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Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone

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Abstract

Prostate cancer (PCa) frequently metastasizes to bone resulting in a mixture of osteolytic and osteoblastic lesions. We have previously reported that monocyte chemotactic protein-1 (MCP-1) is chemotactic for PCa cells, and its receptor, CCR2 expression, correlates with pathological stages. However, the role of MCP-1/CCR2 axis on PCa progression in bone remains unclear. We first evaluated the serum levels of MCP-1 in patients with bone metastases or localized PCa by enzyme-linked immunosorbent assay. We found that MCP-1 levels were elevated in patients with bone metastases compared to localized PCa. We further determined the effects of knockdown CCR2 or MCP-1 on PCa cell invasion and the tumor cell-induced osteoclast activity in vitro, respectively. PCa C4-2B and PC3 cells were transfected stably with either CCR2 short hairpin RNA (shRNA) or a scrambled RNA. CCR2 knockdown significantly diminished the MCP-1-induced PCa cell invasion. In addition, the MCP-1 production was knocked down by MCP-1 shRNA in C4-2B and PC3 cells. Conditioned media (CM) was collected and determined for the CM-induced osteoclast formation in vitro. MCP-1 knockdown significantly decreased the PCa CM-induced osteoclast formation. Finally, MCP-1 knockdown PC3 cells were implanted into the tibia of SCID mice for 4 weeks. Tumor volume was determined by histopathology and bone histomorphometry. MCP-1 knockdown diminished PC3 tumor growth in bone. We concluded that activation of MCP-1/CCR2 axis promotes PCa growth in bone. This study suggests that MCP-1 may be a target for PCa progression.

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Abbreviations

CM:

Conditioned media

ECL:

Enhanced chemiluminescence

ELISA:

Enzyme-linked immunosorbent assay

H&E:

Hematoxylin and eosin

IL-8:

Interleukin-8

MCP-1:

Monocyte chemotactic protein-1

M-CSF:

Macrophage colony-stimulating factor

PCa:

Prostate cancer

PVDF:

Polyvinylidine fluoride

RANKL:

Receptor activator of nuclear factor kappa B ligand

RT-PCR:

Reverse transcriptase-polymerase chain reaction

SCID:

Severe combined immunodeficiency

shRNA:

Short hairpin RNA

TRAP:

Tartrate-resistant acid phosphatase

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Acknowledgments

The authors thank Dr. G. David Roodman for his helpful discussion, Dr. Zhong Cai for his technical help, and Mrs. Donna Gaspich for her editing. This study was supported by Department of Defense PC061231 and University of Pittsburgh Cancer Institute CCSG (J. Zhang).

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Correspondence to Yi Lu or Jian Zhang.

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Lu, Y., Chen, Q., Corey, E. et al. Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone. Clin Exp Metastasis 26, 161–169 (2009). https://doi.org/10.1007/s10585-008-9226-7

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  • DOI: https://doi.org/10.1007/s10585-008-9226-7

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