title: Localization of osteoblast inflammatory cytokines MCP-1 and VEGF to the matrix of the trabecula of the femur, a target area for metastatic breast cancer cell colonization.
abstract: Bone likely provides a hospitable environment for cancer cells as suggested by their preferential localization to the skeleton. Previous work has shown that osteoblast-derived cytokines increased in the presence of metastatic breast cancer cells. Thus, we hypothesized that osteoblast-derived cytokines, in particular IL-6, MCP-1, and VEGF, would be localized to the bone metaphyses, an area to which breast cancer cells preferentially traffic. Human metastatic MDA-MB-231 breast cancer cells were inoculated into the left ventricle of the heart of athymic mice. Three to four weeks later, tumor localization within isolated femurs was examined using muCT and MRI. In addition, IL-6, MCP-1, and VEGF localization were assayed via immunohistochemistry. We found that MDA-MB-231 cells colonized trabecular bone, the area in which murine MCP-1 and VEGF were visualized in the bone matrix. In contrast, IL-6 was expressed by murine cells throughout the bone marrow. MDA-MB-231 cells produced VEGF, whose expression was not only associated with the breast cancer cells, but also increased with tumor growth. This is the first study to localize MCP-1, VEGF, and IL-6 in bone compartments via immunohistochemistry. These data suggest that metastatic cancer cells may co-opt bone cells into creating a niche facilitating cancer cell colonization.
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Bussard
authors.forename: Noriaki
authors.initials: N
authors.lastname: Okita
authors.forename: Neil
authors.initials: N
authors.lastname: Sharkey
authors.forename: Thomas
authors.initials: T
authors.lastname: Neuberger
authors.forename: Andrew
authors.initials: A
authors.lastname: Webb
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Mastro
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000378:metabolism*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A
references.citation: J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):169-80
references.pmid: 16025223
references.citation: J Clin Invest. 1992 Jan;89(1):46-52
references.pmid: 1729280
references.citation: Clin Orthop Relat Res. 2003 Oct;(415 Suppl):S32-8
references.pmid: 14600590
references.citation: Nature. 1996 Apr 4;380(6573):439-42
references.pmid: 8602242
references.citation: Front Biosci. 1999 Jul 01;4:D571-80
references.pmid: 10393126
references.citation: Cancer Metastasis Rev. 1989 Aug;8(2):98-101
references.pmid: 2673568
references.citation: Cancer Res. 2001 Jun 1;61(11):4418-24
references.pmid: 11389070
references.citation: Cancer. 2000 Jun 15;88(12 Suppl):2892-8
references.pmid: 10898330
references.citation: Am J Pathol. 2004 Apr;164(4):1399-406
references.pmid: 15039227
references.citation: Clin Cancer Res. 2006 Mar 1;12(5):1431-40
references.pmid: 16533765
references.citation: Am J Pathol. 2008 Mar;172(3):809-17
references.pmid: 18276787
references.citation: Breast Cancer Res Treat. 2000 Feb;59(3):271-8
references.pmid: 10832597
references.citation: Int J Cancer. 1999 Aug 27;82(5):765-70
references.pmid: 10417778
references.citation: Endocr Relat Cancer. 2006 Sep;13(3):905-19
references.pmid: 16954439
references.citation: Bone. 2003 Jul;33(1):28-37
references.pmid: 12919697
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19069-74
references.pmid: 17148604
references.citation: Clin Exp Metastasis. 2004;21(5):427-35
references.pmid: 15672867
references.citation: Cancer Metastasis Rev. 2006 Dec;25(4):521-9
references.pmid: 17186383
references.citation: J Cell Biochem. 2004 Feb 1;91(2):265-76
references.pmid: 14743387
references.citation: Annu Rev Immunol. 2005;23:1-21
references.pmid: 15771564
references.citation: Endocrinology. 1991 May;128(5):2657-9
references.pmid: 2019273
references.citation: Exp Cell Res. 2008 Jan 1;314(1):173-83
references.pmid: 17976581
references.citation: Clin Cancer Res. 2000 Aug;6(8):3282-9
references.pmid: 10955814
references.citation: Biochem Biophys Res Commun. 2004 Apr 2;316(2):573-9
references.pmid: 15020256
references.citation: Clin Breast Cancer. 2005 Feb;5 Suppl(2):S46-53
references.pmid: 15807924
references.citation: Bone. 2005 Oct;37(4):504-12
references.pmid: 16027056
references.citation: Cancer Res. 2001 Jan 1;61(1):383-91
references.pmid: 11196191
references.citation: Biotechniques. 2002 Dec;33(6):1197-200
references.pmid: 12503297
references.citation: Cancer Res. 2000 Jun 1;60(11):2898-905
references.pmid: 10850435
references.citation: Genes Dev. 2008 Mar 1;22(5):559-74
references.pmid: 18316475
references.citation: J Immunol. 1990 Jun 1;144(11):4226-30
references.pmid: 2341718
references.citation: J Bone Miner Res. 2001 Aug;16(8):1486-95
references.pmid: 11499871
references.citation: Nat Rev Cancer. 2002 Aug;2(8):584-93
references.pmid: 12154351
references.citation: Cancer Metastasis Rev. 2008 Mar;27(1):41-55
references.pmid: 18071636
references.citation: Bone. 1994 Mar-Apr;15(2):161-6
references.pmid: 8086233
references.citation: In Vitro. 1978 Nov;14(11):911-5
references.pmid: 730202