X., Loberg, R., Liao, J., Ying, C., Snyder, L. A., Pienta, K. J., & McCauley, L. K. (2009). A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Research, 69(4), 1685-1692. https://doi.org/10.1158/0008-5472.CAN-08-2164