title: Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow.
abstract: Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDH(high) subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDH(high) tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDH(high) prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453-64. ©2016 AACR.
authors.affiliation: Department of Translational Medicine, Lund University, Lund, Sweden. Department of Genetics, Kazan Federal University, Tatarstan, Russia.
authors.forename: Regina
authors.initials: R
authors.lastname: Miftakhova
authors.affiliation: Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hedblom
authors.affiliation: Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Julius
authors.initials: J
authors.lastname: Semenas
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, New York.
authors.forename: Brian
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Department of Clinical Pathology and Cytology, Skåne University Hospital, Scania, Sweden.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Simoulis
authors.affiliation: Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.affiliation: Department of Genetics, Kazan Federal University, Tatarstan, Russia.
authors.forename: Albert
authors.initials: A
authors.lastname: Rizvanov
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
authors.affiliation: School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Yorkshire Cancer Research Unit, University of York, York, United Kingdom.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
authors.affiliation: School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Allegrucci
authors.affiliation: Department of Translational Medicine, Lund University, Lund, Sweden. jenny_l.persson@med.lu.se.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Persson
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D001853:Bone Marrow / Q000473:pathology*; D045744:Cell Line, Tumor; D056750:Cyclin A1 / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: D056750:Cyclin A1; D001141:Aromatase; D000444:Aldehyde Dehydrogenase