A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone

被引：132

作者：

Li, Xin ^{[1
]}

Loberg, Robert ^{[4
]}

Liao, Jinhui ^{[1
]}

Ying, Chi ^{[4
]}

Snyder, Linda A. ^{[5
]}

Pienta, Kenneth J. ^{[2
,4
]}

McCauley, Laurie K. ^{[1
,3
]}

机构：

[1] Univ Michigan, Dept Periodont & Oral Med, Sch Dent, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pathol, Sch Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Urol, Urol Ctr, Ann Arbor, MI 48109 USA

[5] Centocor R&D, Ortho Biotech Oncol Res & Dev, Radnor, PA USA

来源：

CANCER RESEARCH | 2009年 / 69卷 / 04期

关键词：

MONOCYTE CHEMOATTRACTANT PROTEIN-1; HORMONE-RELATED PROTEIN; PARATHYROID-HORMONE; MACROPHAGE INFILTRATION; ENDOTHELIAL-CELLS; SKELETAL METASTASIS; TUMOR VASCULARITY; IN-VIVO; EXPRESSION; MCP-1;

D O I：

10.1158/0008-5472.CAN-08-2164

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-3 and 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 endothetial 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 TPAP5b levels were decreased by 50-60% in anti-CCL2-treated animals from VCaP or PC-3 cell 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. [Cancer Res 2009;69(4):1685-92]

引用

页码：1685 / 1692

页数：8

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