title: In vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model.
abstract: Bone metastasis, the leading cause of breast cancer-related deaths, is characterized by bone degradation due to increased osteoclastic activity. In contrast, mechanical stimulation in healthy individuals upregulates osteoblastic activity, leading to new bone formation. However, the effect of mechanical loading on the development and progression of metastatic breast cancer in bone remains unclear. Here, we developed a new in vivo model to investigate the role of skeletal mechanical stimuli on the development and osteolytic capability of secondary breast tumors. Specifically, we applied compressive loading to the tibia following intratibial injection of metastatic breast cancer cells (MDA-MB231) into the proximal compartment of female immunocompromised (SCID) mice. In the absence of loading, tibiae developed histologically-detectable tumors with associated osteolysis and excessive degradation of the proximal bone tissue. In contrast, mechanical loading dramatically reduced osteolysis and tumor formation and increased tibial cancellous mass due to trabecular thickening. These loading effects were similar to the baseline response we observed in non-injected SCID mice. In vitro mechanical loading of MDA-MB231 in a pathologically relevant 3D culture model suggested that the observed effects were not due to loading-induced tumor cell death, but rather mediated via decreased expression of genes interfering with bone homeostasis. Collectively, our results suggest that mechanical loading inhibits the growth and osteolytic capability of secondary breast tumors after their homing to the bone, which may inform future treatment of breast cancer patients with advanced disease.
authors: Biomedical Engineering, Cornell University, Ithaca, NY, USA.
authors: Maureen E
authors: ME
authors: Lynch
authors: Daniel
authors: D
authors: Brooks
authors: Sunish
authors: S
authors: Mohanan
authors: Min Joon
authors: MJ
authors: Lee
authors: Praveen
authors: P
authors: Polamraju
authors: Kelsey
authors: K
authors: Dent
authors: Lawrence J
authors: LJ
authors: Bonassar
authors: Marjolein C H
authors: MC
authors: van der Meulen
authors: Claudia
authors: C
authors: Fischbach
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000556:secondary; D001862:Bone Resorption / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D001943:Breast Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D013977:Tibia / Q000473:pathology / Q000503:physiopathology*; D054457:Tissue Scaffolds / Q000737:chemistry; D016474:Weight-Bearing; D055114:X-Ray Microtomography
keywords: BREAST CANCER; MECHANICAL LOADING; METASTASIS; OSTEOLYSIS
references: Lancet. 2000 May 6;355(9215):1607-11
references: 10821365
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Bone. 2005 Jun;36(6):1030-8
references: 15878316
references: J Bone Miner Res. 1995 May;10(5):683-9
references: 7639102
references: Cancer Metastasis Rev. 2008 Mar;27(1):41-55
references: 18071636
references: J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):169-80
references: 16025223
references: Bone. 2007 Feb;40(2):471-8
references: 17092788
references: Nat Med. 2007 Jan;13(1):62-9
references: 17159986
references: Cancer Res. 2008 Oct 1;68(19):7795-802
references: 18829534
references: Med Sci Sports Exerc. 2001 May;33(5):718-23
references: 11323538
references: Rheum Dis Clin North Am. 2006 Nov;32(4):759-73
references: 17288976
references: Cancer Res. 1993 Oct 15;53(20):4890-5
references: 8402677
references: J Biomech. 2010 Oct 19;43(14):2689-94
references: 20673665
references: J Cancer Surviv. 2012 Jun;6(2):189-99
references: 22193780
references: Metabolism. 1970 Dec;19(12):1071-84
references: 4321644
references: Bone. 2005 Dec;37(6):810-8
references: 16198164
references: J Bone Miner Res. 1998 Nov;13(11):1760-7
references: 9797486
references: Oncol Nurs Forum. 2007 May;34(3):627-33
references: 17573321
references: J Bone Miner Res. 2011 Jan;26(1):100-12
references: 20658561
references: Osteoporos Int. 2005 Feb;16(2):191-7
references: 15221206
references: PLoS One. 2010 Jun 17;5(6):e11178
references: 20567514
references: Bone. 2009 May;44(5):822-9
references: 19442630
references: J Biol Chem. 2007 Sep 14;282(37):27298-27305
references: 17623658
references: J Orthop Res. 1996 May;14(3):396-402
references: 8676252
references: Cancer Res. 2002 Oct 1;62(19):5571-9
references: 12359770
references: J Musculoskelet Neuronal Interact. 2002 Dec;2(6):570-2
references: 15758398
references: Nat Protoc. 2008;3(6):1101-8
references: 18546601
references: Bone. 2007 Apr;40(4):1032-40
references: 17251073
references: Nat Methods. 2007 Oct;4(10):855-60
references: 17767164
references: Bone. 2011 Jul;49(1):133-9
references: 21497678
references: PLoS One. 2010 Jan 22;5(1):e8849
references: 20107512
references: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1454-9
references: 15665096
references: J Appl Physiol (1985). 2010 Sep;109(3):685-91
references: 20576844
references: Calcif Tissue Int. 1984;36 Suppl 1:S56-61
references: 6430523
references: Cancer Res. 2004 Jul 1;64(13):4506-13
references: 15231660
references: J Appl Physiol (1985). 2005 Jul;99(1):181-8
references: 15746294
references: Cancer Treat Rev. 2001 Jun;27(3):165-76
references: 11417967
references: Bone. 1998 Oct;23(4):313-8
references: 9763142
references: Lancet. 2001 Feb 17;357(9255):539-45
references: 11229684
references: J Bone Miner Res. 2008 May;23(5):663-71
references: 18433300
references: Bone. 1998 May;22(5):463-9
references: 9600779
references: Endocrinology. 1999 Oct;140(10):4451-8
references: 10499498
references: Osteoarthritis Cartilage. 2009 Apr;17(4):473-81
references: 18974013
references: Cancer Res. 2005 Jul 15;65(14):6130-8
references: 16024614
references: Am J Physiol. 1996 Mar;270(3 Pt 1):E419-23
references: 8638687
references: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E674-80
references: 21876139
references: J Biomech. 2011 Feb 3;44(3):509-16
references: 20888562
references: Biomaterials. 2011 Aug;32(22):5112-22
references: 21507478
references: J Transl Med. 2012 Jul 02;10:138
references: 22747748
references: J Surg Res. 2001 Sep;100(1):18-24
references: 11516200
references: Arthritis Rheum. 1990 Jan;33(1):66-72
references: 2302269
references: Bone. 2006 Mar;38(3):359-67
references: 16278105
references: Int J Cancer. 2008 Sep 1;123(5):1034-42
references: 18546262
references: Nat Rev Cancer. 2002 Aug;2(8):584-93
references: 12154351
references: Nat Rev Cancer. 2011 Jun;11(6):411-25
references: 21593787
references: J Bone Miner Res. 1997 Aug;12(8):1253-61
references: 9258756
references: Henry Ford Hosp Med J. 1983;31(1):3-9
references: 6345475
references: Breast Cancer Res. 2011 Oct 27;13(5):R106
references: 22032690
references: J Clin Invest. 2005 Jan;115(1):44-55
references: 15630443
references: J Bone Miner Res. 2000 Oct;15(10):1924-34
references: 11028444
references: J Bone Miner Res. 2001 Jan;16(1):175-81
references: 11149482
references: Bone. 2011 Sep;49(3):439-46
references: 21642027
references: Breast Cancer Res Treat. 2008 Mar;108(2):279-88
references: 17530428
references: Cancer Res. 2003 May 15;63(10):2631-7
references: 12750290
references: Anal Biochem. 1987 Apr;162(1):156-9
references: 2440339