title: CCL2 is a potent regulator of prostate cancer cell migration and proliferation.
abstract: Tumor cells in the bone interact with the microenvironment to promote tumor cell survival and proliferation, resulting in a lethal phenotype for patients with advanced prostate cancer. Monocyte chemoattractant protein 1 (CCL2) is a member of the CC chemokine family and is known to promote monocyte chemotaxis to sites of inflammation. Here we have shown that human bone marrow endothelial (HBME) cells secrete significantly higher levels of CCL2 compared to human aortic endothelial cells and human dermal microvascular endothelial cells. Furthermore, we demonstrate that CCL2 is a potent chemoattractant of prostate cancer epithelial cells, and that stimulation of PC-3 and VCaP cells resulted in a dose-dependent activation of PI3 kinase/Akt signaling pathway. Activation of the PI3 kinase/Akt pathway was found to be vital to the proliferative effects of CCL2 stimulation of both PC-3 and VCaP cells. Additionally, CCL2 stimulated the phosphorylation of p70-S6 kinase (a downstream target of Akt) and induced actin rearrangement, resulting in a dynamic morphologic change indicative of microspike formation. These data suggest that bone marrow endothelial cells are a major source of CCL2, and that an elevated secretion of CCL2 recruits prostate cancer epithelial cells to the bone microenvironment and regulates their proliferation rate.
authors.affiliation: Department of Urology, University of Michigan Urology Center, Ann Arbor, MI 48109-0946, USA. rloberg@umich.edu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Loberg
authors.forename: LaShon L
authors.initials: LL
authors.lastname: Day
authors.forename: Jason
authors.initials: J
authors.lastname: Harwood
authors.forename: Chi
authors.initials: C
authors.lastname: Ying
authors.forename: Lauren N
authors.initials: LN
authors.lastname: St John
authors.forename: Ryan
authors.initials: R
authors.lastname: Giles
authors.forename: Chris K
authors.initials: CK
authors.lastname: Neeley
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D002633:Chemotaxis; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019869:Phosphatidylinositol 3-Kinases