title: Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype.
abstract: Prostate cancer metastases and hematopoietic stem cells (HSC) frequently home to the bone marrow, where they compete to occupy the same HSC niche. We have also shown that under conditions of hematopoietic stress, HSCs secrete the bone morphogenetic proteins (BMP)-2 and BMP-6 that drives osteoblastic differentiation from mesenchymal precursors. As it is not known, we examined whether metastatic prostate cancer cells can alter regulation of normal bone formation by HSCs and hematopoietic progenitor cells (HPC). HSC/HPCs isolated from mice bearing nonmetastatic and metastatic tumor cells were isolated and their ability to influence osteoblastic and osteoclastic differentiation was evaluated. When the animals were inoculated with the LNCaP C4-2B cell line, which produces mixed osteoblastic and osteolytic lesions in bone, HPCs, but not HSCs, were able to induced stromal cells to differentiate down an osteoblastic phenotype. Part of the mechanism responsible for this activity was the production of BMP-2. On the other hand, when the animals were implanted with PC3 cells that exhibits predominantly osteolytic lesions in bone, HSCs derived from these animals were capable of directly differentiating into tartrate-resistant acid phosphatase-positive osteoclasts through an interleukin-6-mediated pathway. These studies for the first time identify HSC/HPCs as novel targets for future therapy involved in the bone abnormalities of prostate cancer.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Jeena
authors.initials: J
authors.lastname: Joseph
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.forename: Jin Koo
authors.initials: JK
authors.lastname: Kim
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pedersen
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Janet Linn
authors.initials: JL
authors.lastname: Zalucha
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000150:complications / Q000473:pathology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D055396:Bone Morphogenetic Protein 2; D015850:Interleukin-6