Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.
Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Archana
A
Kamalakar
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Manali S
MS
Bendre
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Charity L
CL
Washam
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Tristan W
TW
Fowler
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Adam
A
Carver
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Joshua D
JD
Dilley
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
John W
JW
Bracey
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Nisreen S
NS
Akel
Knoxville Comprehensive Breast Center, Knoxville, TN, USA.
Aaron G
AG
Margulies
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Robert A
RA
Skinner
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Frances L
FL
Swain
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
William R
WR
Hogue
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Corey O
CO
Montgomery
Division of Gastroenterology, San Francisco General Hospital, University of California San Francisco Liver Center, San Francisco, CA, USA.
Parshawn
P
Lahiji
Division of Gastroenterology, San Francisco General Hospital, University of California San Francisco Liver Center, San Francisco, CA, USA.
Jacqueline J
JJ
Maher
Division of Oncology, Pennsylvania State University, Hershey Cancer Institute, Pennsylvania State Hershey Medical Center, Hershey, PA, USA.
Kim E
KE
Leitzel
Division of Oncology, Pennsylvania State University, Hershey Cancer Institute, Pennsylvania State Hershey Medical Center, Hershey, PA, USA.
Suhail M
SM
Ali
Division of Oncology, Pennsylvania State University, Hershey Cancer Institute, Pennsylvania State Hershey Medical Center, Hershey, PA, USA.
Alan
A
Lipton
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Richard W
RW
Nicholas
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Dana
D
Gaddy
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: suvalarryj@uams.edu.
Larry J
LJ
Suva
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001863:Bone Screws; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000556:secondary*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D010014:Osteolysis / Q000378:metabolism*
D016209:Interleukin-8
Chemokine; Osteoclast; Osteolysis; Therapy